1521-0081/65/4/1351–1395$25.00 PHARMACOLOGICAL REVIEWS Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
http://dx.doi.org/10.1124/pr.113.007807 Pharmacol Rev 65:1351–1395, October 2013
ASSOCIATE EDITOR: DAN L. LONGO
Pharmacokinetics, Clinical Indications, and Resistance Mechanisms in Molecular Targeted Therapies in Cancer Benjamin Izar, Julia Rotow, Justin Gainor, Jeffrey Clark, and Bruce Chabner Department of Medicine (B.I., J.R., J.G., J.C., B.C.), and Department of Hematology and Oncology and Cancer Center (J.G., J.C., B.C.), Massachusetts General Hospital, Boston, Massachusetts; and Harvard Medical School, Boston, Massachusetts (B.I., J.R., J.G., J.C., B.C.)
Address correspondence to: Dr. Bruce Chabner, 10 North Grove Street, LRH 214, Boston, MA, 02114. E-mail:
[email protected] dx.doi.org/10.1124/pr.113.007807. 1351
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Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1352 I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1352 A. The Transition from Cytotoxic to Targeted Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1352 B. General Properties of Synthetic Targeted Inhibitor Cancer Drugs. . . . . . . . . . . . . . . . . . . . . . . . 1353 C. Clinical Pharmacology of Monoclonal Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1371 II. Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1372 A. Resistance to Synthetic Targeted Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1373 1. Drugs Targeting Epidermal Growth Factor Receptor Mutations in Non–Small-Cell Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1373 2. Primary Resistance to Epidermal Growth Factor Receptor Tyrosine-Kinase Inhibitors . 1373 3. Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and Strategies to Overcome Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1373 4. Resistance to ALK Inhibitors in Non–Small-Cell Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . 1374 B. Failure to Induce Proapoptotic Signaling and Response to Targeted Therapy. . . . . . . . . . . . . 1375 C. Resistance to BRAF-Targeted Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1375 1. BRAF Mutations in Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1375 2. Mitogen-Activated Protein Kinase–Dependent Mechanisms of Acquired Resistance to BRAF-Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1377 3. Mitogen-Activated Protein Kinase–Independent Mechanisms of Acquired Resistance to Inhibition of BRAFV600E in Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1378 4. Resistance to BRAF Inhibitors in Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1379 D. Resistance to Breakpoint Cluster Region–ABL1, KIT, and Platelet-Derived Growth Factor Receptor–Targeted Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1379 1. Breakpoint Cluster Region–ABL1 Mutations in Chronic Myeloid Leukemia . . . . . . . . . . . 1379 2. Breakpoint Cluster Region-ABL1–Dependent Resistance Mechanisms in Chronic Myeloid Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1380 3. Resistance to KIT/Platelet-Derived Growth Factor Receptor a–Targeted Therapy in Gastrointestinal Stromal Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1380 4. Primary Imatinib Resistance in Gastrointestinal Stromal Tumor . . . . . . . . . . . . . . . . . . . . . . 1380 5. Secondary Imatinib Resistance in Gastrointestinal Stromal Tumor and Response to Next-Generation Tyrosine-Kinase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1381 6. Resistance to Sunitinib in Gastrointestinal Stromal Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . 1381 E. Resistance to Mammalian Target of Rapamycin Inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1382 F. Resistance to Monoclonal Antibody Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1383 1. Drugs Targeting Epidermal Growth Factor Receptor in Colorectal Cancer . . . . . . . . . . . . . 1383 2. Primary Resistance to Monoclonal Antibodies against Epidermal Growth Factor Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1383 3. Secondary Resistance to Epidermal Growth Factor Receptor Monoclonal Antibody. . . . . 1384 4. Resistance to Human Epidermal Growth Factor Receptor 2–Targeted Therapy in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer . . . . . 1384
1352
Izar et al.
5. Primary Resistance to Trastuzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1385 6. Secondary Resistance to Trastuzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1385 G. Resistance to Anti-CD20 Antibodies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1386 H. Resistance to AntiAngiogenic Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1386 III. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1388 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1388
Abstract——The strategy for discovery and development of new cancer drugs has shifted the field from cytotoxic agents to therapies that selectively target oncogenic drivers. In the last decade, a number of targeted cancer therapies have been discovered and proven effective in a variety of hematological and solid malignancies. In this article, we review clinical pharmacokinetic characteristics of the U.S. Food and Drug
Administration–approved targeted therapies and provide an overview of key clinical trials that led to approval of these drugs. The major limiting factor of targeted treatment is the development of resistance. We describe general principles of resistance and specific, clinically confirmed mechanisms of resistance to several therapies in different malignancies.
I. Introduction
the enzymatic target of methotrexate, an antifolate, was shown to be dihydrofolate reductase more than a decade after its initial clinical trials against childhood leukemia (Osborn et al., 1958). The target of anthracyclines, etoposide, and other inhibitors of topoisomerase II was discovered many years after these drugs were shown to be active and were approved for clinical use (Liu, 1989). The transition to rationally designed, molecularly targeted drugs occurred in the period from 1990 to the present, following a dramatic expansion of knowledge of the molecular drivers of cell transformation and the identification of specific signaling pathways that controlled proliferation, cell death, angiogenesis, and metabolism. Based on this new knowledge, and in rapid succession, two different classes of molecules proved the value of the targeted drug discovery approach. Imatinib was the first rationally designed, low molecular weight inhibitor to achieve clinical success. Its target is the intracellular breakpoint cluster region (BCR)–ABL tyrosine kinase that drives cell proliferation in chronic myeloid leukemia. Imatinib produced
A. The Transition from Cytotoxic to Targeted Drugs. The strategy for discovery and development of cancer drugs has undergone a remarkable transformation over the past two decades. The discovery of cytotoxic chemotherapy began with the testing of nitrogen mustard at Yale in the 1940s (Gilman, 1963). For the next four decades, cancer drug discovery relied on efforts to inhibit DNA synthesis or function. One important approach aimed at blocking purine and pyrimidine nucleotide synthesis through the design of antifolates and base or nucleoside analogs such as 6-mercaptopurine or 5-fluorouracil. A second successful approach identified cytotoxic molecules from random natural product collections or from reactive synthetic chemicals (Chabner and Roberts, 2005). These studies did not have specific molecular targets in mind, but used tumor cell death or the inhibition of DNA synthesis as their endpoint. Often the drug’s specific mode of action was not revealed until years after the drug had been widely used in the treatment of human disease. Thus,
ABBREVIATIONS: ADCC, antibody-dependent cellular cytotoxicity; AKT, protein kinase B; ALK, anaplastic lymphoma kinase; AP26113, 2,4-pyrimidinediamine, 5-chloro-N2-[4-[4-(dimethylamino)-1-piperidinyl]-2-methoxyphenyl]-N4-[2-(dimethylphosphinyl)phenyl]-; ASP-3026, N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-[2-[(1-methylethyl)sulfonyl]phenyl]-1,3,5-triazine-2,4-diamine; AZD6244, 6[(4-bromo-2-chlorophenyl)amino]-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide; BCR, breakpoint cluster region; BIBW 2992, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide; BIM, Bcl-2-interacting mediator of cell death; CDC, complement-dependent cytotoxicity; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CRC, colorectal cancer; CRKL, V-Crk sarcoma virus CT10 oncogene homolog-like; CSF, cerebrospinal fluid; EC, endothelial cell; EGFR, epidermal growth factor receptor; EML, echinoderm microtubule-associated protein-like gene; ERK, extracellular signal-regulated kinase; FGF, fibroblast growth factor; FKB, FK506-binding; GBM, glioblastoma multiforme; GIST, gastrointestinal stromal tumor; HER2, human epidermal growth factor receptor 2; HGF, hepatic growth factor; HIF-a, hypoxia-inducible factor a; HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide; IGF-1R, insulin-like growth factor-1 receptor; LDK378, 5-chloro-N2(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine; mAb, monoclonal antibody; MAP, mitogen-activated protein; MAPK, MAP kinase; mCRC, metastatic CRC; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; NSCLC, non–small-cell lung cancer; OCT-1, organic cation transporter 1; p61BRAFV600E, 61-kDa splicing product of BRAFV600E in resistant cell lines; OS, overall survival; PD-1, programmed death-1/programmed death-1 ligand; PDGFR, platelet-derived growth factor receptor; PDGFRA, platelet-derived growth factor receptor a; PF-00299804, (E)-N-[4-(3-chloro-4-fluoro-anilino)-7-methoxy-quinazolin-6-yl]4-(1-piperidyl)but-2-enamide hydrate; PFS, progression free survival; PI3K, phosphatidylinositol 3-kinase; PlGF, placental growth factor; PTEN, phosphatase and tensin homolog; RCC, renal cell carcinoma; TKI, tyrosine-kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; WT, wild type; WZ4002, N-(3-(5-chloro-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-yloxy)phenyl)acrylamide; X-396, (R)-6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-(4-methylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; XL184, N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.
Targeted Therapies in Cancer
long-lasting molecular remissions in this disease in its earliest trials in 1998, and later proved effective against c-KIT–driven gastrointestinal stromal tumors (Druker et al., 2001). The epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib were used with variable success in a small number of patients before the identification of sensitizing EGFR mutations. Identification of this oncogenic driver provided the molecular basis for the stratification of patients with non–small-cell lung cancer (NSCLC) with sensitizing EGFR mutations. Treatment of this patient population with EGFR inhibitors produced consistent responses. At the same time, trastuzumab, a monoclonal antibody against the human epidermal growth factor receptor 2 (HER2),which is amplified in 25% of breast cancers, dramatically enhanced the efficacy of taxanes and other chemotherapy in both metastatic and adjuvant therapy. Other antibodies, including rituximab, which targets CD20 and is effective in the treatment of non–Hodgkin’s lymphoma, showed similar enhancement of chemotherapy. Bevacizumab, a monoclonal antibody that binds the vascular endothelial growth factor (VEGF) and blocks tumor angiogenesis, prolonged cytotoxic drug-induced responses in colon cancer and NSCLC (Hurwitz et al., 2004). Following these fundamental discoveries, a series of more than 30 new drugs, all targeted to specific receptors or enzymes, found useful application in specific subsets of human cancers. Table 1 provides a summary of key clinical trials that led to approval of U.S. Food and Drug Administration–approved targeted therapies. At the same time, interest in the discovery and development of new cytotoxic molecules has waned. Perhaps the only significant new cytotoxics in the past decade have been bendamustine, a unique alkylating agent highly active in lymphoid malignancies and available in Europe since the 1980s (Hoy, 2012); eribulin, a marine natural product active in breast cancer (Scarpace, 2012); and trabectedin, also a marine natural product useful in second-line treatment of sarcomas (Samuels et al., 2013). Although much attention has turned to understanding the molecular interaction of targeted drugs and the pathways they inhibit in cancer cells, less consideration has been paid to the clinical pharmacological properties of these carefully synthesized molecules. For the first time, oncologists now routinely use monoclonal antibodies and oral agents that are largely free of myelosuppression and other serious host toxicity that complicate cytotoxic chemotherapy. An important difference between targeted therapy and conventional chemotherapy with curative intent is the continuous treatment with targeted therapy after treatment response. In the treatment of some malignancies, maintenance therapy with targeted therapies is even continued in cases of progression to prevent uncontrolled tumor growth. Cytotoxic chemotherapy
1353
cannot be used in this way, mostly due to intolerability, except in maintenance therapy of acute leukemia with 6-mercaptopurine and methotrexate, where continuous treatment is curative. Common themes have emerged regarding the pharmacokinetics, toxicities, drug interactions, and mechanisms of tumor cell resistance of these unique agents. In particular, in contrast to natural products or alkylating agents, the synthetic targeted inhibitors incorporate a number of favorable properties not found in most cytotoxics. As a class, they have good bioavailability, a slow rate of metabolism, and favorable distribution, all properties that are engineered into the clinical candidate in the preclinical phase of development. However, unfavorable effects in humans are difficult to predict at the preclinical stage. Off-target toxicities and drug interactions emerge during clinical testing and may present serious hurdles to further clinical development. Understanding and dealing with these pharmacological properties is a critical step in successful drug development. B. General Properties of Synthetic Targeted Inhibitor Cancer Drugs. The discovery of a new targeted agent begins with validation of the target and construction of a high-throughput assay system of identifying inhibitors. Systems for validating the target and establishing high-throughput assays are covered in detail in other articles (Garnett et al., 2012). In most instances, a “hit,” a compound that inhibits the target enzyme or receptor at low micromolar concentrations, is found by screening compounds from an appropriate library, which is often chosen because it contains a collection of synthetic chemicals enriched for structures likely to mimic substrates of the target enzyme. For example, the search for inhibitors of histone methyltransferases centered on analogs of the key substrate, S-adenosyl methionine (Copeland et al., 2013). Through further chemical modification of the lead compound, and often with the guidance of X-ray crystallographic pictures of the inhibitor-enzyme complex, the molecule can be altered to increase ionic and hydrophobic bonding within the substrate pocket and to improve steric conformation, resulting in an inhibitor with low nanomolar potency. The physicochemical properties are further refined to enhance uptake and stability in cell culture systems, to improve pharmacokinetics and bioavailability in vivo, to decrease susceptibility to multidrug resistance, and to produce relative metabolic stability in the presence of human microsomes. Through in vitro testing against human microsomes and studies of metabolism in rodents, it is possible to develop a reasonable prediction of metabolic behavior of the compound in humans, and to further modify the molecule to improve its stability. However, all predictions regarding the properties in humans require confirmation through detailed studies in early clinical trials, as there are often
Bortezomib
3
Metastatic RCC, with INFa
AVOREN Trial
3
2
BRAIN
Ovarian cancer, advanced newly diagnosed and stage IV
2
3
AVAiL
NCI-06-C-0064E
3
E4599
Advanced NSCLC, nonsquamous, with carboplatin/paclitaxel, first-line
Glioblastoma, progressive after prior therapy Accelerated approval
3
Previously treated, N = 339 N = 820
2
ML18147
Previously treated, N = 829
3
E3200
Previously untreated, N = 649
N = 1873
First or second relapse, N = 167
N = 48
N = 1043
N = 878
Previously untreated, N = 813
3
Study 2107
N = 723
N = 149; 3 singlearm studies
N = 297
Study Population, Size
3
N/A
3
Phase
AXIS
Study Name
Metastatic CRC, secondline after first progression on bevacizumab-based chemotherapy
Axitinib Advanced RCC after failure of prior systemic therapy Bevacizumab Metastatic CRC, with 5-FU, first- or secondline therapy
Alemtuzumab B-CLL, previously untreated Initial accelerated approval
Drug, U.S. FDA-Labeled Approval(s)
Carboplatin + paclitexal with placebo or bevacizumab initiation or bevacizumab throughout IFN-a2a with bevacizumab versus IFN with placebo
Bevacizumab +/2 irinotecan
Cisplatin/gemcitabine with bevacizumab 7.5 mg/kg versus bevacizumab 15 mg/kg versus placebo Bevacizumab
Bevacizumab with 5-FU/LV Bevacizumab with chemotherapy (oxaliplatin- or irinotecanbased) versus chemotherapy alone Paclitaxel and carboplatin +/2 bevacizumab
OS: 23.3 versus 21.3 months
PFS 10.3 versus 11.2 versus 14.1 months
Radiographic response rate: 71% PFS: 16 weeks PFS at 6 months: 42.6% bevacizumab versus 50.3% combination*
PFS: 6.7 (7.5 mg/kg) versus 6.5 (15 mg/kg) versus 6.1 months (chemotherapy) *
OS: 12.3 versus 10.3 months*
OS: 11.2 versus 9.8 months*
ORR 1%
OS: 12.9 (combination) versus 10.8 months (FOLFOX)*
OS: 20.3 versus 15.6 months*
Bevacizumab versus placebo, with IFL FOLFOX4, bevacizumab, versus both
PFS: 6.7 versus 4.7 months*
PFS: 14.6 versus 11.7 months*
Primary Outcome(s)
Axitinib versus sorafenib
Alemtuzumab versus chlorambucil Alemtuzumab
Intervention(s)
PFS: 10.2 versus 5.4 months*
(Friedman et al., 2009) OS: 9.2 versus 8.7 months (significance testing not provided) OS 39.3 versus 38.7 versus 39.7
(continued )
(Escudier et al., 2007a, 2010)
(Burger et al., 2011)
(Kreisl et al., 2009)
(Reck et al., 2009, 2010)
(Sandler et al., 2006)
(Bennouna et al., 2013)
(Chen et al., 2006)
(Giantonio et al., 2007)
(Hurwitz et al., 2004)
(Rini et al., 2011)
(Hillmen et al., 2007) PI
Reference(s)
OS: 31 weeks
OS: 13.1 (placebo) versus 13.6 months (7.5 mg/kg) versus 13.4 months (15 mg/kg)
PFS: 6.2 versus 4.5 months* ORR: 33% versus 15%*
PFS: 10.6 versus 6.2 months* ORR: 44.8% versus 34.8%* PFS: 7.3 versus 4.7 months* ORR: 22.7% versus 8.6% * PFS: 3.5 months OS: 9 months PFS: 5.7 versus 4.1 months*
ORR: 19.4% versus 9.4%*
RR: 83.2% versus 55.4% * PR: 21%–31% CR: 0%–2%
Selected Secondary Outcomes
This table gives an overview of clinical trials that led to approval of each drug and extension of the FDA label for particular indications following initial approval. Important key trials were added at the discretion of the authors. Accelerated approval of drugs for particular indications is highlighted in the indications column.
TABLE 1 FDA–approved targeted therapies with specific FDA-labeled indications
1354 Izar et al.
Metastatic CRC, K-RAS WT, EGFR+, with irinotecan, in patients refractory to irinotecan-based chemotherapy Metastatic CRC, K-RAS WT, EGFR+, single agent, in patients who have failed oxaliplatin and irinotecan-
Cetuximab Metastatic CRC, K-RAS WT, EGFR+, with FOLFIRI, first-line
Brentuximab vedotin Hodgkin’s lymphoma, relapsed/refractory after auto SCT or at least two chemotherapy regimens Accelerated approval sALCL, after failed systemic therapy Accelerated approval Carfilzomib Multiple myeloma, relapsed/refractory Accelerated approval
2
BOND
Cetuximab with versus without irinotecan
Cetuximab versus BSC
N = 572
FOLFIRI with versus without cetuximab
Carfilzomib
Brentuximab vedotin
Brentuximab vedotin
Bortezomib
Bortezomib SQ versus i.v.
OS:6.1 months versus 4.6 months*
PFS (K-RAS WT): 9.9 versus 8.4 months* ORR: 22.9% (combination) versus 10.8% (cetuximab)*
PFS: 8.9 versus 8.0 months*
PFS: HR 0.68*
OS (K-RAS WT): 23.5 versus 20 months* ORR (K-RAS WT): 59.3 versus 43.2%* TTP: 4.1 versus 1.5 months* OS: 8.6 versus 6.9 months
OS: 15.6 months PFS: 3.7 months
DR: 7.8 months
OS: 22.4 months DR: 12.6 months
CR 34% ORR: 86%
ORR: 23.7%
PFS: 5.6 months
TTP: 11 months (1.3 mg/m2), 7 months (1 mg/m2) OS: median not reached (1.3 mg/m2) and 26.7 months (1 mg/m2) TTP: 10.4 versus 11.7 months OS, 1 year: 72.6% versus 76.7% ORR: 33% DR 9.2 months TTP: 6.2 months
CR: 30% versus 4%* OS, median: 56. 4 versus 43.1 months * ORR: 38% versus 18%* OS: 29.8 versus 23 months* OS: 16 months DR: 12 months
Selected Secondary Outcomes
ORR: 75%
TTP versus historical controls: insufficient controls
ORR at 4 months: 42% in both groups
ORR: 50% (1.3 mg/m2), 33% (1 mg/m2)
ORR: 35%
TTP: 6.22 versus 3.49 months*
Bortezomib versus high-dose dexamethasone Bortezomib (+dexamethasone if poor response) Bortezomib (two dosages, with dexamethasone if poor response)
TTP: 24 versus 16.6 months*
Primary Outcome(s)
Melphalan/prednisone +/2 bortezomib
Intervention(s)
N = 329
N = 1198
N = 266
2
3
N = 58
2
CRYSTAL
N = 102
Relapsed after 1–3 prior therapies, N = 222 N = 155
N = 54
Relapsed after 1-3 prior therapies, N = 669 N = 202
Ineligible for stem cell transplant, N = 682
Study Population, Size
2
2
PINNACLE
Mantle cell lymphoma, previously treated
2
CREST
3
2
SUMMIT
Multiple myeloma, SQ administration
3
APEX
Multiple myeloma, relapsed/refractory
3
Phase
VISTA
Study Name
Multiple myeloma, first-line
Drug, U.S. FDA-Labeled Approval(s)
TABLE 1—Continued
(continued )
(Jonker et al., 2007)
(Cunningham et al., 2004)
(Van Cutsem et al., 2009, 2011)
(Siegel et al., 2012)
PI
(Younes et al., 2012)
(Fisher et al., 2006)
(Moreau et al., 2011)
(Jagannath et al., 2004)
(Richardson et al., 2003)
(Richardson et al., 2005, 2007)
(San Miguel et al., 2008)
Reference(s)
Targeted Therapies in Cancer
1355
CML advanced phase or Ph+ ALL, resistant or intolerant to imatinib Accelerated approval
CML-CP, resistant or intolerant to imatinib, once daily dosing Accelerated approval for daily dosing
Dasatinib CML-CP, Ph+, newly diagnosed Accelerated approval
Recurrent or metastatic SCCHN, with platinum-based therapy/5-FU Recurrent locoregional/ metastatic SCCHN, single agent, after failure of platinumbased chemotherapy Crizotinib NSCLC, locally advanced or metastatic, ALK positive Accelerated approval
based therapy or are intolerant to irinotecan Locoregionally advanced SCCHN, with radiation therapy
Drug, U.S. FDA-Labeled Approval(s)
CML-CP, N = 150
CML-AP, MB, LB, Ph+ ALL, N = 611
2
3
START-R
CML-CP, N = 186
CML-CP, N = 670
3
2
CML-CP, N = 519
3
N = 119
START-C
DASISION
1
Study B
N = 136
N = 103
2
2
N = 442
N = 424
Study Population, Size
3
3
Phase
Study A
EXTREME
Study Name
Dasatinib 140 mg daily versus 70 mg BID
Dasatinib BID (70 mg PO BID) versus imatinib
Dasatinib BID
Dasatinib dose optimization
Dasatinib (once daily) versus imatinib
Crizotinib
Crizotinib
Platinum-based chemotherapy with versus without cetuximab Cetuximab, with platinum-based chemotherapy if poor response
Radiotherapy with versus without cetuximab
Intervention(s)
TABLE 1—Continued
CHR: 93% versus 82%* TTF: not reached versus 3.5 months* PFS: HR 0.14* OS: 63 vs. 72% (no significant difference) CML-AP: 63% versus 72%, Est 24-month CML-MB: 7.9 versus 7.7 months, median CML-LB: 11.4 versus 9.0 months, median Ph+ ALL: 6.5 versus 9.1 months, median
MCyR at 24 months: 53% versus 33%*
Ph+ ALL: 38% vs32%
CML-LB: 42% versus 32%
CML-MB: 28% versus 28%
CML-AP: 66% versus 68%
MaHR: Daily versus BID
140 mg daily: 94$ 70 mg BID: 88% 100 mg daily: 91% 50 mg BID: 90% CHR: 90%
OS, estimated at 24 months
MMR: 52% versus 34%*
DR: 48 weeks PFS: 10 months
DR: 41.9 weeks
OS: 49 versus 29.3 months* PFS: 17.1 versus 12.4 months* PFS: 5.6 versus 3.3 months* ORR: 36% versus 20%* TTP: 70 days OS: 178 days
Selected Secondary Outcomes
140 mg daily: 63% 70 mg BID: 61% 100 mg daily: 63% 50 mg BID: 61% MCyR: 52%
CCyR at 12 months: 77 versus 66%* MCyR:
ORR: 61%
ORR: 50%
ORR: 13%
OS: 10.1 versus 7.4 months*
Duration of disease control: 24.4 versus 14.9 months*
Primary Outcome(s)
(continued )
(Kantarjian et al., 2009; Lilly et al., 2010; Saglio et al., 2010a)
(Hochhaus et al., 2007) (Kantarjian et al., 2007a)
(Shah et al., 2008, 2010)
(Kantarjian et al., 2010, 2012)
b
PIa
(Vermorken et al., 2007)
(Vermorken et al., 2008)
(Bonner et al., 2006)
Reference(s)
1356 Izar et al.
Everolimus Advanced HER2(2), HR(+) breast cancer, postmenopausal women, with exemestane, after failed letrozole or anastrozole Progressive PNET, locally advanced/metastatic disease Advanced RCC, after failure of sunitinib or sorafenib Renal angiomyolipoma with TSC, not requiring immediate surgery SEGA, TSC-associated, unresectable Accelerated approval for oral suspension and tablets
Locally advanced or metastatic pancreatic cancer, with gemcitabine, first-line
Erlotinib Locally advanced or metastatic NSCLC, maintenance after first-line therapy Locally advanced or metastatic NSCLC, after prior failed chemotherapy
Denileukin diftitox Persistent or recurrent CD25+ CTCL Initial accelerated approval
Drug, U.S. FDA-Labeled Approval(s)
3
3 3 3 3
RADIANT-3
RECORD-1
EXIST-2
EXIST-1
N = 117
N = 118
N = 410
N = 410
N = 724
N = 569
N = 731
3
3
N = 889
3
BOLERO-2
SATURN
CTCL, stage Ib to IVa, N = 71
Ph+ ALL, N = 36
3
2
START-L
CML-LB, N = 42
CML-MB, N = 74
CTCL, stage IA to III, N = 144
2
START-B and START-L
CML-AP, N = 174
Study Population, Size
3
2
Phase
START-A
Study Name
Everolimus (suspension) versus placebo
Everolimus versus placebo Everolimus versus placebo Everolimus versus placebo
Exemestane, with everolimus versus placebo
Gemcitabine with versus without erlotinib
Erlotinib
Erlotinib versus placebo
Denileukin diftitox
Denileukin diftitox versus placebo
Dasatinib BID
Dasatinib BID
Dasatinib BID
Intervention(s)
TABLE 1—Continued
50%+ reduction of target lesion volume: 35% versus 0%*
PFS:11.0 versus 4.6 months* PFS: 4.0 versus 1.9 months* ORR: 42% versus 0%*
PFS: 10.6 versus 4.1 months*
OS: 6.24 versus 5.91 months*
OS: 6.7 versus 4.7 months*
PFS: 12.3 versus 11.1 weeks*
ORR: 49.1% (18 mg/kg)* versus 37.8% (9 mg/kg)* versus 15.9% (placebo) ORR: 30%
MaHR: 42% OHR: 50%
OHR: 53% (CML-MB), 36% (CML-LB)
MaHR: 34% (CMLMB), 31% (CML-LB)
MaHR: 64%
Primary Outcome(s)
(Franz et al., 2013)
Est PFS at 6 months: 100% versus 86% *
(continued )
(Motzer et al., 2008) (Bissler et al., 2013)
(Yao et al., 2011)
(Baselga et al., 2012a)
(Moore et al., 2007)
(Cappuzzo et al., 2010; Shepherd et al., 2005).
(Olsen et al., 2001)
(Prince et al., 2010)
(Ottmann et al., 2007)
(Cortes et al., 2007)
(Apperley et al., 2009)
Reference(s)
OS: no significant difference
ORR: 9.5% versus 0.4%*
ORR: 8.9% versus ,1%* PFS: 2.2 versus 1.8 months* One year survival: 23% versus 17%* PFS: 3.75 versus 3.55 months*
OS: 12.0 vs11.0 months*
DR: 6.9 months
PFS: 971 days (18 mg/kg) * versus 794 days (9 mg/kg) * versus 124 days (placebo)
PFS, at 12 months: 66% OS, at 12 months: 82% PFS: 6.7 months (CML-MB), 3.0 months (CML-LB) OS: 11.8 months (CML-MB), 5.3 months (CML-LB) PFS: 3 months OS at 24 months: 31%
Selected Secondary Outcomes
Targeted Therapies in Cancer
1357
Refractory to rituximab, N = 54 N = 30
NS
CML-blast crisis, N = 260
2
2
3
EORTC Study STSBG62005
Ph+ ALL, relapsed/refractory
3
SWOB S0033
KIT+ GIST, unresectable/ metastatic Initial accelerated approval
3
1
1
N = 48
N = 946
N = 746
N = 713
Pediatric CMLCP, N = 51 Pediatric CML-CP, recurrent, N = 14 CML-CP, resistant to IFN-a, N = 3 N = 397
CML-AP, N = 235
2
2
CML, late chronic phase, N = 532
2
3
N = 1106
Rituximab naïve, N = 130
3
2
Stage III/IV, N = 414
N = 28
Study Population, Size
3
1-2
Phase
Scandinavian Sarcoma Group XVIII/AIO ACOSOG Z9001 Trial
IRIS
FIT
Study Name
KIT+ GIST, adjuvant treatment after resection Initial accelerated approval
CML, pediatric (initial) accelerated approval
Ph+ CML (CP, AP, or BC), after failed IFN-a therapy Initial accelerated approval
Imatinib Ph+ CML, chronic phase, newly diagnosed Initial accelerated approval
Relapsed/refractory low-grade or follicular non–Hodgkin’s lymphoma Accelerated approval
Ibritumomab tiuxetan Follicular lymphoma, consolidation therapy after response to first-line therapy
Drug, U.S. FDA-Labeled Approval(s)
Imatinib
Imatinib daily versus BID
Imatinib daily versus BID
Imatinib versus placebo
Imatinib for 12 versus 36 months
Imatinib
Imatinib
Imatinib
Imatinib
Imatinib
Imatinib
Imatinib versus INF-a + low-dose cytarabine
Ibritumomab regimen
Ibritumomab regimen
Ibritumomab regimen versus rituximab
Ibritumomab regimen versus observation
Everolimus (tablets)
Intervention(s)
TABLE 1—Continued
5-year OS: 92% versus 81.7%*
OS, 6 year estimated: 76% CCyR 57% MCyR: 24% PFS, 12 month: 59% OS, 12 month: 74% DR, hematological: 10 months MCyR: 16.2% OS: 6.9 months CCyR 65%
OS at 84 months: 86.4% versus 83.3%* CHR: 96.6% versus 56.6%* MCyR: 85.4% versus 16.8%* CHR: 96%
TTP: 6.8 months DR: 6.4 months TTP: 9.4 months DR: 11.6 months
CR/CRu: 87.5% versus 53.3% (significance testing not provided) TTP: 12.1 versus 10.1 months
Median one fewer seizure over 6 months*
Selected Secondary Outcomes
1-year OS: No significant difference PFS: 18 months (daily) OS: 55 months (daily) versus 20 months (BID) versus 51 months (BID) CR: 5%, no significant PFS at median 760 difference day follow-up: 56% (one between groups daily) versus 50% (twice daily)* CHR: 19% TTP 2.2 months
1-year RFS: 98% versus 83%*
5-year RFS: 65.6% versus 47.9%*
CCyR: 2 of 3 patients
CCyR 7/13
CHR 78% at 8 weeks
Sustained hematological response, lasting at least 4 weeks: 30.6%
CHR: 53%
MCyR: 60%
PFS at 84 months: 81.2% versus 60.6%*
ORR: 74% CR: 15% ORR: 83% CR 37%
ORR: 83% versus 55%*
PFS: 36.5 versus 13.3 months*
Median reduction in primary lesion volume at 6 months: 0.80 cm3*
Primary Outcome(s)
(continued )
(Verweij et al., 2004)
(Blanke et al., 2008)
(Dematteo et al., 2009)
(Joensuu et al., 2012)
PI
PI
PI
(Sawyers et al., 2002)
(Talpaz et al., 2002)
(Hochhaus et al., 2008; Kantarjian et al., 2002)
(O’Brien et al., 2003)
(Witzig et al., 2002b) (Wiseman et al., 2002)
(Witzig et al., 2002a)
(Morschhauser et al., 2008)
(Krueger et al., 2010)
Reference(s)
1358 Izar et al.
Ofatumumab CLL, relapsed/refractory Accelerated approval
Ph+ CML, CP or AP, imatinib resistant/intolerant Accelerated approval
Accelerated approval
Lapatinib HER2+ breast cancer, locally advanced or metastatic, with capecitabine, after prior therapy HER2+, HR+ breast cancer, metastatic, with letrozole, for postmenopausal women in whom hormonal therapy is indicated Accelerated approval Nilotinib Ph+ CML-CP, newly diagnosed
HES/CEL, with FIP1L1PDGFRalpha or unknown status DFSP, unresectable/ recurrent/metastatic Ipilimumab Melanoma, unresectable/ metastatic
MDS/MPD, with PDGFR rearrangement ASM without c-Kit mutation/ unknown c-Kit status
Drug, U.S. FDA-Labeled Approval(s)
ENESTnd
Study Name
Phase 2/case reports, N = 18 N = 676
NA 3
Nilotinib 300 or 400 mg PO BID versus imatinib
Letrozole with versus without lapatinib
Capecitabine with versus without lapatinib
Ipilimumab with gp100 vaccine, versusipilumimab versus vaccine
Imatinib
Imatinib
Imatinib
Imatinib
Intervention(s)
N = 154 N = 33
1/2
Ofatumumab dose escalation
Ofatumumab
N = 321(CP cohort) Nilotinib and 137 (AP cohort)
N = 846
N = 1286 (219 HER2+ patients)
NS
2
3
3
N = 399
Phase 2/case reports, N = 176
NA
NA
Phase 2/case reports, N = 31 Phase 2/case reports, N = 28
Study Population, Size
NA
Phase
TABLE 1—Continued
ORR: 44%
ORR: 42%
AP: Hematological response: 55%
CP: MCyR: 59%
12 month MMR: 44% (300 mg nilotinib)* versus 43% (400 mg nilotinib)* versus 22% (imatinib)
PFS (HER2+): 35.4 versus 13.0 weeks*
TTP: 8.4 versus 4.4 months*
OS: 10.0 months (combination) * versus 10.1 months (ipilimumab)* versus 6.4 months (gp100)
Primary Outcome(s)
DR: 6.5 months
CCyR: 44% Est OS, at 24 months: 87% CML - AP: CCyR 21% Est OS at 24 months: 70%
CCyR at 12 months: 80% (nilotinib 300 mg)* versus 78% (nilotinib 400 mg) * versus 65% (imatinib) OS at 3 years: no significant difference CML - CP:
ORR (HER2+): 27.9 versus 14.8%*
ORR: 22% versus 14%* OS, adjusted for crossover: 75 versus 56.4 weeks*
ORR: 10.9% (ipilimumab)* versus 5.7% (combination)* versus 1.5% (gp 100 alone)
CHR 45% MCyR: 39% CHR: 29% Partial hematological response: 32% CHR: 61% Partial hematological response: 13% CR: 39% PR: 44%
OS: 4.9 months
Selected Secondary Outcomes
(continued )
(Wierda et al., 2010), PI (Coiffier et al., 2008)
(le Coutre et al., 2008, 2012; Kantarjian et al., 2007b, 2011)
(Larson et al., 2012; Saglio et al., 2010b)
(Schwartzberg et al., 2010), PI
(Cameron et al., 2010; Geyer et al., 2006)
(Hodi et al., 2010)
PI
PI
PI
(Ottmann et al., 2002) PI
Reference(s)
Targeted Therapies in Cancer
1359
3 3
MInT Study
ECOG 4494 trial
Age 60–80, N = 632
Age 18–60 years, N = 824
N = 60
2
DLBCL, in combination with CHOP or anthracyclinebased chemotherapy
N = 37
2
N = 321 N = 166
3
ECOG 1496
After response to rituximab + chemotherapy, N = 1018 N = 311
NS
3
PRIMA
N = 808
Follicular/low-grade NHL, relapsed/refractory
3
CLEOPATRA
First-line or cytokine refractory, N = 435 N = 369
N = 463
N = 444
Study Population, Size
3
3
3
3
2
Phase
PALETTE
PACE
Study Name
Follicular lymphoma, previously untreated
Advanced soft tissue sarcoma, after prior chemotherapy Pertuzumab Metastatic breast cancer, HER2+, no prior HER2 therapy or chemotherapy for metastatic disease, with trastuzumab/docetaxel Rituximab Low-grade/follicular NHL, after response to firstline induction
Pazopanib Advanced RCC
Panitumumab Metastatic CRC, K-RAS WT, single agent, after progression on fluoropyrimidine, oxaliplatin, and irinotecan
Ponatinib CML or Ph+ ALL, resistant or intolerant to tyrosine kinase inhibitor therapy Accelerated approval
Drug, U.S. FDA-Labeled Approval(s)
CHOP-like chemotherapy+/2 rituximab CHOP with versus without rituximab
Rituximab
Rituximab
Rituximab
3-year event-free survival: 79% versus 59%* 3-year FFS: 53% versus 46%*
CVP followed by rituximab PFS: 4.3 versus versus observation 1.3 years* CVP chemotherapy with TTF: 27 versus versus without rituximab 7 months*
PFS, adjusted: 3.1 versus 1.6 years*
3-year OS: 92% versus 86%* CR: 30% versus 8%* TTP: 32 versus 15 months* ORR 48% Estimated TTP: 12.5 months ORR 57% TTP: not reached at 19.4 months. ORR 40% Estimated TTP: 17.8 months OS, at 3 years: 93% versus 84%*
(continued )
(Habermann et al., 2006), PI
(Pfreundschuh et al., 2006)
(Davis et al., 2000)
(Piro et al., 1999)
(McLaughlin et al., 1998)
(Hochster et al., 2009) (Marcus et al., 2005)
(Salles et al., 2011) PFS at mean 36 months follow-up: 74.9% versus 57.6%*
Rituximab maintenance versus observation
OS: no significant difference
OS (median 19.3 month (Baselga et al., 2012b) follow-up): 23.6% versus 17.2%*
PFS: 18.5 months versus 12.4 months*
(van der Graaf et al., 2012)
(Sternberg et al., 2010)
Trastuzumab plus docetaxel, with versus without pertuzumab
ORR: 30% versus 3%*
(Amado et al., 2008; Van Cutsem et al., 2007)
(Cortes et al., 2012)
Reference(s)
OS: 12.5 months versus 10.7 months
PFS: 9.2 versus 4.2 months*
OS, K-RAS WT: 8.1 versus 7.6 months*
ORR: 10% versus 0%*
CML-CP: 84 days Duration of MaHR: CML-AP: 9.5 months CML-BP: 4.7 months Ph+ ALL: 3.2 months
CML-CP: 54% MaHR: CML-AP:52% CML-BP: 31% Ph+ ALL: 41% PFS: 8 weeks versus 7.3 weeks* Retrospective: K-RAS WT: 12.3 versus 7.3 weeks* K-RAS+: 7.4 versus 7.3 weeks
Time to MCyR:
Selected Secondary Outcomes
MCyR
Primary Outcome(s)
PFS: 4.6 versus 1.6 months*
Pazopanib versus placebo
Pazopanib versus placebo
Panitumomab versus BSC
Ponatinib
Intervention(s)
TABLE 1—Continued
1360 Izar et al.
Ruxolitinib Intermediate or highrisk myelofibrosis
PTCL, after at least one prior therapy Accelerated approval
Regorafenib Metastatic CRC, previously treated with fluoropyrimidine/ oxaliplatin/irinotecan-based chemotherapy, VEGF therapy and anti-EGFR therapy if K-RAS WT Romidepsin CTCL after at least one prior systemic therapy
Previously untreated follicular NHL or DLBCL, as 90-minute infusion CLL
Drug, U.S. FDA-Labeled Approval(s)
3
3
COMFORT-II
N = 219
N = 309
N = 47
2
N = 71
2 N = 130
N = 96
2
2
N = 760
CLL, previously treated, N = 552
3
COMFORT-I
CORRECT
3
CLL, previously untreated, N = 817
3
REACH
N = 363
NS
RATE
Age 60–80, N = 399
Study Population, Size
3
Phase
GELA/LNH-98.5
Study Name
Ruxolitinib versus best available therapy
Ruxolitinib versus placebo
Romidepsin
Romidepsin
Romidepsin
Romidepsin
Regorafenib versus placebo
Follicular lymphoma: R- CVP DLBCL: R-CHOP Fludarabine/ cyclophosphamide with versus without rituximab Fludarabine/ cyclophosphamide with versus without rituximab
CHOP with versus without rituximab
Intervention(s)
TABLE 1—Continued
Spleen volume decreased by .35%, at 48 weeks: 28 versus 0%*
Spleen volume decreased by .35% at 24 weeks: 41.9% versus 0.7% *
ORR: 38% (95% CI 24%–53%) CR: 18%
CR+CRu: 14.6% (95% CI 9%–21.9%)
ORR: 34%
OS: 6.4 versus 5.0 months*
PFS: 27 versus 21.9 months*
EFS, at median 24 months: 57% versus 49%* Grade 3–4 infusion reactions: 2.8% starting at cycle 2 PFS at 3 years: 65% versus 45%*
Primary Outcome(s)
Symptom improvement: 45.9% versus 5.3%* OS at median 51 weeks: 91.6% versus 84.4%* No significant difference in TTP or OS at
TTR: 1.9 months DR: 16.6 months DR: 8.9 months
DR: 15 months Improved pruritus: 43%, median duration 6 months ORR: 34% CRR 7% DR: 13.7 months ORR: 25.4%
PFS: 2.0 versus 1.7 months* ORR: 1% versus 0.4%
OS: No significant difference, crossover design ORR: 69.9% versus 58%*
OS at 3 years: 87% versus 83%
OS, 2 year, adjusted: 74% versus 63%* OS: 8.4 versus 3.5 years*
Selected Secondary Outcomes
(continued )
(Harrison et al., 2012)
(Verstovsek et al., 2012)
(Piekarz et al., 2011)
(Coiffier et al., 2012)
(Piekarz et al., 2009)
(Whittaker et al., 2010)
(Grothey et al., 2013), PI
(Robak et al., 2010)
(Hallek et al., 2010)
c
(Coiffier et al., 2002)
Reference(s)
Targeted Therapies in Cancer
1361
Breast cancer, HER2+, adjuvant
Tositumomab Relapsed/refractory CD20+ NHL, progression after/on rituximab Trastuzumab Metastatic gastric or GE junction adenocarcinoma, HER2+
Temsirolimus Advanced RCC
PNET, unresectable or metastatic
Advanced RCC Initial accelerated approval
Sunitinib GIST, after imatinib resistance/intolerance
Unresectable HCC
Sorafenib Advanced RCC
Drug, U.S. FDA-Labeled Approval(s)
NCCTG N9831; NSABP B-31
ToGA
SHARP
TARGET
Study Name
3
3
2
3
3
2
2
N = 3351
Previously untreated for metastatic disease, N = 594
N = 40
Metastatic RCC, N = 626
No prior treatment, N = 750 Refractory to cytokines, N = 106 Refractory to cytokines, N = 63 N = 171
N = 55
NS 3
N = 312
Refractory to standard therapy, N = 903 Refractory to standard therapy, N = 202 No prior systemic treatment, N = 602
Study Population, Size
3
3
2
3
Phase
(Romond et al., 2005) OS at 4 years: 91.4% versus 86.6%* Disease-free survival, median 4-month follow-up: 85.3% versus 67.1%*
(continued )
(Bang et al., 2010)
PFS: 6.7 versus 5.5 months*
OS: 13.8 versus 11,1 months* Capecitabine or fluorouracil, with cisplatin, with versus without trastuzumab Doxorubicin/ cyclophosphamide with paclitaxel, with versus without trastuzumab
(Horning et al., 2005)
(Hudes et al., 2007)
PFS: 10.4 months CR: 33% DR: 16 months
ORR: 8.6% (temsirolimus) versus 4.8% (IFN) versus 8.1% (combination)
TTP: 8.7 months OS: 16.4 months ORR: 9.3% versus 0%* OS at 6 months: 92.6% versus 85.2%*
(Motzer et al., 2006a) (Motzer et al., 2006b) (Raymond et al., 2011)
(Motzer et al., 2007)
(Demetri et al., 2006) PI
(Llovet et al., 2008)
(Ratain et al., 2006)
(Escudier et al., 2007b)
Reference(s)
ORR: 68%
OS: 10.9 months (temsirolimus)* versus 7.3 months (IFN) versus 8.4 months (combination)
PFS: 11.4 versus 5.5 months*
ORR: 40% PR
PFS: 8.3 months
ORR: 31% versus 6%*
PFS: 11 versus 5 months* ORR: 34%
PFS: 24.1 versus 6 weeks* PR: 9.1%
TTP: 27.3 versus 6.4 weeks*
Time to radiological progression: 5.5 versus 2.8 months*
PFS: 24 versus 6 weeks*
PFS: 5.5 versus 2.8 months*
48-week follow-up
Selected Secondary Outcomes
Tositumomab therapeutic regimen
Temsirolimus versus IFN-a versus combination
Sunitinib versus placebo
Sunitinib
Sunitinib
Sunitinib versus placebo Sunitinib dose escalation Sunitinib versus IFN-a
OS: 10.7 versus 7.9 months* Time to symptomatic progression: 4.9 versus 4.1 months
PFS at 24 weeks: 50% versus 18%*
Sorafenib versus placebo Sorafenib versus placebo
OS: 14.7 months versus not reached*
Primary Outcome(s)
Sorafenib versus placebo
Intervention(s)
TABLE 1—Continued
1362 Izar et al.
Vismodegib BCC, metastatic or recurrent locally advanced, not surgical or radiation therapy candidate Vorinostat CTCL, cutaneous manifestations, despite two prior systemic therapies
Trastuzumab-DM1 Metastatic breast cancer, HER2 +, second-line after prior treatment with trastuzumab and a taxane Vandetanib Medullary thyroid cancer, symptomatic or progressive, and unresectable/metastatic Vemurafenib Melanoma, with the BRAF V600E mutation, unresectable or metastatic
HER2+ breast cancer, metastatic
Drug, U.S. FDA-Labeled Approval(s)
N = 74 N = 33
2
Previously treated, N = 132
2B
2
BRIM2
Previously untreated, N = 675
N = 96
3
BRIM3
N = 331
N = 991
Progressive despite 1–2 prior chemotherapy regimens, N = 222
Previously untreated, N = 469
N = 3222
N = 3401
Study Population, Size
2
3
ZETA
ERIVANCE
3
2
H0649g
EMILIA
3
3
BCIRG 006
H0648g
3
Phase
HERA
Study Name
ORR: 45% versus 29%* OS: 25.1 versus 20.3 months* DR: 9.1 months OS: 13 months
TTP: 7.2 versus 4.5 months*
Vorinostat
Vorinostat
Vismodegib
ORR: 24.2%
ORR: 29.7%
ORR: 30% (metastatic), 43% (locally advanced)
OS at 6 months: 84% versus 64%* PFS: 5.3 versus 1.6 months* ORR at 12.9-month follow-up: 53%
Vemurafenib versus dacarbazine Vemurafenib
PFS: 30.5 versus 19.3 months*
PFS: 9.6 versus 6.4 months* OS: 30.9 versus 25.1 months*
DR: 15.1 weeks
DR: Est 185+ days
DR: 7.6 months PFS: 9.5 months
DR: 6.7 months PFS: 6.8 months OS: 15.9 months
ORR: 48% versus 5%*
ORR: 45% versus 13%*
ORR: 43.6% versus 30.8%*
OS at 5 years (estimated): 87% (AC-T) versus 92% (AC-T + trastuzumab) versus 91% (TCH) *
DFS at 5 years (estimated): 75% (AC-T), 84% (AC-T + trastuzumab) * versus 81% (TCH) *
ORR: 15%
OS at 4 years: 89.3% versus 87.7%
Selected Secondary Outcomes
DFS at 4 years: 78.6% versus 72.2%*
Primary Outcome(s)
Vandetanib versus placebo
Trastuzumab-DM1 versus lapatinib with capecitabine
Trastuzumab
AC-T (doxorubicin + cyclophosphamide and docetaxel q3 weeks) versus AC-T with trastuzumab for 52 weeks versus docetaxel and carboplatin with trastuzumab for 52 weeks (TCH) Paclitaxel or AC with versus without trastuzumab
Trastuzumab versus observation
Intervention(s)
TABLE 1—Continued
(continued )
(Duvic et al., 2007)
(Olsen et al., 2007)
(Sekulic et al., 2012)
(Sosman et al., 2012)
(Chapman et al., 2011; Flaherty et al., 2010)
(Wells et al., 2010, 2012)
(Verma et al., 2012)
(Cobleigh et al., 1999)
(Eiermann, 2001; Slamon et al., 2001),PI
(Gianni et al., 2011; PiccartGebhart et al., 2005) (Slamon et al., 2011)
Reference(s)
Targeted Therapies in Cancer
1363
1364 AC, anthracycline plus cyclophosphamide; AC-T, anthracycline, cyclophosphamide, taxol; ALL, acute lymphoblastic leukemia; AP, accelerated phase; ASM, aggressive systemic mastocytosis; BCC, basal cell carcinoma; B-CLL, B cell CLL; BID, twice daily; BP, blast phase; BSC, best supportive care; CCyR, complete cytogenetic response; CEL, chronic eosinophilic leukemia; CHOP, cyclophosphamide, hydroxyldaunorubicin, oncovin, and prednisone; CHR, complete hematological response; CP, chronic phase; CR, complete response; CRu, unconfirmed complete response; CTCL, cutaneous T-cell lymphoma; CVP, cyclophosphamide, vincristine, and prednisone; DFS, disease-free survival; DFSP, dermatofibrosarcoma protuberans; DLBCL, diffuse large B cell lymphoma; DR, disease recurrence; EFS, event-free survival; FFS, failure-free survival; 5-FU, 5-fluorouracil; FOLFIRI, leucovorin, fluorouracil, irinotecan; FOLFOX, leucovorin, fluorouracil, oxaliplatin; GE, gastroesophageal; HCC, hepatocellular carcinoma; HES, hypereosinophilic syndrome; HR, hazard ratio; IFN-a, interferon-a; LB, lymphoid blast; LV, leucovorin; MaHR, major hematological response; MB, myeloid blast; MCyR, major cytogenetic response; MDS, myelodysplastic syndromes; MMR, major molecular response; MPD, myeloproliferative disease; N/A, not applicable; NHL, non– Hodgkin’s lymphoma; NS, not significant; OHR, overall hematological response; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PI, package information, package insert; PO, by mouth; PR, partial response; PTCL, peripheral T cell lymphoma; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-CVP, rituximab, cyclophosphamide, vincristine, prednisone; RFS, recurrence-free survival; RR, response rate; sALCL, systemic anaplastic large-cell lymphoma; SCCHN, squamous cell carcinoma of the head and neck; SCT, stem cell transplant; SEGA, subependymal giant cell astrocytoma; SQ, subcutaneous; TCH, docetaxel, carboplatin, trastuzumab; TSC, tuberous sclerosis complex; TTF, time to treatment failure; TTP, time to progression; TTR, time to recurrence. a Crinò et al., 2011. b Camidge et al., 2011. c Dakhil et al., 2011. d Joulain et al., 2012. *Statistically significant difference (P , 0.05).
PFS: 6.90 versus 4.67 months* ORR: 19.8% versus 11.1%* OS: 13.5 versus 12.06 months* FOLFIRI with Ziv-aflibercept versus placebo N = 1226 3 VELOUR Ziv-aflibercept Metastatic CRC, with FOLFIRI, after progression on an oxaliplatincontaining regimen
Intervention(s) Study Population, Size Phase Study Name Drug, U.S. FDA-Labeled Approval(s)
TABLE 1—Continued
Primary Outcome(s)
Selected Secondary Outcomes
PId
Reference(s)
Izar et al.
unanticipated toxicities and pharmacokinetic issues forthcoming in the transition from rodents to people. Biodistribution will vary among species according to differences in protein binding, body composition (fat, muscle, bone), and active transporters in the central nervous system and liver. Lipid solubility is one of the more important factors that determines penetration into the central nervous system and storage in fatty tissues, and may influence the pattern of toxicity as well as the potential value of the compound for reaching primary brain tumors and metastases in the brain. The aim of most pharmacokinetic studies is to provide data for assessing the optimal schedule of drug administration, and to determine rates and route(s) of elimination. A host of factors (bioavailability, stability in plasma, protein binding, biodistribution, and rates of metabolism and renal clearance) will determine the peak concentration and half-life of drug in plasma, and therefore the duration of inhibition of the target protein. Because the aim of targeted drug therapy is to maintain target inhibition continuously over the duration of treatment, and the most convenient regimen is once a day oral dosing, a plasma half-life of 8–12 hours is most desirable. Shorter half-lives may require multiple daily doses, whereas longer half-lives will lead to increasing drug levels in plasma (a steady state will be achieved after three to five half-lives), and will also increase the potential for prolonged periods of toxicity. Thus, careful studies of the rates of appearance and disappearance (clearance) of an experimental drug from plasma, and the specific pathways of drug elimination, provide invaluable information in adjusting dose and schedule of administration and in understanding potential drug-drug interactions. Although it is not possible to sample tissues to establish drug distribution patterns, periodic sampling of cerebrospinal fluid and imaging of positron emission tomography–labeled molecules can add important insights into drug distribution in humans (Smith-Jones et al., 2004; Slobbe et al., 2012). Tables 2 and 3 provide a compilation of detailed pharmacokinetics information (with references) on currently approved small molecules and antibodies for targeted cancer therapy. Most abide by the general principles enumerated earlier. Most approved targeted drugs exhibit favorable pharmacokinetics: adequate bioavailability when administered in the fasting state, halflives in plasma of 8–12 hours or longer, slow metabolic inactivation by cytochrome P450 isoenzymes, and some limited penetration into the cerebrospinal fluid and central nervous system (in the few molecules studied to date). A few outliers, such as nilotinib, have longer half-lives and demonstrate accumulation of parent compound until a plateau is reached in plasma after several weeks. In a few cases, such as with the conversion of sorafenib to its N-oxide, a parent compound is converted to an active metabolite, but most drugs are
Sorafenib
VEGFR1-3,
Pazopanib
aM= pyridine n-oxide
p38-alpha, B-raf
CYP3A4
and 2C8
CYP3A4, 1A2,
CYP3A4, 2C19, and A2
CYP3A4
FLT3, c-KIT,
1-2 d
31 h
2.5-6.1 h
22.5 h
PDGFR-A,
VEGFR2, VEGFR3,
ITK, LCK, C-FMS
3, c-KIT,
FGFR1 AND
PDGFR,
VEGFR1-3
LYN, HCK
BCR-ABL, SRC,
UGT1A9
and/or amidases
19
,4
23
3
Dialysis: not studied
None studied
None
None
None
None
Sev: not
not use
Sev: do
studied Mod:75%
Sev: not
Mod: 50%
or sev: 60%
Mild, mod
rash, desquamation
dyspnea and
HTN,
toxicity, high-grade
skin
persistent
Recurrent/
surgery
proteinuria,
HTN,
Hepatotoxicity,d
bleeding, surgery
Sz, proteinuria,
Yes
Yes
Yes
Yes
Yes
No
Yes (weak)
No
agents
prolonging
(continued )
agents
QT prolonging
QT
None reported
absorption HTN, HTNassociated
hepatotoxicity Yes
PPIs/antacids - decr.
No qt prolongation,
Yes thrombocytopenia,
pancreatitis Neutropenia,
arrhythmias,
cardiac
cytopenias,
GI perforation,
complications, hemorrhage,
and 2C8, 2D6 and 3A5
healing
(including T315I),
Yes
absorption Ponatinib
TIE-2, FLT-3
No
KIT, RET,
Yes
absorption
PPIs/antacids decr.
agents.
prolonging
QT prolonging
QT
levothyroxine dose
increase
Hypothyroidism:
hepatotoxicity.
Tylenol: increased
Others
decr.
lipase/
amylase elev Arterial
Yes
No
No
Yes
Inh. P450c
agents. PPIs/ antacids -
Yes
Yes
Yes
P450 Ind.b
d
Yes
Yes
Yes
P450 Inh.a
thrombocytopenia, QT prolongation,
Neutropenia,
thrombocytopenia
Neutropenia,
Neutropenia, thrombocytopenia
Severe Toxicities
and P-gp
Not studied
None
None
CrCl,20: caution
ml/min: 50%
CrCl 20-39
to 600 mg/d
CrCl 4059: limit
CrCl in ml/min
Renal Ins
wound
Not studied
25%–33%
Mild, mod or sev:
None
sev: 25%
Hep Ins
FGFR, SRC,
5
5
Par. Comp.
Drug Interactions
VEGFR, PDGFR,
Esterases
4
13
%
Total
Dose Adjustment (% Reduction of Recommended Dose if Available)
inhibits ABCG2
CYP3A4
CYP3A4
CYP3A4
piperazine
demethylated
Other
Renal Excretion
d
24 h
17 h
3-5 h
and 2C19;
40 h) aM = N-
CYP3A4, 1A2, 2D6, 2C9
P450
Primary Metabolism
18 h (aM =
Plasma T 1/2
thrombosis,da hepatotoxicity,
BCR-ABL
PDGFR
BCR-ABL, KIT,
Axitinib
Bosutinib
Ponatinib
Nilotinib
BCR-ABL, KIT,
Dasatinib
PDGFR
BCR-ABL, KIT, PDGFR
Target of Inhibition
Imatinib
Agent
TABLE 2 Pharmacokinetics of Food and Drug Administration–approved targeted therapies
Targeted Therapies in Cancer
1365
HER-1/EGFR
HER-1 and
Gefitinib
Lapatinib
Cabozantinib
UGT1A1
studied
Mod: 50% Sev: not
studied
Sev: not
None
Hep Ins
LVEF
None
infections,
Pneumonitis, serious
(up to 200%) None
reduced
surgery,
Hepatotoxicity,d
Severe Toxicities
higher dose
Dialysis:
None
Renal Ins
N-oxide
FLT-3,
AXL, and TIE-2
and 2C9. aM=XL184
VEGFR-3, KIT, TRKB,
RET, MET,
Not studied
caution.
CrCl , 30,
not studied
30: none CrCl,30:
CrCl.
studied
none Mod-sev: not
Mild:
studied)
None (not
None
(not studied)
None
d
PRES, GI
bleeding, cardiotoxicity,
Hepatotoxicity,d
prolongation
LVEF, QT
pneumonitis, reduced
ILD/
Hepatotoxicity,
ILD
toxicities
dermatological
thrombembolism, PPES
PRES,
complications,
wound healing
and fistulas,d hemorrhage,d
GI perforation
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
agents
prolonging
(continued )
is a P450 inducer
Cabozantinib
UGT1A9, UGT1A1
Inhibits
QT
Warfarin - bleeding.
inducer.
a P450
Gefitinib is
Statins rhabdomyolysis
absorption.
Hepatotoxicity,
decr. bilirubinemia
Yes
agents
prolonging
Warfarin
QT
infection by live vaccines
risk of
Increased
None reported
agents
PPIs/antacids -
Yes
Others QT prolonging
transaminitis/
Yes
Yes (weak)
No
No
No
Inh. P450c
rash,
Yes
Yes
Yes
Yes
Yes
P450 Ind.b
and NSAIDs bleeding.
Yes
Yes
Yes
Yes
Yes
P450 Inh.a
Drug Interactions
severe diarrhea,
Skin reactions,
QT prolongation
bilirubinemia,
Transaminitis/
healing complications,
studied
Sev: not
Mild-mod: none
Breast cancer: 40%
Sev, met.
Sev: 33%
None
None
Not studied in
30: none
CrCl.
fistula, wound
,1
,1
caution
Not studied,
Sz, psychosis
thrombosis, ILD, bowel perforation,
thrombocytopenia,
Neutropenia,
SAPK2, PTK5 and ABL
27
17
,2
4
8
22
not use
mod/sev: do
Mild: 40%.
perforation,
CYP3A4
CYP3A4
CYP3A4/5
CYP3A4
and 1A1
CYP3A4, 1A2,
CYP3A4/5
sirolimus
aM =
BRAFV600E,
55 h
25 - 51 h
14.2-24 h
6 - 49 h
36.2 h
42 h
(aM = 54h)
RAF-1, BRAF,
TRK2A, EPH2A,
PDGFRA, PDGFRB, FGFR1-2, TIE2, DDR2,
RET, VEGFR1-3, KIT
HER-2
HER-1/EGFR
Erlotinib
everolimus
Same as
complex
signaling, TORC-1
ALK, ROS-1, MET
Regorafenib
2.3
Par. Comp.
of lymphoma
4.6
5
16
Total
Dose Adjustment (% Reduction of Recommended Dose if Available)
development
CYP3A4.
Other
Renal Excretion
mTOR
17.3 h
CYP3A
CYP3A4
P450
Primary Metabolism
that inhibits
with FKBP-12
30 h
80–110 h)
Complex formation
(aM =
1-3, c-KIT
40–60 h
Plasma T 1/2
PDGFR-B,VEGFR
PDGFR-A,
Target of Inhibition
Crizotinib
Temsirolimus
Everolimus
Sunitinib
Agent
TABLE 2—Continued
1366 Izar et al.
B-raf
Hedgehog
Vemurafenib
Vismodegib
4-12 d
57 h
19 d
2.8-5.8 h
Plasma T 1/2
and 3A4/5
(likely) CYP2C9
N-oxide unknown
vandetanib-
vandetanib and
N-desmethyl-
CYP3A4. aM=
CYP3A4
P450
Other
FMO
Primary Metabolism
4.4
1
25
74
Total
Par. Comp.
Renal Excretion
not use
sufficiently studied
sufficiently studied
Not
studied
studied
Not
sufficiently
CrCl , 30: not
Sev: not sufficiently
None
33%.
33%-50% CrCl,50:
None
do not use
Mod-sev:
None
. 200:
platelets
dilaysis +
100-200: 50%-62.5%.
platelets
dialysis +
not use.
CrCl , 15: do
, 100: do
, 100: do not use
platelets
+ platelets
30%-50% CrCl 15-59 +
mod, sev
Mild,
platelets 100-150:
15-59 +
150: 33%-50%.
CrCl
Renal Ins
platelets 100-
Mild, mod, sev +
Hep Ins
Severe Toxicities
birth defects
death/ severe d
prolongation
sudden deathd
pointes,d
torsades de
prolongation,d
Embryo-fetal
QT
QT
anemia
Thrombocytopenia,
Dose Adjustment (% Reduction of Recommended Dose if Available)
No
Yes
Yes
Yes
P450 Inh.a
No
Yes
Yes
Yes
P450 Ind.b
No
Yes
No
No
Inh. P450c
Drug Interactions
agents
prolonging
absorption
antacids decr.
PPIs/
agents
prolonging
- bleeding. QT
Warfarin
inducer.
a P450
Vemurafenib is
QT
Others
ABCG2, ATP-binding cassette subfamily G member 2; aM, active metabolites; AXL, axl receptor tyrosine kinase; BBW, Black Box Warning; C-FMS, colony-stimulating factor-1 receptor; DDR2, discoidin domain receptor tyrosine kinase; FKBP, FK506-binding protein; FLT-3, fms-like tyrosine kinase-3; FMO, Flavin-containing monooxygenase; GI, gastrointestinal; HCK, hematopoietic cell kinase; Hep Ins, hepatic insufficiency; HTN, hypertension; ILD, interstitial lung disease; ITK, interleukin-2-inducible T-cell kinase; JAK, Janus kinase; LCK, lymphocyte-specific protein tyrosine kinase; LVEF, left ventricular ejection fraction; LYN, V-Yes-1 Yamaguchi sarcoma viral related oncogene homolog; mod, moderate; NSAID, nonsteroidal anti-inflammatory drug; P450, cytochrome P450; Par. Comp., parent compound; P-gp, P-glycoprotein; PPES, palmar-plantar erythrodysesthesia syndrome; PPI, proton-pump inhibitor; PRES, posterior reversible encephalopathy syndrome; PTK, protein tyrosine-kinase; RET, Ret Proto Oncogene; ros-1, c-Ros oncogene 1, receptor tyrosine kinase; SAPK, stress-activated protein kinase; sev, severe; Sz, seizure; TIE2, tunica interna endothelial cell kinase; TRKB, tyrosine kinase receptor B; UGT,UDP-glucuronosyltransferases. a P450 inhibitors resulting in increased concentrations of drug. b P450 inducers resulting in decreased drug concentration. c Drug inhibits P450, leading to increased concentration of drugs metabolized by P450. d BBW.
of Smoothened
pathway via inhibition
EGFR and VEGF
JAK-1 and JAK-2
Dysregulated
Target of Inhibition
Vandetanib
Ruxolitinib
Agent
TABLE 2—Continued
Targeted Therapies in Cancer
1367
CD20
4–6 d CD30. Internalization and disruption of microtubules by MMAE inhibiting
Ofatumumab
Brentuximab vedotin
12–14 d Metabolized by CYP3A4/5; 24% renal excretion
None None (not determined for MMAE) None (not determined for MMAE)
None
None
None
12 d
None
None
CD52 on several immune cells
None
None
5–78 d
8d
Alemtuzumab
Rituximab
Tositumomab I131
None
None
27–30 h
CD20. Tiuxetan links the antibody and Y-90, a highenergy beta emission CD20. Binding of the I131 loaded antibody and beta emission CD20
Ibritumomab tuixetan Y-90
6%–11% renal excretion, 7.2% parent compound
CrCl. 30: none CrCl, 30: none (not studied)
None (not studied)
None
CrCl in ml/min
Renal Ins
18 d
None
Hep Ins
Cardiotoxicity,d reduced LVEF,d serious infusion reactions,d pulmonary toxicities,d nephrotic syndrome (rare) Cardiotoxicity, reduced LVEF, serious infusion reactions, embryofetal toxicityd Serious infusion reactions,d severe cytopenias,d cut. and mucocut. reactions,d radiation injury Infusion-related reactions,d prolonged and severe cytopenias,d anaphylactic reactions Serious infusion reactions,d TLS,d severe mucocut. reactions,d PMLd Cardiotoxicity, serious infusion reactions,d infections,d cytopeniasd Infusion-related reactions Neutropenia, PNP, PMLd
Severe Toxicities
Dose Adjustment (% Reduction of Recommended Dose if Available)
HER2
Likely eliminated via RES
Pharmacokinetics
Pertuzumab
5.8 d
Plasma T 1/2
HER2
Target of Inhibition
Monoclonal antibodies Trastuzumab
Agent
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
P450 P450 Inh. Inh.a Ind.b P450c
TABLE 3 Pharmacokinetics of Food and Drug Administration–approved targeted therapies
Bleomycin - increased lung toxicity
None reported
(continued )
Increased risk of infection by live vaccines
Cisplatin-renal failure. Infection by live vaccines. Inadequate immunological response to influenza and pneumococcal vaccine
None reported
Several medications (including but not limited to aspirin, clopidogrel, warfarin, heparin, enoxaparin, dalteparin, fondaparinux) – bleeding
None reported
Anthracyclines, paclitaxel, and cyclophosphamide - increased cardiotoxicity. Paclitaxel increased levels
Others
Drug Interactions
1368 Izar et al.
EGFR
Cetuximab
Panitumumab
6d
7.5 d
3–7 d
20 d
14.7 d
Plasma T 1/2
Proteasome inhibitor Bortezomib
26S proteasome
9–15 h
Peptide immunotoxins 70–80 min Denileukin Cells that diftitox express high affinity for IL-2 receptor (CD25, CD122, CD152)
Binds VEGFR-1 and 2 ligands
EGFR
Bevacizumab
VEGFR-1 and 2 fusion Ziv-aflibercept
VEGF
Ipilimumab
Target of Inhibition
cancer cell growth CTLA4
Agent
Metabolized by CYP3A4, 2D6, 2C19, 2C9, 1A2;
Internalization in liver and skin
Pharmacokinetics
Mild: none Mod-sev: ;45%
None
Mild-mod: none, severe (not studied)
None
None
None
None
Hep Ins
Severe infusion reactions,d capillary leak syndrome,d loss of visual acuity,d avoid in hypoalbuminemia , 3g/dl
Clotting (arterial), bleeding,d proteinuria, compromised wound healing,d GI perforation,d PRES, neutropenia, HTN
Rare (enterocolitis,d hepatitis,d dermatitis,d TEN,d PNP,d and endocrinopathyd) Clotting (arterial and venous), bleeding,d proteinuria, surgery and wound healing complications,d GI perforation,d PRES Serious infusion reactions,d ILD, acne form rash, cardiopulmonary arrest and/or sudden deathd Infusion-related reactions,d dermatological toxicitiesd
Severe Toxicities
None Thrombocytopenia, Dialysis: PNP administer postdialysis
None
None
None
None
None
None
Renal Ins
Dose Adjustment (% Reduction of Recommended Dose if Available)
TABLE 3—Continued
Yes
No
No
No
No
No
No
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
P450 P450 Inh. Inh.a Ind.b P450c
None reported
None reported
None reported
None reported
None reported
None reported
None reported
Others
Drug Interactions
(continued )
Targeted Therapies in Cancer
1369
Similar to bortezomib
Target of Inhibition
Same as vorinostat
3h
2h
,1 h
Plasma T 1/2 Hep Ins
Metabolism through glucuronidation, hydrolysis, and betaoxidation; 52% renal excretion, less than 1% parent compound Metabolized by CYP3A4
None
Renal Ins
No
Yes
Neutropenia, None ESRD: Mild: none thrombocytopenia not studied, Mod-sev: not caution studied, caution
n/a
Yes
No
n/a
No
No
n/a
P450 P450 Inh. Inh.a Ind.b P450c
Severe thrombocytopenia and leukopenia
PAH, hepatotoxicity, cardiotoxicity, thrombocytopenia
Severe Toxicities
Dose Adjustment (% Reduction of Recommended Dose if Available)
Not Mild-mod: not sufficiently sufficiently studied, studied, caution Sev: caution contraindicated
extent of renal excretion unclear Not studied Possibly metabolized by CYP3A4/5; metabolized by P-glycoprotein; extent of renal excretion unclear
Pharmacokinetics
None reported
Warfarin and valproic acid - bleeding
None reported
Others
Drug Interactions
BBW, Black Box Warning; CTLA4, cytotoxic T lymphocyte–associated antigen 4; cut., cutaneous; ESRD, end-stage renal disease; GI, gastrointestinal; Hep Ins, hepatic insufficiency; HTN, hypertension; IL-2, interleukin-2; ILD, interstitial lung disease; LVEF, left ventricular ejection fraction; MMAE, monomethyl auristatin E; mod, moderate; mucocut., mucocutaneous; n/a, not applicable; NSAID, nonsteroidal anti-inflammatory drug; P450, cytochrome P450; PAH, pulmonary artery hypertension; PML, progressive multifocal leukencephalopathy; PNP, peripheral neuropathy; PPES, palmar-plantar erythrodysesthesia syndrome; PPI, proton-pump inhibitor; PRES, posterior reversible encephalopathy syndrome; Renal Ins, renal insufficiency; sev, severe; Sz, seizure; TEN, total epidermal necrolysis; TLS, tumor lysis syndrome. a P450 inhibitors resulting in increased concentrations of drug. b P450 inducers resulting in decreased drug concentration. c Drug inhibits P450, leading to increased concentration of drugs metabolized by P450. d BBW.
Romidepsin
Histone deacetylase inhibitors Histone deacetylase inhibitors Vorinostat Histone deacetylases that are overexpressed in some cancer cells
Carfilzomib
Agent
TABLE 3—Continued
1370 Izar et al.
Targeted Therapies in Cancer
inactivated in their initial metabolic transformation. Many of the orally administered drugs have significant toxicity to intestinal epithelium and frequently cause mild hepatocellular toxicity (where the highest drug concentrations are found). Idiosyncratic severe or fatal hepatic toxicity and pulmonary toxicity occur infrequently, but have been reported with many agents. Other drugs, including the second- and third-generation BCR-ABL inhibitors, may prolong the QT interval and cause serious cardiac arrhythmias. Because most synthetic targeted inhibitors are administered continuously over weeks to months, there exists the possibility for changes in drug clearance due to induction of metabolism or transporters, buildup of an inhibitory metabolite, changes in hepatic function, or other pharmacokinetics factors. For example, a large populationbased pharmacokinetics study of imatinib suggested an increase of 33% in drug clearance in the first month of drug administration, a finding that could explain decreased toxicity of the drug over time (Judson et al., 2005). A similar finding, a 25% decrease in drug exposure after 3 months of treatment, was reported for sorafenib in patients with hepatocellular cancer, and exposure was almost 50% lower at the time of disease progression as compared with the exposure after 1 month of treatment (Arrondeau et al., 2012). The authors suggest that disease progression could be related to changes in drug pharmacokinetics over time. Drug interactions are common for the small molecules and result from their susceptibility to changes in cytochrome P450 isoenzyme activity, which may be induced or inhibited by nononcological drugs. Dose adjustment is usually necessary when the oral synthetic targeted inhibitors are used with inhibitors of cytochrome P450 metabolism such as calcium channel blockers, antibiotics (erythromycin, antifungal imidazoles), herbal medications (St. John’s wort), or antiretroviral drugs (ritonavir), or with inducers of metabolism such as glucocorticoids, phenytoin, or proton-pump inhibitors. The issue of drug interactions becomes increasingly important as combinations of targeted agents are used to overcome or circumvent drug resistance (Kwak et al., 2007). Studies of pharmacokinetics and toxicity of targeted drugs in patients with hepatic or renal dysfunction have yielded important insights. In general, doses of targeted drugs do not have to be reduced in patients with mild hepatic dysfunction and normal bilirubin levels (ChildPugh A), the exceptions being bosutinib and ruxolitinib (Tables 1 and 2), which do require dose reduction in this circumstance. Higher levels of hepatic dysfunction (ChildPugh B and C), with increasingly abnormal serum bilirubin levels, in general require that the dose be decreased by 50–75%. Renal dysfunction does not directly affect most targeted drugs since renal excretion plays a minor role in elimination of these agents. Dose adjustment is necessary for ruxolitinib, vandetanib, and imatinib when the creatinine clearance falls below 30 ml/min.
1371
Central nervous system penetration of most targeted drugs is quite limited. In the few examples where simultaneous blood and cerebrospinal fluid (CSF) samples were analyzed, agents such as gefitinib and crizotinib do penetrate at rates that produce responses in brain metastases (Falk et al., 2012; Kuiper and Smit, 2013) but are not sufficient enough to prevent progression of central lesions. The occasional dramatic response to targeted therapies, such as crizotinib in the treatment of anaplastic lymphoma kinase (ALK)-positive NSCLC, may be due to disruption of the blood-brain barrier, allowing for higher concentrations of the compound. C. Clinical Pharmacology of Monoclonal Antibodies. As clinical agents, monoclonal antibodies have had a major impact on cancer treatment, primarily as components of combination therapy. They possess many favorable properties, which are summarized as follows: 1. Monoclonal antibodies have few drug interactions, as they do not affect hepatic microsomal metabolism. Their pharmacokinetics are unaffected by renal or hepatic dysfunction. 2. They have prolonged half-lives in plasma, due to their slow elimination by the reticuloendothelial system, thus allowing intermittent weekly or monthly dosing. Half-lives are typically 7–23 days. IgG-1,-2, and -4 isotypes have the longest survival in plasma, whereas IgG-3 has the shortest (7 days). Antibodies are removed through interaction with the FcRB (Brambell) receptor on the vascular endothelium, a process that may accelerate in the presence of inflammation, fever, and cytokine release. 3. They have highly specific drug action, with few off-target side effects. The least toxic are antibodies that target unique receptors on tumor cells, but other target molecules such as HER2, CD20, EGFR, and VEGF are found on normal tissues, leading to significant toxicities when antibodies are administered. For example, HER2 is found on cardiac myocytes and participates in repair and remodeling of cardiac tissue. Trastuzumab, an antiHER2 antibody, causes myocardial injury (Cote et al., 2012). Rituximab, an anti-CD20 antibody, depletes both malignant and normal B-lymphocytes and increases the risk of opportunistic infection. Gemtuzumab ozogamicin, an anti-CD33/toxin conjugate, potently kills myeloid leukemic cells but produces prolonged depletion of platelet precursors (Ravandi et al., 2012). The radioconjugate Y-90 Zevalin (ibritumomab) produces severe myelosuppression in patients with lymphoma and involvement of bone marrow. 4. Because of their ability to target specific cell types, monoclonal antibodies can be used to carry extremely potent cytotoxins with minimal toxicity
1372
Izar et al.
to the host. Toxins such as bacterial peptides (pseudomonas exotoxin), radionuclides (yttrium90 or iodine-131), and potent small molecules (maytansine and aurestatin antimitotic derivatives) have been linked to antibodies. The resulting conjugates are highly effective in clinical use (see Table 1). 5. They have the ability to recruit T cells, macrophages, and complement to targeted cells, thus amplifying their action. 6. They may potentiate the action of cytotoxic drugs with minimal overlapping toxicity. This compatibility of antibodies with cytotoxics has allowed the addition of antibodies to combination chemotherapy regimens, without dose reductions and with significant enhancement of activity in breast cancer (trastuzumab with taxanes), colon cancer (cetuximab with fluorouracil/irinotecan, bevacizumab with fluorouracil/oxaliplatin), and lung cancer (bevacizumab with platinum-based combinations) and in non-Hodgkin’s lymphoma (rituximab with cyclophosphamide, hydroxyldaunorubicin, oncovin, and prednisone) (see Table 3 for references). The penetration of solid malignancies by monoclonal antibodies is in part determined by the size of the antibody. In many cases, such as bevacizumab, antibodies are used in conjunction with chemotherapeutics. Antibodies can potentiate the response to cytotoxic therapy significantly. Synergistic effects may be due to drug interactions with vessels or interference with survival pathways of cancer cells, making them more susceptible to DNA damaging agents. Despite their obvious advantages, monoclonal antibodies have a few negative pharmacological features: 1. The molecules are more complex than synthetic targeted inhibitors, making them difficult to manufacture, and require humanization to avoid allergic responses. Thus, they tend to be costly. 2. Despite their “humanization” (the insertion of human sequences in place of mouse antibody peptides), they can provoke febrile and systemic toxicity, which usually decreases in succeeding cycles of therapy. Partially humanized antibodies, such as rituximab, or mouse antibodies, such as Bexxar (tositumomab), are more immunogenic than fully humanized molecules. 3. Because of their high molecular weight, they do not penetrate well into the central nervous system. 4. Most require intravenous administration, an inconvenient and expensive restriction on their use. The reader is referred to primary texts (Laurent et al., 2011) for a more complete discussion of the mechanism of action and clinical applications of monoclonal antibodies.
II. Resistance Despite considerable success of targeted treatments, resistance emerges after several months of treatment in most patients. The only exception is the experience with BCR-ABL–targeted drugs in chronic myeloid leukemia (CML), a setting in which long-term stable molecular remissions have been achieved with imatinib and the second- and third-generation inhibitors (Table 1). The investigation of resistance mechanisms allows further understanding of the adaptability of malignancies on a molecular level and leads to insights crucial for the development of treatment alternatives, including new drug development and multiagent approaches. In general, resistance is characterized as either intrinsic (i.e., primary) or acquired (i.e., secondary) resistance. Intrinsic resistance describes a de novo lack of response to therapy, whereas secondary resistance emerges following drug exposure and manifests after a period of response. Often, the mechanisms of primary and secondary resistance are the same, although the understanding of both is far from complete. Well established mechanisms of acquired resistance include 1) clonal selection of pre-existing resistant cells present at low allelic frequencies and selected to grow out through the pressure of drug, or 2) genetic events acquired during the course of therapy. It is notable that resistance mechanisms to targeted therapies are similar to mechanisms of resistance to chemotherapeutic agents. In general, mechanisms of resistance to targeted drugs have been much more carefully studied in the clinic through rebiopsy of patients at the time of progression. Distinct mechanisms of resistance, such as activation of alternative pathways that are less frequently seen in resistance to cytotoxic agents, seem to predominate with targeted therapies. In the following section, we will provide an overview of specific mechanisms of resistance to targeted therapy. We will emphasize resistance mechanisms identified through analysis of patient-derived specimens. Where clinical evidence is lacking, we will provide an overview of preclinical data on resistance mechanisms. An examination of mechanisms of resistance to various agents across malignancies of diverse molecular backgrounds and treatment experience may provide a more global view that will inform strategies for overcoming resistance. Despite the diversity of specific resistance mechanisms across human malignancies, a number of common principles have emerged. These general mechanisms include genetic alterations that alter the level of expression of the target or the conformation of its catalytic pocket (e.g., BCR-ABL-1 in CML, EGFR and EML4/ALK in NSCLC) and activation of pathways that bypass the inhibited target and lead to downstream signaling cascades (e.g., N- and K-RAS activation in BRAF-positive melanoma or MET amplification
Targeted Therapies in Cancer
in EGFR-mutated NSCLC). Often, secondary mutations of the primary oncogenic driver lead to decreased binding affinity of the inhibitor to the catalytic pocket of the enzyme, restrict access to the pocket, or change the configuration of the enzyme. Additional factors, such as failure of apoptotic mechanisms (for example, low BIM (Bcl-2-interacting mediator of cell death) expression), pharmacokinetics factors, and major histological changes that likely reflect altered gene expression (epithelial-tomesenchymal transformation), may contribute to resistance and will be discussed in the appropriate section. We will consider resistance affecting specific agents in the following sections. A. Resistance to Synthetic Targeted Inhibitors 1. Drugs Targeting Epidermal Growth Factor Receptor Mutations in Non–Small-Cell Lung Cancer. NSCLC constitutes approximately 80% of all lung cancers and is associated with an overall 5-year mortality rate of 85% (Jemal et al., 2010). The majority of NSCLC cases present with locally advanced or metastatic disease. Chemotherapy has been modestly effective in prolonging survival to approximately 1 year in these patients, but at the cost of significant toxicity. An important insight into tumor biology occurred with the observation that 10% of U.S. patients with NSCLC, primarily nonsmokers, express a mutated form of the EGFR encoded by the EGFR (ErbB1) gene. In its physiological state, EGFR is a transmembrane protein with intracellular tyrosine kinase activity that transduces growth and survival signals via the mitogen-activated protein (MAP) kinase and phosphatydinositol kinase (PI3K) pathways. In NSCLC, oncogenic mutations are found in the EGFR receptor’s catalytic domain, which extends from exon 18 through 21. The most common alterations are exon 19 deletions (45% of cases), exon 21 point mutation L858R (42%), rare substitutions in exon 18 (3%), and insertions or substitutions in exon 20 (4%) (Lynch et al., 2004; Paez et al., 2004; Shepherd et al., 2005). Activating EGFR mutations are transforming in vitro and in vivo, and affected cells become dependent on EGFR signaling for survival and proliferation. Loss of signaling causes the “addicted” cell to undergo apoptosis, although there is unexplained heterogeneity in the ability to induce apoptosis in similar cells with the same oncogenic driver (Faber et al., 2011) (see “Failure to Induce Proapoptotic Signalling and Response to Targeted Therapy”). The concept of “oncogene addiction” provides a rationale for targeted therapies in oncogene-driven malignancies, such as EGFR- and ALK-mutated NSCLC, c-KIT–mutated gastrointestinal stromal tumor (GIST), CML, and B-RAF–mutated melanoma. The reversible EGFR inhibitors gefitinib and erlotinib are effective in the management of EGFR mutant tumors. Approximately 70% of patients with advanced NSCLC with EGFR mutation initially respond to treatment
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with these tyrosine-kinase inhibitors (TKIs), which improve progression-free survival and tolerability. These drugs cause mild toxicity when compared with conventional management with standard chemotherapy (Shepherd et al., 2005; Mok et al., 2009; Rosell et al., 2012). “Classic” exon 19 and 21 mutations are associated with marked sensitivity to the EGFR TKIs (Lynch et al., 2004; Paez et al., 2004). However, NSCLC patients relapse after a median of 10 months following TKI treatment initiation. 2. Primary Resistance to Epidermal Growth Factor Receptor Tyrosine-Kinase Inhibitors. Thirty percent of patients show primary resistance to TKI treatment (defined as less than 30% objective response by Response Evaluation Criteria In Solid Tumors criteria) (Therasse et al., 2000). At presentation, tumors with exon 20 mutations or the T790M mutation (also a common mutation associated with acquired resistance) have a low response rate to EGFR TKI (Yasuda et al., 2012). In a compilation of published data, only one of 20 patients with an exon 20 mutation had a response to EGFR inhibitor therapy (Yasuda et al., 2012). In vitro studies likewise demonstrated resistance of cells with exon 20 mutations to multiple reversible and irreversible EGFR TKIs (Yasuda et al., 2012). 3. Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and Strategies to Overcome Resistance. Rebiopsy of tumor at the time of progression has disclosed that T790M is the most frequent genetic change conferring acquired resistance to EGFR TKIs, accounting for 30– 68% of such cases (Kobayashi et al., 2005; Arcila et al., 2011; Sequist et al., 2011). This point mutation, which results in a threonine-to-methionine amino acid change, affects the “gatekeeper” residue in the catalytic domain of the kinase and restricts access to the pocket. Most oncogenic EGFR mutations reduce the enzyme’s affinity for ATP. T790M may also contribute to resistance by restoring the ATP affinity of mutant EGFR back to wild-type levels, an action not duplicated by gatekeeper mutations of other oncogenic tyrosine kinases (Yun et al., 2008). When present as the initial and sole mutation in EGFR, T790M enhances kinase activity and oncogenicity, resulting in resistance. In combination with other classic activating mutations, T790M confers resistance to EGFR TKIs (Godin-Heymann et al., 2007; Mulloy et al., 2007; Vikis et al., 2007). However, in recent in vitro studies, T790M, as a secondary mutation, was associated with a growth disadvantage relative to parental cells (Chmielecki et al., 2011). In line with this observation, patients with acquired T790M mutation seem to have a more indolent clinical course when maintained on treatment despite progression (Chmielecki et al., 2011; Oxnard et al., 2011). When EGFR inhibitors are discontinued in drug-resistant NSCLC, sensitivity to TKIs may be restored, as the original cell
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line re-emerges and the T790M mutation disappears. It is uncertain whether continued TKIs in patients with resistant tumors, either with chemotherapy or in combination with new TKI inhibitors, will delay disease progression (Chmielecki et al., 2011). Other mutations besides T790M, such as D761Y (Balak et al., 2006), L747S (Costa et al., 2007), and T854A (Bean et al., 2008), confer secondary resistance and together account for fewer than 5% of cases. In an attempt to overcome resistance, second-generation EGFR TKIs with greater potency against T790M-resistant cells are being evaluated. These are irreversible inhibitors, and many block other members of the ErbB family (Kwak et al., 2005; Shimamura et al., 2008). Some of these second-generation inhibitors, including the dual EGFR/ HER2 inhibitors HKI-272 [(2E)-N-[4-[[3-chloro-4-[(pyridin2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6yl]-4-(dimethylamino)but-2-enamide] (Sequist et al., 2010) and BIBW 2992 [N-[4-[(3-chloro-4-fluorophenyl) amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]4(dimethylamino)-2-butenamide] (Yap et al., 2010) and the multi-TKI PF-00299804 [(E)-N-[4-(3-chloro4-fluoro-anilino)-7-methoxy-quinazolin-6-yl]-4-(1-piperidyl)but2-enamide hydrate] (Engelman et al., 2007a), have completed phase II clinical trials, but results were disappointing. These inhibitors have a high affinity to wildtype (WT) EGFR and, therefore, a lower therapeutic index. Given that the T790M mutation restores ATP affinity to a level comparable to that of WT EGFR (Yun et al., 2008), concentrations of second-generation TKIs necessary to inhibit T790M-mutated tumors in patients may result in side effects that ultimately limit their use. Third-generation TKIs, such as WZ4002 [N-(3-(5-chloro2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-yloxy)phenyl)acrylamide] and CO-1686, may be more promising. They are irreversible inhibitors with a different structural scaffold (and an allosteric binding site). They are highly selective for T790M-mutated cells and have marginal activity against WT EGFR (Zhou et al., 2009; Walter et al., 2011), which should decrease host toxicity and allow dose escalation. A mouse model in which the tumor carries the compound Del19-T790M or L858R-T790M mutation may allow testing of the efficacy of different compounds and combination therapies against T790M tumors in vivo (Xu et al., 2012). Amplification of the MET oncogene that encodes for a transmembrane TK receptor is the second most common mechanism of acquired resistance to EGFR TKIs, accounting for 5–20% of acquired resistance (Engelman et al., 2007b; Arcila et al., 2011; Sequist et al., 2011). In the presence of EGFR TKIs, amplification of MET leads to resistance by dimerizing with and transactivating ErbB3, which subsequently activates PI3K/AKT and thereby bypasses EGFR signaling (Engelman et al., 2007b). In addition to MET amplification, the same pathway may be activated by overexpression of its ligand,
hepatic growth factor (HGF), a change that confers both primary and secondary resistance to EGFR inhibitors in experimental systems. Yano et al. (2008) demonstrated that HGF induces gefitinib resistance in PC-9 and HCC827 cells through MET/PI3K activation, independent from ErbB3/PI3K signaling, and may also confer primary resistance to gefitinib and erlotinib. High expression of HGF was found in tumor specimens from patients with primary resistance and in patients with acquired resistance, whereas responding tumors exhibited low expression levels of HGF (Yano et al., 2008; Turke et al., 2010). These findings were confirmed in a study by Engelman et al. (2007a,b). The authors also examined 16 patient-derived resistant specimens. Four of these patients showed MET amplification in pretreatment tumor specimens, and all four subsequently developed MET amplification as their sole resistance mechanism following treatment, supporting the idea that resistance arises due to a pre-existing MET-amplified clone that expands under gefitinib/erlotinib selection pressure (Turke et al., 2010). Less frequent mechanisms that confer resistance via bypass tract activation include CRKL amplification (Cheung et al., 2011), loss of phosphatase and tensin homolog (PTEN) (Sos et al., 2009), BRAF mutations (Ohashi et al., 2012), HER2 amplification (Takezawa et al., 2012), PI3KCA mutations (Sequist et al., 2011), and less well understood mechanisms, such as epithelialto-mesenchymal transformation. In a minority of resistant tumors, a remarkable transformation from NSCLC to small-cell lung cancer (Sequist et al., 2011) is seen in the resistant tumor, which retains the original EGFR mutation, suggesting a major reprogramming of gene expression. 4. Resistance to ALK Inhibitors in Non–Small-Cell Lung Cancer. A subset of NSCLC carries a chromosomal translocation that activates the ALK. Approximately 3–5% of NSCLC patients (;8000 patients in the United States every year) have tumors that harbor a translocation that connects the 59 end of the ALK gene to the echinoderm microtubule-associated proteinlike 4 gene (EML4); although this is the most common activating mutation, other partners can produce transformation with ALK (Chiarle et al., 2008). Based on retrospective observations, resulting malignancies are associated with advanced stage at presentation and with a more aggressive phenotype (Rodig et al., 2009; Shaw et al., 2009; Doebele et al., 2012a). Lung cancers with ALK translocations rely on ALK kinase activity as their oncogenic driver, and most are exquisitely sensitive to ALK inhibition. The ALK inhibitor crizotinib was granted accelerated U.S. Food and Drug Administration approval based on phase 1 and phase 2 trials, both of which resulted in a response rate of ~60% and a long progression-free survival of ~10 months (Kwak et al., 2010). However, development of resistance to crizotinib is a major limiting factor.
Targeted Therapies in Cancer
The first report on clinically relevant acquired mechanisms of resistance described point mutations 4374G→A and 4493C→A, resulting in nonoverlapping C1156Y and L1196M mutations, respectively (Choi et al., 2010). Interestingly, L1196M corresponds to T790M in EGFR mutant NSCLC and T315I in the ABL oncogene, and represents the “gatekeeper” position. In each case, these amino acid changes lead to steric interference with inhibitor entry into the active site of the enzyme. Other clinically relevant mutations are listed in Table 4 and confer variable levels of resistance. S1206Y and G1202R (which is analogous to the G340W mutation in imatinibresistant CML) were first identified as conferring resistance in a random mutagenesis screen, likely because of their decreased binding affinity for crizotinib (Katayama et al., 2012). Aside from secondary mutations in the EML4-ALK kinase, less frequent mechanisms that contribute to the spectrum of crizotinib resistance include ALK amplification, c-KIT amplification, EGFR activation (Katayama et al., 2012; Sasaki et al., 2011), loss of the ALK fusion gene, and activating mutations of K-RAS (Doebele et al., 2012b). Despite the great diversity of ALK secondary mutations discovered thus far, only 30% of clinically resistant tumors have clearly defined mutations. The absence of mutations may imply inadequate crizotinib potency or unfavorable pharmacokinetics. Addressing this possibility, five next-generation ALK inhibitors are currently in phase I trials (LDK378, AP26113, CH5424802, ASP3026, and X-396) and have more potent inhibitory activity against the resistant enzyme and broad activity against EML4-ALK tumor cells with mutations in the catalytic pocket in culture (Sakamoto et al., 2011). The farthest advanced of these is LDK378, which achieved a remarkable objective response rate of 81% in 56 patients whose tumors were resistant to crizotinib (Shaw et al., 2012). CH5424802 has similar activity, albeit in fewer patients tested (n = 34) (Nishio et al., 2012). B. Failure to Induce Proapoptotic Signaling and Response to Targeted Therapy The circumvention of apoptosis by dysregulation of endogenous mechanisms is a hallmark of cancer. Essential to the group of proapoptotic regulators are Bcl2–like proteins. One member of this group, BIM, an activator of apoptosis, has been repeatedly implicated as playing an essential role in the induction of apoptosis by TKIs in both hematological and solid tumor cell lines (Kuroda et al., 2006; Cragg et al., 2007; Gong et al., 2007; Faber et al., 2011; Ng et al., 2012). Activation of the PI3K/AKT pathway results in inhibition of BIM. For reasons that are yet to be identified, human tumors with the same oncogenic driver express different levels of BIM at baseline and show a variable response of BIM levels to targeted treatment. Lower pretreatment levels of BIM are associated with worse
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response to TKIs, such as gefitinib in NSCLC, imatinib in CML, and trastuzumab in HER2-positive breast cancer, and confer intrinsic resistance to these therapies (Faber et al., 2011; Ng et al., 2012). Lower BIM mRNA levels in 24 NSCLC specimens derived from patients receiving gefitinib/erlotinib treatment were associated with worse progression-free survival compared with patients with higher BIM transcript levels. A common BIM deletion polymorphism that lacks the proapoptotic BCL-2–homology domain 3 was found to be associated with impaired ability to induce apoptosis in vitro and worse clinical outcomes in patients with NSCLC and CML when compared with patients with the BIM wild-type allele (Ng et al., 2012). This variability in apoptotic potential may contribute to variable resistance in malignancies with the same oncogenic driver. Interestingly, BIM levels were not predictive of response to cytotoxic chemotherapy in EGFR-mutant cancer cell lines. Further studies are required to determine whether BIM plays a role in acquired resistance to targeted therapy. C. Resistance to BRAF-Targeted Therapy 1. BRAF Mutations in Melanoma. Melanoma is an aggressive skin cancer with a yearly incidence of 180,000 cases worldwide. It causes 48,000 deaths a year. It is the second most common malignancy in patients aged ,40 years (Jemal et al., 2010). Treatment of patients with advanced melanoma has been ineffective until development of targeted therapies, including the monoclonal antibody ipilimumab, which inactivates the cytotoxic T lymphocyte–associated antigen 4 (Hodi et al., 2010; Robert et al., 2011), and vemurafenib (Flaherty et al., 2010, 2012), a selective, low-molecular-weight BRAF inhibitor. A second, highly promising set of antibodies targeting the PD-1/PDL-1 axis, which downregulates T cell autoimmunity, is early in development, but clearly active in melanoma and lesser autoimmune adverse effects observed with BRAF inhibitors (hypophysitis, thyroiditis) (Brahmer et al., 2010; Topalian et al., 2012). Among melanomas of advanced stage, 50% harbor an activating mutation of the gene encoding the serine-threonine protein kinase BRAF, most commonly due to V600E and V600K mutations (Davies et al., 2002). Treatment of patients with BRAFV600E positive advanced melanoma with vemurafenib led to an unparalleled ;80% antitumor response rate (Flaherty et al., 2010). BRAF is part of the RAS/RAF/MAP kinase (MAPK) pathway, which is activated through ligand binding to a TK receptor, such as EGFR and platelet-derived growth factor receptor (PDGFR) (Fig. 1). This binding results in interaction of transducer proteins with the RAS protein, ultimately leading to RAS cleavage, methylation, and activation through its translocation to the cell membrane. Downstream from RAS, three RAF isoforms
CRC
CRC
CML
CML CML Melanoma
Cetuximab
Panitumumab
Imatinib
Dasatinib Nilotinib Vemurafenib
K-RAS mutation (Lièvre et al., 2006; Bardelli and Siena, 2010)
K-RAS mutation (Lièvre et al., 2006; Bardelli and Siena, 2010) BRAFV600E (Loupakis et al., 2009)
K-RAS mutations (Pao et al., 2005) Low BIM expression and BIM polymorphism (Faber et al., 2011; Ng et al., 2012)
EGFR activation or mutation (Doebele et al., 2012b; Katayama et al., 2012) K-RAS mutation (Doebele et al., 2012b)
KIT amplification (Katayama et al., 2012)
MET amplification (Engelman et al., 2007b) (HGF induced) MET activation (Yano et al., 2008), CRKL amplification (Cheung et al., 2011) Loss of PTEN (Sos et al., 2009) BRAF (G469A and V600E) (Ohashi et al., 2012), PIK3CA (Sequist et al., 2011) HER2 amplification (Takezawa et al., 2012) Transformation to SCLC (Sequist et al., 2011)
Acquired Resistance Due to Bypass Tracts and Other Mechanism(s)
BRAF splicing variants (Poulikakos et al., 2011)
(M244V, L248V, G250E, Q252R/H, Y253F/H, E255K/V, D276G, F311L/I, T315I, F317L, M351T/V, E355G/D, F359V/I, L387F/M, H396R/P, T277A, P296H, V379I, A380T, F382L, S417Y, E459K/Q, F486S, M343T) (Shah et al., 2002; Soverini et al., 2006) Low BIM expression and BIM polymorphism (Faber et al., 2011; Ng et al., 2012) BCR-ABL, Kit, PDGFR T315I (Müller et al., 2009) BCR-ABL, Kit, PDGFR 315I (Müller et al., 2009) BRAF BRAF amplification (Shi et al., 2012)
Multiple (Shah et al., 2002; Soverini et al., 2006) ABL amplification (Gorre et al., 2001)
(continued )
MEK1P124L and MEK1C121S (Emery et al., 2009; Wagle et al., 2011) N-RAS Q61K/R (Nazarian et al., 2010) PDGFRB overexpression IGF-1 overexpression (Villanueva et al., 2010)
K-RAS mutations Expansion of pre-existing K-RAS clones (Diaz et al., 2012; Misale et al., 2012) HER2 amplification (Bertotti et al., 2011) K-RAS amplification K-RAS mutations Expansion of pre-existing K-RAS clones (Diaz et al., 2012; Misale et al., 2012) Low OA (White and Hughes, 2009; White et al., 2010)
ALK mutations (L1196M, L1152R, G1202R, G1296A, S1206Y) (Choi et al., 2010; Sasaki et al., 2011; Katayama et al., 2012) EGFR S492R (Montagut et al., 2012) K-RAS amplification
EML4-ALK amplification (Katayama et al., 2012) Loss of ALK (Doebele et al., 2012b)
D761Y (Balak et al., 2006) T854A (Bean et al., 2008)
(Shih et al., 2005) EGFR exon 20 mutations (Yasuda et al., 2012)
Acquired Resistance Due to Genetic Alteration of Target(s)
T790M (Kobayashi et al., 2005) L747S (Costa et al., 2007)
Primary Resistance
MET amplification (Turke et al., 2010) Primary T790M mutation (Maheswaran et al., 2008)
BCR-ABL, Kit, PDGFR Multiple
EGFR
EGFR
ALK-1
NSCLC
Crizotinib
Primary Target(s)
EGFR
Cancer
Gefitinib, erlotinib NSCLC
Drug
TABLE 4 Clinically validated mechanisms of resistance to targeted therapy
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GBM Bevacizumab
COT, Cot (cancer Osaka thyroid) oncogene; CRKL, V-Crk sarcoma virus CT10 oncogene homolog-like; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; OA, organic cation transporter-1 activity; SCLC, small-cell lung cancer.
Breast cancer HER2 Trastuzumab
VEGF
p95HER2 (Scaltriti et al., 2007) PTEN loss (Nagata et al., 2004) PIK3CA (H1047R, E542K, E545K) (Berns et al., 2007)
GIST
BCR-ABL, Kit, PDGFR PDGFRA D842V or D846V (Antonescu et al., 2005; Miselli et al., 2007; Liegl et al., 2008) KIT V654A (Heinrich et al., 2003b)
KIT amplification Loss of WT KIT allele (Miselli et al., 2007; Liegl et al., 2008) KIT Exon 11: L576P Exon 13: V654A Exon 14: T670l Exon 17: D816A/H/V, D820A/G/Y, N822H/K, Y823D Exon 18: A829P (Miselli et al., 2007; Liegl et al., 2008; Conca et al., 2009)
MET amplification (Jahangiri et al., 2013)
Alternative RAF activation (Dumaz et al., 2006; Poulikakos et al., 2010; Villanueva et al., 2010) COT overexpression (Johannessen et al., 2010) BRAF (Agaram et al., 2008) Imatinib
Primary Resistance Primary Target(s) Cancer Drug
TABLE 4—Continued
Acquired Resistance Due to Genetic Alteration of Target(s)
Acquired Resistance Due to Bypass Tracts and Other Mechanism(s)
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(ARAF, BRAF, and CRAF) form a family of serine/ threonine kinases. Upon RAS activation, RAF proteins are phosphorylated, dimerize, and phosphorylate the downstream proteins MEK and ERK1 or ERK2. The ERK proteins ultimately control multiple nuclear transcription factors and kinases that alter gene expression. 2. Mitogen-Activated Protein Kinase–Dependent Mechanisms of Acquired Resistance to BRAFInhibitors. Acquired resistance to vemurafenib develops within a median of 6 months. Sequencing of all BRAF exons in 16 patients with acquired vemurafenib resistance failed to show mutations of BRAF beyond the initial BRAFV600E mutation. There were no gatekeeper mutations (Nazarian et al., 2010). Unlike other malignancies, drug resistance in melanoma relies on mechanisms other than secondary mutations in the BRAF gene. Amplification of BRAF was found to be one mechanism of acquired resistance in four out of 20 patients who had an initial response to vemurafenib and subsequently relapsed on treatment (Shi et al., 2012) (Fig. 2). Alternative splicing of the BRAF message may account for other cases of resistance. Poulikakos et al. (2011) reported a 61-kDa splicing product of BRAFV600E in resistant cell lines, herein called p61BRAFV600E. This variant results from a deletion of exons 4–8 and lacks the RAS binding domain, which is critical for RASdependent BRAF activation. This truncated protein activates ERK independently from RAS (Poulikakos et al., 2011). Furthermore, p61BRAFV600E shows enhanced dimerization properties compared with full-length enzyme. This results in p61BRAFV600E dimerization and signaling at BRAF inhibitor concentrations that effectively inhibit BRAFV600E catalytic function, thus leading to resistance to vemurafenib. To investigate the clinical role of splicing variants as a mechanism of vemurafenib resistance, 19 patientderived specimens were analyzed. Five of 19 vemurafenibresistant tumors harbored BRAFV600E splicing variants. One patient had the truncated protein that was found in vitro (deletion of exons 4–8), and four patients had other splicing products. All products resulted in a protein that lacked the RAS binding domain, whereas the kinase domain that carries the BRAFV600E mutation in exon 15 remained intact. Pretreatment tumors from these 19 patients did not contain splicing variants of BRAF, nor did pretreatment tumors from 27 additional melanomas. These findings suggest that variant splicing may be a mechanism of acquired rather than primary resistance. In the same study, four of the 19 vemurafenibresistant patients had tumors with activating N-RAS mutations (Q61K and Q61R) that occurred mutually exclusive from BRAF splicing variants. N-RAS activation has been confirmed as a mechanism of resistance
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Fig. 1. Physiology of major transmembrane tyrosine-kinase receptors and associated intracellular pathways. Receptors are displayed as homodimers. Note that most of these receptors may form heterodimers to activate the same intracellular pathways. The blue background highlights intracellular tyrosine kinases of the PI3K/AKT pathway; the yellow background highlights the RAS/RAF/ERK pathway. There is cross-talk between both pathways on multiple levels, three of which are displayed, including RAF-dependent Src activation, MEK-dependent BIM activation, and RAS-dependent PI3K activation. COT, Cot (cancer Osaka thyroid) oncogene; CRKL, V-Crk sarcoma virus CT10 oncogene homolog-like.
in other patient specimens and in preclinical experiments (Nazarian et al., 2010; Poulikakos et al., 2011). The ability of N-RAS to maintain ERK activation despite BRAF inhibition may be explained by alternative RAS-dependent activation of wild-type A- and CRAF isoforms (Poulikakos et al., 2010). In vitro studies showed that wild-type A- and/or CRAF isoforms dimerize and maintain ERK phosphorylation despite concomitant inhibition of BRAF. In the presence of upstream activation of RAS oncoproteins, only simultaneous knockdown of all three isoforms prevents downstream activation of ERK in vitro (Dumaz et al., 2006; Hatzivassiliou et al., 2010; Heidorn et al., 2010; Poulikakos et al., 2010; Villanueva et al., 2010). A recent study also demonstrated the ability of ARAF to bind to BRAFV600E in vitro (Rebocho and Marais, 2013). Consistent with these observations, increased CRAF overexpression was validated as a clinically relevant resistance mechanism in an independent study in a patient specimen (Montagut et al., 2008). Further proof of the ability of RAS to signal through the inhibited BRAF comes from a study of the combination of a BRAF and a MEK inhibitor. Activated K-RAS in premalignant skin lesions leads to squamous cell carcinomas when patients receive vemurafenib, a side effect that is almost completely abolished by cotreatment with a MEK (downstream) inhibitor (Johannessen et al., 2010). Activating mutations of MEK1, downstream from B-RAF, may confer resistance to BRAF inhibitors. In preclinical studies, MEK1P124L and MEK1C121S mediated
resistance to monotherapy with BRAF or MEK inhibitors (Emery et al., 2009; Wagle et al., 2011). A C to T transition in MEK1 exon 3 at codon 124 encodes an activating proline-to-leucine substitution (MEK1P124L), and was identified in a patient with relapsed metastatic melanoma following AZD6244 (a MEK1 inhibitor) treatment. In a subsequent study, a cysteine-to-serine substitution at codon 121 (MEK1C121S) was confirmed in a vemurafenib-resistant patient specimen. BRAF-independent activation of MEK1 by COT [Cot (Cancer Osaka Thyroid) Oncogene] overexpression, which encodes for a MAPK downstream of BRAF, was also established as a clinically relevant resistance mechanism (Johannessen et al., 2010). 3. Mitogen-Activated Protein Kinase–Independent Mechanisms of Acquired Resistance to Inhibition of BRAFV600E in Melanoma. Other mechanisms of resistance that originate upstream of BRAF and bypass its blockade confer resistance to BRAF inhibition. These mechanisms include platelet-derived growth receptor b activation and insulin-like growth factor-1 receptor (IGF-1R)–mediated activation of AKT (Villanueva et al., 2010). Loss of PTEN function (Villanueva et al., 2010), an important inhibitor of the PI3K/AKT pathway, has also been identified in resistant tumors. In an effort to overcome resistance through mutations upstream from BRAF, dabrafenib, a BRAF inhibitor, was combined with trametinib, a MEK inhibitor. The combination has produced a longer duration of freedom from progression as well as an improved toxicity profile (fewer squamous-cell skin cancers) in the first
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Fig. 2. Mechanisms of BRAF-inhibitor resistance in BRAF-mutated melanoma. (A) Drug response with initial treatment with a BRAF inhibitor resulting in abrogated activation of MEK1. (B) MAPK pathway–dependent resistance mechanisms with intact MEK1 sensitivity to MEK inhibitors. These mechanisms include activating mutations of N-RAS, heterodimerization with WT RAF, homodimerization of overexpressed CRAF, BRAF amplification, and BRAF-splicing variants (p61kD) –dependent MEK1 phosphorylation. (C) MAPK pathway–dependent resistance through downstream activating mutations of MEK1 and alternative ERK activation through COT overexpression. (D) MAPK pathway–independent bypass mechanisms via the AKT pathway due to alternative growth factor receptor signaling or loss of PTEN inhibitory function.
reported combination trial in melanoma patients (Flaherty et al., 2012). This study highlights a promising strategy in overcoming resistance to single-agent treatment: combination of targeted therapies. Unlike other approaches, such as designing and developing nextgeneration TKIs with improved drug characteristics, the successful rationale combines drugs that target the same pathway on multiple levels and does this before mutations emerge clinically. 4. Resistance to BRAF Inhibitors in Colorectal Cancer. Although BRAF mutations in melanoma create marked sensitivity to vemurafenib, colorectal cancers (CRCs) with the same BRAF mutations are unresponsive to BRAF inhibition. In cell culture experiments, this insensitivity to BRAF inhibition was linked to a rapid feedback activation of EGFR, which in turn maintains a strong oncogenic signal in the presence of BRAF inhibition (Prahallad et al., 2012). Ectopic expression of EGFR in BRAF-mutant melanoma cells rendered these
cells resistant to BRAF inhibition, supporting the notion that EGFR expression in BRAF inhibitor–resistant tumors is responsible for resistance. Combined inhibition of EGFR with a monoclonal antibody (mAb) or an EGFR TKI and a BRAF inhibitor resulted in sensitivity in BRAFmutated CRC cells in experimental models (Corcoran et al., 2012). D. Resistance to Breakpoint Cluster Region–ABL1, KIT, and Platelet-Derived Growth Factor Receptor– Targeted Therapy 1. Breakpoint Cluster Region–ABL1 Mutations in Chronic Myeloid Leukemia. Targeted therapy was pioneered in the 1990s with the introduction of imatinib for the treatment of CML. CML is a myeloproliferative disorder that is characterized by the Philadelphia chromosome, created by a translocation t(9;22) (q34;q11), resulting in the fusion gene BCR-ABL1 with activation of the ABL kinase function. This gene lacks
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feedback regulation and results in uncontrolled cell proliferation. BCR-ABL1 is essential to the pathogenesis of CML and therefore became a major focus of initial efforts at targeted small-molecule drug development. First approved in 2001, the BCR-ABL1 inhibitor imatinib yielded response rates approaching 100% in its initial trials, and revolutionized the treatment of this disease (Druker et al., 2001). Despite the remarkable initial success of imatinib, resistance was recognized as a limiting factor, developing in about 2–3% of patients per year of observation (Baccarani et al., 2009). Early identification of resistance mechanisms has led to successful development of more potent and non–cross-resistant secondgeneration drugs (dasatinib, nilotinib, and bosutinib) and most recently the very promising third-generation TKI ponatinib. 2. Breakpoint Cluster Region-ABL1–Dependent Resistance Mechanisms in Chronic Myeloid Leukemia. The most common and best-characterized resistance mechanism to imatinib is attributable to mutations of the primary target gene BCR-ABL1. Overall, the appearance of resistance-associated BCR-ABL1 mutations correlates with the approaching onset of advanced disease state (accelerated or blast-phase CML) and worse clinical outcomes. More than 50 different resistance-associated mutations of BCR-ABL1 have been identified. They cause either conformational changes in the enzyme or disrupt contact points in the catalytic pocket of imatinib, thereby leading to insensitivity to the drug. The majority of these mutations hold the enzyme in an active conformation. Mutations can be found in pretreatment specimens and, under the pressure of drug exposure, emerge to become the major tumor population during treatment. Mutations of the P (phosphate-binding) loop of the kinase domain are associated with imatinib resistance (Shah et al., 2002). Imatinib is an ATP mimetic compound that only binds to the closed or inactive conformation of the enzyme. Mutations that hold the kinase domain in its active configuration result in suboptimal binding of the drug and loss of potent inhibition. In contrast to imatinib, second-generation TKIs, such as dasatinib or nilotinib, bind potently and inhibit the active enzyme conformation and overcome imatinib resistance due to P-loop mutations. The gatekeeper T135I mutation directly impairs binding of both imatinib and the second-generation inhibitors and leads to high-level resistance. A thirdgeneration TKI, ponatinib, was designed to bypass the T315I mutation and exhibits a high level of activity in patients refractory to imatinib, including those with T315I mutations (Cortes et al., 2012). Ponatinib is the first example of TKI targeted therapy that overcomes resistance mediated by the gatekeeper mutation, serves as a model for overcoming other gatekeeper mutant TKs, and has received accelerated approval for treatment of T315I-resistant CML.
Although target mutations are the most frequent findings in resistant CML, other mechanisms have been implicated, albeit less frequently. Amplification of BCR-ABL1 has been found in resistant CML cells, but is uncommon (Gorre et al., 2001). Transport of drug across the intestinal epithelial barrier may also influence response. The organic cation transporter 1 (OCT-1) is the major transmembrane channel responsible for influx transport of imatinib. Low OCT-1 activity, related to polymorphisms in the OCT-1 gene, has been associated with worse clinical outcomes and treatment resistance (White and Hughes, 2009; Bazeos et al., 2010). Dose escalation of imatinib from 400 to 600–800 mg/day converts 30% of poorly responding patients to a meaningful clinical response. One potential explanation for treatment success in these patients is achieving higher plasma and intracellular drug levels due to low activity of transporters, such as OCT-1 (White et al., 2010). Switching to a secondgeneration TKI is an alternative option in patients with low OCT-1 activity, since neither dasatinib nor nilotinib transport depends on OCT-1 (Hiwase et al., 2008). Resistance to second-generation TKIs, such as dasatinib and nilotinib, is mechanistically similar to that of imatinib. In addition to T315I, other mutations (F317L, and particular P-loop mutations such as E255K/V or Q252H) also confer resistance to dasatinib and nilotinib (Müller et al., 2009). At this point, ponatinib resistance has not been clearly characterized. 3. Resistance to KIT/Platelet-Derived Growth Factor Receptor a–Targeted Therapy in Gastrointestinal Stromal Tumor. In addition to its activity against BCR-ABL1, imatinib is highly active against c-KIT and the structurally related plateletderived growth factor receptor a (PDGFRA) kinase, either of which may act as an oncogenic driver in the pathogenesis of GISTs. Virtually all GISTs expresses c-KIT, 80% with an activating c-KIT mutation, 5–10% have an activating PDGFRA mutation, and only 10– 15% lack mutations in either KIT or PDGFRA (Heinrich et al., 2003a; Debiec-Rychter et al., 2006). Imatinib produced a 50%–75% objective response rate in its early clinical trials (van Oosterom et al., 2001; Demetri et al., 2002; Blanke et al., 2008). The degree of responsiveness to imatinib varies depending upon the underlying mutation. The best clinical responses are found in patients with exon 11 mutations. These mutations are associated with dysregulation of the autoinhibitory region of c-KIT, resulting in a hyperactive kinase, which is effectively inhibited by imatinib (Heinrich et al., 2003b). 4. Primary Imatinib Resistance in Gastrointestinal Stromal Tumor. Primary resistance to imatinib (progression within 6 months of treatment initiation) occurs in 10–15% of patients and is associated with emergence of tumors with acquired mutations in the
Targeted Therapies in Cancer
catalytic domain of c-KIT or PDGFRA (Demetri et al., 2002; Verweij et al., 2004). Primary resistance mutations of c-KIT are most frequently found in exon 9 (Heinrich et al., 2003b) (Fig. 3). The most common PDGFRA mutations that underlie primary imatinib resistance are D842V and, less frequently, D846V (Antonescu et al., 2005; Miselli et al., 2007; Liegl et al., 2008). 5. Secondary Imatinib Resistance in Gastrointestinal Stromal Tumor and Response to NextGeneration Tyrosine-Kinase Inhibitors. Acquired resistance to imatinib in GISTs occurs after a median of 2 years of treatment and most frequently due to a second c-KIT mutation in tumors that carry a primary exon 11 mutation. Secondary mutations mostly involve exons 17, 13, and, less frequently, 14. Some of these mutations, such as V654A, cause intrinsic resistance to imatinib when introduced into wild-type protein. Other mutations, such as N822K, are associated with greater sensitivity to imatinib when occurring alone, but in combination with an underlying exon 11 mutation confer imatinib resistance, possibly due to combined structural changes in the protein (Heinrich et al., 2006). It remains unclear why exon 9 mutations confer primary imatinib resistance. Understanding resistance is further
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complicated by the genetic inter- and intraindividual heterogeneity of this disease, the interplay of different mutations, and the resulting dysregulation of the oncoprotein (Antonescu et al., 2005; Wardelmann et al., 2005). 6. Resistance to Sunitinib in Gastrointestinal Stromal Tumor. Sunitinib is the agent of choice in patients with imatinib-resistant GISTs. In addition to its inhibition of KIT and PDGFRA, sunitinib inhibits VEGF receptors (VEGFRs) 1–3, FLT3 (Fms-related tyrosine kinase 3) and RET (Ret proto-oncogene), all of which have well defined roles in carcinogenesis. Similar to imatinib, sunitinib competes with ATP for binding to the kinase domain of KIT and PDGFRA. Its ability to block tumor growth through VEGFR inhibition may also contribute to its antitumor activity (Demetri et al., 2006; Heinrich et al., 2008; George et al., 2009). Tumors with primary (preimatinib) exon 9 mutations that developed imatinib resistance were more responsive to sunitinib than those with primary exon 11 mutation, and had improved PFS and OS on sunitinib, as compared with the exon 11–mutated tumors. Furthermore, tumors with secondary exon 13 or 14 mutations had better outcomes on sunitinib compared with those with secondary exon 17– or 18–mutated GISTs (Prenen et al., 2006; Heinrich et al., 2008). These findings
Fig. 3. Exon sequence of exons 9–18 of the c-KIT gene. The table denotes primary mutations of the c-KIT and PDGFR genes with associated frequency in GISTs. The associated clinical response rate to imatinib is given for each exon. Frequency and location of secondary mutations of the c-KIT and PDGFR gene are given, and associated treatment response to second-line treatment (i.e., sunitinib) are shown for each exon. Figure references: Demetri et al., 2006, 2013; Dewaele et al., 2008; Nishida et al., 2008; Schöffski et al., 2010; Benjamin et al., 2011; Reichardt and Montemurro, 2011; Sawaki et al., 2011; Montemurro et al., 2013. JM, juxtamembrane domain; CB, clinical benefit.
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differ from the genetic patterns that underlie imatinib responsiveness, and may suggest the possible importance of the ability of sunitinib to inhibit multiple pathways and to inhibit KIT kinase associated with the gatekeeper mutation T670I (Guo et al., 2007). Resistance to sunitinib develops after a median of 12 months. The mechanisms are poorly understood (Demetri et al., 2006). Recently, the novel multikinase inhibitor regorafenib was approved for patients whose tumors progress on imatinib and sunitinib. Regorafenib produced a median PFS of 4.8 months compared with approximately 1 month in the placebo group (Demetri et al., 2013). E. Resistance to Mammalian Target of Rapamycin Inhibitors The serine/threonine kinase mammalian target of rapamycin (mTOR) controls cell survival, proliferation, and intermediary metabolism in both normal and malignant cell types. It is positioned at a central point in the PI3K/AKT pathway, receiving upstream signals from a number of cell-surface TK receptors such as the IGF-1R and insulin receptor, as well as cross-talk from adjacent pathways (Fig. 4). mTOR participates in two multiprotein complexes, mTORC1 and mTORC2, each of which has unique components and which carry out different biochemical
functions. mTORC1 activates protein synthesis (and proliferation) via activation of S6K1 (P70 S6 kinase, alpha) and by inhibition of 4E-BP1 (eukaryotic translation initiation factor 4E-binding protein 1), a translation repressor. mTORC2 activates PI3K as well as other downstream targets. PI3K phosphorylation leads to activation of mTORC1 and to cell proliferation, and its stimulation by growth factor receptors may overcome inhibition by selective inhibitors of the mTORC1 complex. The PI3K/AKT pathway is activated by mutations at any one of several sites (PI3K, AKT) in at least 50% of human tumors (Rodon et al., 2013). Alternatively, the pathway may be activated by loss of function or deletion of the PI3K antagonist PTEN, which dephosphorylates phosphoinositol triphosphate, or by loss of function of tuberous sclerosis complex 1, a negative regulator of mTOR. Specific pathway-activating mutations of mTOR pathway components (PI3K, AKT, PTEN, and S6K1) are found in subsets of many epithelial cancers, including endometrial, pancreatic, neuroendocrine, colon, lung, and breast cancers, and may occur in conjunction with other mutations. However, no clear relationship between specific pathway mutations, or PTEN loss, and response to mTOR inhibition has been established in clinical trials.
Fig. 4. (A) Physiological PI3K/AKT/mTOR pathway and inhibition by mTORi. (B) Mechanisms of resistance to mTOR inhibitors (refer to text for explanation). FKBP12, FK506-binding protein 1A, 12kDa; GBL, mTOR-associated protein, LST8 homolog (S. cerevisiae); PDK1, 3-phosphoinositidedependent protein kinase 1; PRR5, proline rich 5 (renal); Sin1, mitogen-activated protein kinase-associated protein 1. TSC, tuberous sclerosis complex.
Targeted Therapies in Cancer
Two allosteric mTOR inhibitors, everolimus and temsirolimus, are currently approved for cancer indications. Both drugs are useful for renal cell cancer treatment, whereas everolimus has additional activity against pancreatic neuroendocrine tumors, breast cancer, and astrocytoma. Both agents are relatively selective inhibitors of mTORC1 activity, sparing mTORC2. They bind to FKB12, and the complex then binds to and inhibits mTORC1. A number of mechanisms of resistance to mTORC1 complex inhibition have been identified in preclinical studies, and one prominent mechanism, compensatory AKT activation, has been verified in studies of human tumors during treatment. Selective mTORC1 inhibition activates multiple feedback loops, leading to activation of receptor tyrosine kinases and phosphorylation/ activation of AKT at Thr308 (via PI3K) and Ser473 (via mTORC2). These changes tend to override mTORC1 inhibition. In clinical specimens from different malignancies, including breast cancer, cervical cancer, leukemia, and lymphoma, increased AKT activity correlated with poor response to mTOR inhibitors (Carracedo et al., 2008; Gupta et al., 2009; Ihle et al., 2009; Janes et al., 2010; Janku et al., 2012). On the other hand, constitutive PI3K activation, due to activating PI3K mutations or due to loss of PTEN, has been proposed as a marker for sensitivity to mTOR inhibition in melanoma and glioblastoma multiforme (Galanis et al., 2005; Margolin et al., 2005). In a phase I trial of 78 patients with refractory metastatic CRC treated with a combined PI3K/AKT/mTOR inhibitor, 18 (23%) responded (partial response, complete response, or stable disease .6 months). Activation of alternative pathways may contribute to resistance to mTOR inhibition. Mutations of either K-RAS or BRAF were associated with a worse survival in this analysis, indicating that activation of alternative pathways may contribute to resistance to inhibitors of mTOR. Consistent with this observation, patients with metastatic colorectal cancer with PI3K and concomitant K-RAS mutation seem to have a lower response rate to mTOR inhibition (Garrido-Laguna et al., 2012). Other mutations that modify mTOR activity or cell death responses may influence the efficacy of mTOR inhibitors. In metastatic bladder cancer patients, loss of function mutation in tuberous sclerosis complex 1, an mTOR regulatory protein, was identified in 8% of 109 patients and was associated with sensitivity to everolimus (Iyer et al., 2012). Preclinical experiments have implicated other resistance mechanisms, as yet not validated in clinical studies. These alternative mechanisms include hyperactivity of PIM [Pim oncogene (proviral integration site)] kinases as found in hematopoietic cells (Hammerman et al., 2005), pyruvate dehydrogenase kinase 1– dependent myelocytomatosis phosphorylation (Liu
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et al., 2011), overexpression of the mTORC1 substrate eukaryotic translation initiation factor 4E (Dilling et al., 2002),imbalance of pro- and antiapoptotic proteins [BIM and BCL-2 or BLC-2 homologous proteins (inhibitor of apoptosis protein, IAPs)] (Gyrd-Hansen and Meier, 2010; Mahalingam et al., 2010), and mutation of FKBP-12 or the FKB domain of mTOR (Feldman et al., 2009). Strategies to overcome resistance to mTOR inhibition have reached the stage of clinical development. Novel inhibitors that block both mTORC complexes (1 and 2) have entered clinical trials, as have single agents with combined mTORC1 and PI3K inhibition. Results are thus far inconclusive. Combinations of a drug that inhibits mTOR and a second agent that blocks upstream kinases (AKT or PI3K) or receptors (IGFR) are also under investigation. There are clear opportunities to expand the clinical application of the mTOR inhibitor class of drugs. Of great interest is the finding that activation of the PI3K pathway may underlie resistance to hormonal therapy and to inhibitors of cell-surface receptors such as HER2. One successful trial has shown that everolimus significantly enhances the response to second-line antiestrogen therapy in breast cancer (Baselga et al., 2012a). F. Resistance to Monoclonal Antibody Therapies 1. Drugs Targeting Epidermal Growth Factor Receptor in Colorectal Cancer. Colorectal cancer remains the third most common cancer worldwide, and nearly half of newly diagnosed patients have metastatic disease that is associated with a poor median overall survival of 18–21 months (Ferlay et al., 2007; Jemal et al., 2010). In refractory metastatic CRC (mCRC), two monoclonal antibodies directed against EGFR, cetuximab and panitumumab, were found to be effective when combined with conventional chemotherapy or used as monotherapy (Cunningham et al., 2004; Saltz et al., 2004; Chung et al., 2005). In contrast to NSCLC, somatic mutations of the EGFR gene in CRC are exceedingly rare and do not explain the sensitivity of CRCs to these antibodies (Cunningham et al., 2004; Chung et al., 2005). Modestly increased EGFR copy number (3- to 5-fold) correlates with improved response to cetuximab and panitumumab. However, the increased gene dose does not result in increased expression of EGFR, and, for reasons that are unclear, increased EGFR expression does not correlate with response to these antibodies (Moroni et al., 2005). Expression of other biomarkers, such as amphiregulin and epiregulin, may be more useful in predicting response to monoclonal antibodies directed against EGFR (Moroni et al., 2005; Khambata-Ford et al., 2007). 2. Primary Resistance to Monoclonal Antibodies against Epidermal Growth Factor Receptor. Only 10–20% of patients with mCRC respond to EGFR-mAb monotherapy or combination therapy with chemotherapy
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(Cunningham et al., 2004; Saltz et al., 2004; Chung et al., 2005). Intrinsic or primary resistance, therefore, is a major limitation of the use of mAbs directed against EGFR. Mutations of K-RAS have been identified as strong negative predictive markers and may explain resistance in about 40% of the treatment-resistant population (Linardou et al., 2008). This observation was initially made in retrospective studies (Lièvre et al., 2006) and later confirmed in several prospective trials (Bardelli and Siena, 2010). This finding resulted in limiting the use of cetuximab and panitumumab to only K-RAS wild-type tumors. A retrospective study of patients with K-RAS G13D (n = 32) treated with cetuximab alone or in combination with chemotherapy found that these patients had a higher response rate (9.1 vs. 1%) and a longer PFS (4.0 vs. 1.9 months) and OS (7.6 vs. 5.7 months) compared with patients with other K-RAS mutations. The authors concluded that, despite the presence of a K-RAS mutation, these patients should receive anti-EGFR–targeted treatment (De Roock et al., 2010). However, this observation contradicts results from two prospective trials (Andreyev et al., 2001; Roth et al., 2010) and needs further investigation. A second important oncogenic driver of resistance to EGFR is mutated BRAF (V600E being the most common), which is found mutated in 5–15% of CRC patients. This mutation in CRC is mutually exclusive from K-RAS mutations (Di Nicolantonio et al., 2008; Loupakis et al., 2009; Safaee Ardekani et al., 2012). Together, mutations in the K-RAS and BRAF pathways account for ;50% of primary resistance to EGFRmAb therapy. Other mutated drivers that may impair responsiveness to EGFR-targeted therapy in CRC include PTEN and PI3K, although data are conflicting and the association with resistance is not as strong as for K-RAS or BRAF mutations (Jhawer et al., 2008; Perrone et al., 2009; Prenen et al., 2009). PI3K mutations, with or without concomitant loss of PTEN, occur in ;15% of resistant tumors. Although mutations of K-RAS and BRAF are mutually exclusive, they can each occur in conjunction with either PTEN or PI3K mutations. These combined mutations of BRAF or K-RAS with mutations in the PI3K pathway account for 5–10% of all resistance mutations (Bardelli and Siena, 2010). 3. Secondary Resistance to Epidermal Growth Factor Receptor Monoclonal Antibody. Although patients who respond to cetuximab or panitumumab may show a dramatic regression of their disease, tumor recurs in 9–18 months (Cunningham et al., 2004; Diaz et al., 2012; Misale et al., 2012). In contrast to the extensive clinical evidence for drivers of primary resistance, little was known about mechanisms of secondary resistance to EGFR-mAb in colorectal cancer until recent studies shed some light on this important issue (Bertotti et al., 2011; Diaz et al., 2012;
Misale et al., 2012; Montagut et al., 2012). Montagut et al. (2012) first identified a missense mutation in the extracellular domain of EGFR. This mutation involves a substitution of serine to arginine at amino acid 492 (S492R). In 2 of 10 patients with CRC who developed resistance to cetuximab, biopsies postcetuximab treatment carried this mutation, whereas 156 specimens from treatment-naïve patients were free of this mutation. Other mechanisms of secondary resistance may involve K-RAS. These include 1) expansion of a pre-existing K-RAS mutant clone, 2) de novo K-RAS mutations in tumors that were K-RAS wild type prior to treatment, and 3) amplification of K-RAS post-treatment. In the most extensive clinical study, investigators found new K-RAS mutations post-treatment in 6 of 10 patients who, pre-treatment, had K-RAS wild-type disease (Misale et al., 2012). Four of the 6 patients had tumors harboring the point mutation G13D, 1 patient had a Q61H mutation, and 1 patient developed a combined mutation (G12D and G13D) in post-treatment samples. A seventh patient had K-RAS amplification. Furthermore, by analyzing circulating tumor DNA, it was possible to detect mutations in K-RAS in another group months prior to radiographic recurrence (Diaz et al., 2012). These investigators took monthly serum samples from 24 patients with K-RAS wild-type disease during panitumumab treatment and found that 9 patients had K-RAS mutations, all on exon 12. Using a mathematical model that incorporates the initial tumor burden, doubling time, and circulating tumor DNA levels of post-treatment K-RAS-mutant patients, the authors predicted that a population of K-RAS-mutant cells must have been present prior to treatment. Using an elegant method that involves transplantation of patient-derived tumors (metastasis) of patients treated with cetuximab, Bertotti and colleagues (2011) identified amplification of HER2 as a resistance mechanism independent from K-RAS mutation status. Patient-derived tumors with this resistance mechanism treated with a combination of lapatinib and cetuximab or pertuzumab had long-lasting response compared with monotherapy with either drug in the same patient-derived tumor, indicating that combination therapy may provide clinical benefit (Bertotti et al., 2011). 4. Resistance to Human Epidermal Growth Factor Receptor 2–Targeted Therapy in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer. Approximately 25% of invasive breast cancers have amplified HER2. This finding is associated with aggressive clinical behavior, chemotherapy resistance, and a worse clinical outcome than HER2-negative tumors. HER2 is a member of the EGFR family, but lacks intrinsic ligand-induced signaling. Its signaling requires formation of heterodimers with any of the
Targeted Therapies in Cancer
other three ligand binding members of the EGFR(-like) receptor family (HER1, 3, or 4). The HER2 heterodimers activate intracellular pathways (MAP kinase and PI3K/AKT), resulting in cancer cell survival and proliferation. The HER2/HER3 dimer strongly phosphorylates and activates PI3K. Trastuzumab, a humanized recombinant monoclonal antibody, targets the extracellular domain of the HER2 protein, and significantly inhibits growth of HER2-positive breast cancer (Slamon et al., 2001; Romond et al., 2005). Although most HER2-positive patients have no response to treatment with trastuzumab as a single agent, the drug significantly enhances effectiveness of taxanes and other chemotherapy in both the adjuvant setting and in the treatment of metastatic disease. Virtually all patients with metastatic disease will develop resistance. 5. Primary Resistance to Trastuzumab. Approximately 75% of patients with HER2-positive breast cancer do not respond to trastuzumab. However, the clinical endpoint of primary resistance to trastuzumab monotherapy is difficult to recognize in the clinical setting, since a significant portion of patients respond to treatment with trastuzumab when given with cytotoxic therapy. The latter is indicated by the major benefit of trastuzumab in combination with cytotoxic therapy in metastatic and adjuvant therapy, settings in which it produces a doubling of response rates and prolonged disease-free survival. The biological effect of trastuzumab may be due to slowing tumor growth and sensitizing the cells to DNA damage by cytotoxic chemotherapy. Even with patients who progress on trastuzumab, the drug is usually continued for the life of the patient as clinical studies have defined benefit (slower tumor growth) in this setting. A minor subgroup of HER2-positive breast cancers express a truncated 95–100 kDa receptor, p95HER2, which lacks the ectodomain of the full-length protein. Indeed, in some tumors, these fragments can be the predominant form of HER2 (Molina et al., 2002). p95HER fragments have preserved kinase activity and are associated with an aggressive trastuzumab-resistant course (Sáez et al., 2006; Scaltriti et al., 2007). The lack of response to trastuzumab in these tumors is likely due to absence of a critical portion of the extracellular domain of HER2, the primary target of trastuzumab. 6. Secondary Resistance to Trastuzumab. With the knowledge that HER2 signals as a dimer through the PI3K pathway, it was logical to examine activation of the latter pathway as a cause of resistance. Attention has focused on PTEN (Nagata et al., 2004), which inactivates PI3K function. Reduced expression or loss of PTEN in 47 HER2-positive tumors in patients treated with trastuzumab plus taxane (paclitaxel or docetaxel) correlated with a worse response compared with the outcome in patients with PTENpositive tumors. In another group of patients with
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HER2-negative tumors (n = 37), levels of PTEN expression did not influence outcome of taxane-based therapy. These results are limited by the lack of sequential biopsy data showing a loss of PTEN expression as tumors become resistant during treatment, but overall, the study suggests that a lack of PTEN expression results in increased trastuzumab resistance, presumably via release of PI3K/AKT signaling. Inhibition of PI3K inhibits cells depleted of PTEN in vitro, supporting this idea. Furthermore, mutations of PI3K have been found in tumors resistant to trastuzumab (Berns et al., 2007). Alternative TK receptor signaling may also contribute to resistance to trastuzumab. Trastuzumab lacks activity against other EGFR family growth factor receptors, such as EGFR(HER1) and HER3. Homodimerization (EGFR/EGFR) or heterodimerization (EGFR/ HER3) of these alternative receptors, with subsequent downstream activation of the PI3K/AKT pathway, has been demonstrated in cells exposed to trastuzumab and may contribute to resistance (Motoyama et al., 2002). Additional studies in the preclinical setting implicate increased levels of IGF-1R and its ability to build heterodimers with HER2, despite treatment with trastuzumab (Lu et al., 2001; Nahta et al., 2005). The clinical role of IGF-1R in trastuzumab-resistant HER2positive breast cancer is uncertain. Although some studies failed to show a significant correlation of IGF-1R expression with trastuzumab response (Smith et al., 2004; Köstler et al., 2006), others indicate that IGF-1R expression is associated with poor clinical outcomes, particularly when associated with concomitant activation of downstream effectors such as mTOR (Harris et al., 2007; Gallardo et al., 2012; Yerushalmi et al., 2012). Finally, MET was found to be overexpressed in HER2 breast cancer cell lines treated with trastuzumab. MET expression led to decreased treatment response, and MET short hairpin RNA interference was able to restore sensitivity to trastuzumab (Shattuck et al., 2008). Further potential mechanisms have been suggested, but not clinically validated (Nahta and Esteva, 2006). Newer anti-HER2 antibodies, which differ in their mechanism of cell killing and which may overcome resistance, have been approved for clinical use. Pertuzumab prevents HER2/HER3 dimerization and enhances trastuzumab activity when the two antibodies are given in combination (Baselga et al., 2012b). Herceptin emtansine is a covalent conjugate of the antibody with a maytansine derivative. It delivers a potent cytotoxin through its binding to the HER2 receptor, as the antibody-toxin conjugate is internalized and the toxin is released intracellularly in lysosomes. It retains activity in patients resistant to trastuzumab (Baselga et al., 2010). The mechanisms of resistance to these newer products are unknown.
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G. Resistance to Anti-CD20 Antibodies Two anti-CD20 antibodies, rituximab (1997) and ofatumumab (2011), have been approved for treatment of lymphoid tumors (see Table 1). They engage different epitopes on CD20, differ in their level of activation of complement-dependent cytotoxicity, and are at least partially non–cross-resistant clinically, ofatumumab having clinical activity in rituximab refractory follicular lymphoma (Czuczman et al., 2012). Rituximab is extensively used with chemotherapy for treatment of chronic lymphocytic leukemia, follicular lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, and has additional indications for a variety of autoimmune disorders. It has multiple potential mechanisms of antitumor activity (Alduaij and Illidge, 2011; Rezvani and Maloney, 2011). Its engagement of CD20 leads to complement fixation through the antibody’s Fc arm, which binds to the C1q component of complement, mediating complement-dependent cytotoxicity (CDC) of the lymphoma cell and normal B cells. Rapid depletion of complement follows infusion of rituximab, perhaps the byproduct of complement fixation accompanying infusion reactions (fever, chills, rash, urticaria). The same Fc arm can bind to the Fc gamma receptor of macrophages, activating antibody-dependent cellular cytotoxicity (ADCC). Engagement of CD20 by antibody may cause a nonapoptotic cell death in its own right. Finally, the anti-CD20 antibodies may promote dendritic cell appreciation of B cell antigens and lead to adoptive cellular immunity. Of these mechanisms, ADCC seems most important for rituximab, whereas ofatumumab may have stronger CDC activity (Teeling et al., 2006). Resistance to rituximab is incompletely understood (Rezvani and Maloney, 2011). Animal models suggest that the predominant mechanism of cytotoxicity is ADCC, but clinical studies are inconclusive, and its efficacy may depend heavily on the interaction of rituximab with cells exposed simultaneously to chemotherapy. The level of expression of CD20, which is highest in follicular lymphoma and lowest in chronic lymphocytic leukemia (CLL), influences the response to monotherapy. Loss of CD20 expression, either through internalization of the complex or “shaving” of the complex by macrophages, has been implicated in resistant clinical tumors. Specific polymorphisms of the Fcg RIIIa (the valine/valine variant at position 158) and the Rcg RIIa receptors with higher affinity for IgG antibodies confer a better therapeutic response to rituximab in patients with follicular lymphoma (Weng and Levy, 2003), but this has not been a consistent finding in CLL (Rezvani and Maloney, 2011). In CLL, CDC may play a more important role, as resistant cells may express high levels of inhibitors of complement fixation (CD55 and CD59). Pharmacokinetic factors may play a role in resistance. Higher sustained levels of rituximab and slower
clearance are associated with response, as is a low tumor burden. A large tumor burden leads to depletion of antibody during monotherapy with rituximab, although the efficacy of rituximab in combination with chemotherapy is less affected by tumor burden. There has been no prospective study of individualizing dose or schedule of either rituximab or ofatumumab to adjust to interindividual differences in pharmacokinetics and drug exposure. H. Resistance to AntiAngiogenic Drugs Angiogenesis and the formation of an extensive vasculature bed are required for growth of solid malignancies beyond a few millimeters in size. The construction of a vascular network for tumors requires proliferation of vascular endothelial cells (ECs) and the recruitment of supporting pericytes, a process known as the angiogenic switch (Folkman, 1971). A number of growth factors are responsible for the early differentiation of mesodermal precursor cells to ECs and for their sprouting. These factors include the VEGF, which interacts with three receptor isoforms (VEGFRs 1–3). Of these VEGFRs, VEGFR2 (or kinase insert domain receptor) has been the most consistent target of successfully developed agents. Other factors, including matrix metalloproteinases, PDGF-b, its receptor PDGFR-b, transforming growth factor b, and angiopoietins with their tie-1 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 1) receptor, facilitate vascular invasion of extracellular matrix, induce pericyte recruitment, stabilize new vessels, and promote tumor angiogenesis (Risau, 1997). Gene expression of PDGF-b and VEGF is regulated by the hypoxiainducible factor a (HIF-a). Multiple stimuli and signaling pathways activate HIF, including local hypoxia, mTORC1 activation, and loss of the tumor suppressor Von Hippel– Lindau, and all of these factors activate transcription of proangiogenic genes. There are three clinically successful approaches to antiangiogenic therapy for cancer: 1) antibody-mediated binding of VEGF by bevacizumab; 2) ziv-aflibercept, a humanized chimeric protein that contains the extracellular domains of VEGFR1 and VEGFR2 and acts as a decoy receptor; and 3) small molecules that directly inhibit VEGFR(s) and PDGFR-b signaling (sunitinib, sorafenib, axitinib, pazopanib, and vandetanib). Antiangiogenic drugs are approved as single agents for various solid tumors, including renal cell carcinoma (RCC), sarcomas, GIST, PNET, HCC, glioblastoma multiforme (GBM), and medullary thyroid carcinoma. They are further approved for use in combination with cytotoxic chemotherapy for colorectal cancer, NSCLC, and ovarian cancer. The benefits of sunitinib against GIST and vandetanib against medullary thyroid carcinoma are likely related to off-target inhibition of c-KIT and RET, respectively.
Targeted Therapies in Cancer
Unlike resistance to treatment directed against other targets, such as BCR-ABL, KIT, and EGFR, resistance to antiangiogenic therapy does not rely on mutation of the target cell-surface TK (VEGFR), which is situated on normal endothelial cells. The mechanism is poorly understood, but likely to be rather complex, perhaps transient, and even reversible, as evidenced by recent studies. Mice bearing RCC xenografts were exposed to sorafenib until resistance developed, while a second group did not receive any treatment (untreated group). Resistant tumors were then transplanted into naïve mice, followed by a treatment break from sorafenib. The gene expression profiles of reimplanted tumors, after a treatment break, were very similar to the profiles of untreated tumors, but were distinct from profiles of tumors examined at the height of resistance. Accordingly, reimplanted tumors responded when re-exposed to sorafenib (Zhang et al., 2011). Translating this observation into clinic, one could hypothesize that continued administration or readministration of antiangiogenic agents, even in the case of prior development of resistance, may be beneficial. In the clinic, reversible/transient resistance was observed in a small study that included patients with RCC who progressed on sunitinib treatment. There is anecdotal evidence that readministration of sunitinib after tumor progression may be beneficial. Two of five patients with metastatic RCC relapsed at the site of prior metastasis 3 and 8 months after sunitinib discontinuation, respectively. Readministration of sunitinib resulted in major responses in both patients (Johannsen et al., 2009). Similar responses were observed in 5 of 23 patients with RCC who had previously progressed on sunitinib and were rechallenged, after a treatment break, with the same agent (Zama et al., 2010). Tumors thought to be resistant to one anti-VEGF(R) therapy appear to remain dependent on VEGF signaling. This was further evidenced by objective response in clinical trials of patients with RCC undergoing sequential antiangiogenic therapy with sunitinib and axitinib after disease progression on bevacizumabbased therapy and sorafenib, respectively (Rini et al., 2008, 2009). A similar observation was made in patients with mCRC who progressed on a bevacizumabbased regimen. Continued inclusion of bevacizumab plus chemotherapy produced improved survival when compared with chemotherapy alone (Bennouna et al., 2013). Overall, data on specific mechanisms of resistance to antiangiogenic treatment are mostly limited to preclinical observations. Clinical evidence is scarce and fragmented. Research on mechanisms of resistance to antiangiogenesis has focused on two factors: 1) VEGFsignaling pathways and 2) VEGF-independent restoration of angiogenesis. Experimentally, blockade of VEGF signaling leads to a drastic decrease in blood flow to the tumor, but
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reperfusion of the tumor occurs months after treatment and corresponds to tumor regrowth (Schor-Bardach et al., 2009). Cessation of blood flow results in hypoxia and necrosis of tumor tissue. A potential resistance mechanism in this setting could be hypoxia-induced HIF upregulation and target gene transcription, including VEGF and other proangiogenic factors, ultimately resulting in revascularization and reperfusion of tumor tissue. Additionally, tumor cells that are more resistant to hypoxia could be selected to grow in this constricted microenvironment. In fact, it has been hypothesized that disintegration of the primary tumor by VEGF blockade may lead to selection of more invasive, hypoxia-resistant tumor cells that have increased potential to invade and metastasize (Ebos et al., 2009; Pàez-Ribes et al., 2009). Evidence for MET as an important hypoxia-induced factor was proposed in clinical specimens from 22 GBM patients with disease recurrence on bevacizumab treatment. In a xenograft model with bevacizumabresistant GBMs, increased MET expression and phosphorylation of its downstream targets were associated with the development of anti-VEGF therapy resistance. Treatment with the MET inhibitor XL184 led to tumor shrinkage and prolonged survival of mice with bevacizumab-resistant GBM, and short hairpin RNA– mediated blockade of MET-abrogated resistance to bevacizumab (Jahangiri et al., 2013). In addition, the same study also found compensatory upregulation of VEGF, VEGFR, and basic fibroblast growth factor (FGF) in resistant GBMs, indicating that angiogenesis continues to be, at least in part, dependent on VEGF signaling. Thus, relative underdosing of antiangiogenic therapy at that particular state of disease development may be an additional factor that is currently not recognized due to lack of clinical specimens from resistant tumors. Increased expression of alternate proangiogenic factors and endothelial receptors is able to promote angiogenesis independent of VEGF signaling. These angiogenic factors include FGF-1 and FGF-2, ephrinA1 and -A2, and angiopoietin-1 in pancreatic island cells (Casanovas et al., 2005); FGF-2 and stem cell– derived factor-1 in GBM (Batchelor et al., 2007); placental growth factor (PlGF) in various tumor cells (Fischer et al., 2007); interleukin-8 in colon cancer cells (Mizukami et al., 2005); PDGF-C (Crawford et al., 2009); and PlGF, basic FGF, and HGF from sera of patients with colon cancer recurrent on a bevacizumabbased treatment regimen (Kopetz et al., 2010). Notably, some proangiogenic factors, including PlGF, osteopontin, and granulocyte colony-stimulating factor are induced by sunitinib in a manner independent of tumor type (Ebos et al., 2007). Furthermore, various circulating host cells and cells of the tumor microenvironment have been implicated in angiogenesis of resistant tumors. These include bone
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marrow–derived cells, such as CD11b+/Gr1+ myeloid suppressor-type cells activated through granulocyte colony-stimulating factor and Bv8–dependent mechanisms, and endothelial TEK tyrosine kinase (Tie2)– expressing monocytes via angiopoieten-2–dependent signaling, tumor-associated macrophages, circulating endothelial precursors, and circulating ECs and tumor fibroblasts (Lewis et al., 2007; Shojaei et al., 2007, 2009; Ferrara, 2010). These cells may be recruited to the tumor microenvironment and contribute to VEGFindependent angiogenesis in anti-VEGF–resistant tumors. Tumor-associated macrophages also contribute to local PDGF-C expression (Crawford et al., 2009). Pericytes may facilitate revascularization by retaining a vascular scaffold that supports EC adhesion and proliferation (Mancuso et al., 2006). Finally, the utilization of pre-existing healthy vasculature by tumor growth around already present vessels, a process called vascular co-option, has been observed in glioma and NSCLC models, may provide nutrition and oxygen delivery to the tumor without the need for de novo angiogenesis, and may support anti-VEGF treatment resistance (Kunkel et al., 2001; Offersen et al., 2001). In conclusion, the biology behind resistance to antiangiogenic therapies is poorly understood at both the experimental and the clinical level. Although many factors are known to contribute to tumor angiogenesis in model systems, none has been clearly implicated in the response to currently used small molecules or antiangiogenic antibodies. The identification of a biomarker that predicts response could lead to the development of new agents with different targets in the angiogenic cascade. III. Conclusion Mechanisms of resistance to targeted therapies have been identified for BRAF,- EGFR-, ALK-, and BCRABL–driven tumors, and have led to new and, in some cases, successful strategies that use new drugs or new drug combinations to restore sensitivity to treatment. However, resistance in even the best understood tumors is poorly understood, and major areas of research into drug resistance, such as antiangiogenic therapies, are fragmentary. Virtually unexplored is the relationship of individual pharmacokinetics with response, the impact of polymorphisms on drug receptors and metabolic pathways, and the differences in tumor response that are governed by the tissue of origin (as seen in the variability of response to inhibitors of BRAFV600E in melanoma, colon, lung, and thyroid malignancies). A better understanding of drug resistance to targeted agents will require carefully planned and executed prospective trials in which patients’ tumors are sequentially biopsied before treatment and at the time of progression. This seems like a simple mandate, but one that is extremely difficult to pursue clinically. With a detailed knowledge of mutations and their interaction
with specific drugs, it is possible to design new molecules that overcome specific forms of resistance, as illustrated by the success of ponatinib in CML and LDK378 in NSCLC. Activation of alternative pathways presents a more complex and challenging problem, in that it will be necessary to inhibit the initial activating mutation as well as the new contributing pathway with a combination of drugs. Authorship Contributions
Wrote or contributed to the writing of the manuscript: Izar, Chabner, Rotow, Gainor, Clark.
References Agaram NP, Wong GC, Guo T, Maki RG, Singer S, Dematteo RP, Besmer P, and Antonescu CR (2008) Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer 47:853–859. Alduaij W and Illidge TM (2011) The future of anti-CD20 monoclonal antibodies: are we making progress? Blood 117:2993–3001. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, and Radinsky R, et al. (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634. Andreyev HJ, Norman AR, Cunningham D, Oates J, Dix BR, Iacopetta BJ, Young J, Walsh T, Ward R, and Hawkins N, et al. (2001) Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer 85:692–696. Antonescu CR, Besmer P, Guo T, Arkun K, Hom G, Koryotowski B, Leversha MA, Jeffrey PD, Desantis D, and Singer S, et al. (2005) Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 11:4182–4190. Apperley JF, Cortes JE, Kim D-W, Roy L, Roboz GJ, Rosti G, Bullorsky EO, Abruzzese E, Hochhaus A, and Heim D, et al. (2009) Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial. J Clin Oncol 27:3472–3479. Arcila ME, Oxnard GR, Nafa K, Riely GJ, Solomon SB, Zakowski MF, Kris MG, Pao W, Miller VA, and Ladanyi M (2011) Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res 17:1169–1180. Arrondeau J, Mir O, Boudou-Rouquette P, Coriat R, Ropert S, Dumas G, Rodrigues MJ, Rousseau B, Blanchet B, and Goldwasser F (2012) Sorafenib exposure decreases over time in patients with hepatocellular carcinoma. Invest New Drugs 30:2046–2049. Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, Cervantes F, Deininger M, Gratwohl A, and Guilhot F, et al.; European LeukemiaNet (2009) Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 27:6041–6051. Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, Chiang A, Yang G, Ouerfelli O, and Kris MG, et al. (2006) Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 12: 6494–6501. Bang Y-J, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, and Satoh T, et al.; ToGA Trial Investigators (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376:687–697. Bardelli A and Siena S (2010) Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol 28:1254–1261. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, and Lebrun F, et al. (2012a) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366: 520–529. Baselga J, Cortés J, Kim S-B, Im S-A, Hegg R, Im Y-H, Roman L, Pedrini JL, Pienkowski T, and Knott A, et al.; CLEOPATRA Study Group (2012b) Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366: 109–119. Baselga J, Gelmon KA, Verma S, Wardley A, Conte P, Miles D, Bianchi G, Cortes J, McNally VA, and Ross GA, et al. (2010) Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 28:1138–1144. Batchelor TT, Sorensen AG, di Tomaso E, Zhang W-T, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen P-J, and Zhu M, et al. (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95. Bazeos A, Marin D, Reid AG, Gerrard G, Milojkovic D, May PC, de Lavallade H, Garland P, Rezvani K, and Apperley JF, et al. (2010) hOCT1 transcript levels and single nucleotide polymorphisms as predictive factors for response to imatinib in chronic myeloid leukemia. Leukemia 24:1243–1245. Bean J, Riely GJ, Balak M, Marks JL, Ladanyi M, Miller VA, and Pao W (2008) Acquired resistance to epidermal growth factor receptor kinase inhibitors
Targeted Therapies in Cancer associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clin Cancer Res 14:7519–7525. Benjamin RS, Schöffski P, Hartmann JT, Van Oosterom A, Bui BN, Duyster J, Schuetze S, Blay J-Y, Reichardt P, and Rosen LS, et al. (2011) Efficacy and safety of motesanib, an oral inhibitor of VEGF, PDGF, and Kit receptors, in patients with imatinib-resistant gastrointestinal stromal tumors. Cancer Chemother Pharmacol 68:69–77. Bennouna J, Sastre J, Arnold D, Österlund P, Greil R, Van Cutsem E, von Moos R, Viéitez JM, Bouché O, and Borg C, et al.; ML18147 Study Investigators (2013) Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 14:29–37. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, and Hauptmann M, et al. (2007) A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12:395–402. Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C, Corà D, Di Nicolantonio F, Buscarino M, and Petti C, et al. (2011) A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov 1:508–523. Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, Sauter M, Nonomura N, Brakemeier S, and de Vries PJ, et al. (2013). Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 381:817–824. Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B, Fletcher JA, Corless CL, Fletcher CDM, Roberts PJ, and Heinz D, et al. (2008) Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 26:620–625. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, and Jassem J, et al. (2006) Radiotherapy plus cetuximab for squamouscell carcinoma of the head and neck. N Engl J Med 354:567–578. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, and McMiller TL, et al. (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28: 3167–3175. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, Mannel RS, Homesley HD, Fowler J, and Greer BE, et al.; Gynecologic Oncology Group (2011) Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365:2473–2483. Cameron D, Casey M, Oliva C, Newstat B, Imwalle B, and Geyer CE (2010) Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist 15:924–934. Camidge DR, Bang Y, Kwak EL, Shaw AT, Iafrate AJ, Maki RG, Solomon BJ, Ou SI, Salgia R, and Wilner KD, et al. (2011) Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC). J Clin Oncol 29(Suppl 15):2501; ASCO Annual Meeting Proceedings; 2011; Chicago, IL. Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, Esteban E, Molinier O, Brugger W, and Melezínek I, et al.; SATURN investigators (2010) Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 11:521–529. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, and Kozma SC, et al. (2008). Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 118:3065–3074. Casanovas O, Hicklin DJ, Bergers G, and Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8:299–309. Chabner BA and Roberts TG Jr (2005) Timeline: Chemotherapy and the war on cancer. Nat Rev Cancer 5:65–72. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, and Maio M, et al.; BRIM-3 Study Group (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516. Chen HX, Mooney M, Boron M, Vena D, Mosby K, Grochow L, Jaffe C, Rubinstein L, Zwiebel J, and Kaplan RS (2006) Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. J Clin Oncol 24:3354–3360. Cheung HW, Du J, Boehm JS, He F, Weir BA, Wang X, Butaney M, Sequist LV, Luo B, and Engelman JA, et al. (2011) Amplification of CRKL induces transformation and epidermal growth factor receptor inhibitor resistance in human non-small cell lung cancers. Cancer Discov 1:608–625. Chiarle R, Voena C, Ambrogio C, Piva R, and Inghirami G (2008) The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer 8:11–23. Chmielecki J, Foo J, Oxnard GR, Hutchinson K, Ohashi K, Somwar R, Wang L, Amato KR, Arcila M, and Sos ML, et al. (2011) Optimization of dosing for EGFRmutant non-small cell lung cancer with evolutionary cancer modeling. Sci Transl Med 3:90ra59. Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T, Yatabe Y, Takeuchi K, Hamada T, and Haruta H, et al.; ALK Lung Cancer Study Group (2010) EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 363:1734–1739. Chung KY, Shia J, Kemeny NE, Shah M, Schwartz GK, Tse A, Hamilton A, Pan D, Schrag D, and Schwartz L, et al. (2005) Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 23:1803–1810. Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, and Lieberman G, et al. (1999) Multinational study of the
1389
efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639–2648. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, and Gaulard P, et al. (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235–242. Coiffier B, Lepretre S, Pedersen LM, Gadeberg O, Fredriksen H, van Oers MHJ, Wooldridge J, Kloczko J, Holowiecki J, and Hellmann A, et al. (2008) Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood 111:1094–1100. Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, Caballero D, Borchmann P, Morschhauser F, and Wilhelm M, et al. (2012) Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 30:631–636. Conca E, Negri T, Gronchi A, Fumagalli E, Tamborini E, Pavan GM, Fermeglia M, Pierotti MA, Pricl S, and Pilotti S (2009). Activate and resist: L576P-KIT in GIST. Mol Cancer Ther 8:2491–2495. Copeland RA, Moyer MP, and Richon VM (2013) Targeting genetic alterations in protein methyltransferases for personalized cancer therapeutics. Oncogene 32: 939–946. Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, Brown RD, Della Pelle P, Dias-Santagata D, and Hung KE, et al. (2012) EGFR-mediated reactivation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov 2:227–235. Cortes J, Rousselot P, Kim D-W, Ritchie E, Hamerschlak N, Coutre S, Hochhaus A, Guilhot F, Saglio G, and Apperley J, et al. (2007) Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 109:3207–3213. Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, O’Hare T, Hu S, Narasimhan NI, and Rivera VM, et al. (2012) Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 367:2075–2088. Costa D.B., Halmos B., Kumar A., Schumer S.T., Huberman M.S., Boggon T.J., Tenen D.G., and Kobayashi S. (2007). BIM mediates EGFR tyrosine kinase inhibitorinduced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med 4: 1669–1680. Cote GM, Sawyer DB, and Chabner BA (2012) ERBB2 inhibition and heart failure. N Engl J Med 367:2150–2153. Cragg MS, Kuroda J, Puthalakath H, Huang DCS, and Strasser A (2007). Gefitinibinduced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. PLoS Med 4:1681–1689 1690. Crawford Y, Kasman I, Yu L, Zhong C, Wu X, Modrusan Z, Kaminker J, and Ferrara N (2009) PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell 15: 21–34. Crinò L, Kim D, Riely GJ, Janne PA, Blackhall FH, Camidge DR, Hirsh V, Mok T, Solomon BJ, and Park K, et al.. (2011) Initial phase II results with crizotinib in advanced ALK-positive non–small cell lung cancer (NSCLC): PROFILE 1005. J Clin Oncol 29(Suppl 15):7514; 2011; ASCO Annual Meeting Proceedings; Chicago, IL. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, and Verslype C, et al. (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345. Czuczman MS, Fayad L, Delwail V, Cartron G, Jacobsen E, Kuliczkowski K, Link BK, Pinter-Brown L, Radford J, and Hellmann A, et al.; 405 Study Investigators (2012) Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood 119:3698–3704. Dakhil SR, Hermann R, Chai A, Hurst D, Fine G, and Richards P (2011) Final results of a single arm phase III multicenter, open-label study of rituximab administered by faster infusion in patients with previously untreated diffuse large-B cell (DLBCL) or follicular non–Hodgkin’s lymphoma (FL). Blood (ASH Annual Meeting Abstracts) 118:2703; 2011 Nov; San Diego, CA. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, and Bottomley W, et al. (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954. Davis TA, Grillo-López AJ, White CA, McLaughlin P, Czuczman MS, Link BK, Maloney DG, Weaver RL, Rosenberg J, and Levy R (2000) Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin’s lymphoma: safety and efficacy of retreatment. J Clin Oncol 18:3135–3143. Debiec-Rychter M, Sciot R, Le Cesne A, Schlemmer M, Hohenberger P, van Oosterom AT, Blay J-Y, Leyvraz S, Stul M, and Casali PG, et al.; EORTC Soft Tissue and Bone Sarcoma Group; ; Italian Sarcoma Group; ; Australasian GastroIntestinal Trials Group (2006) KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42:1093–1103. Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PWT, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, and Brennan MF, et al.; American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team (2009) Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 373:1097–1104. Demetri GD, Reichardt P, Kang Y-K, Blay J-Y, Rutkowski P, Gelderblom H, Hohenberger P, Leahy M, von Mehren M, and Joensuu H, et al.; GRID study investigators (2013) Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381: 295–302. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, and Janicek M, et al. (2002) Efficacy and
1390
Izar et al.
safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, and Morgan JA, et al. (2006) Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368:1329–1338. De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, Lamba S, Arena S, Frattini M, and Piessevaux H, et al. (2010) Association of KRAS p. G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 304:1812–1820. Dewaele B, Wasag B, Cools J, Sciot R, Prenen H, Vandenberghe P, Wozniak A, Schöffski P, Marynen P, and Debiec-Rychter M (2008) Activity of dasatinib, a dual SRC/ABL kinase inhibitor, and IPI-504, a heat shock protein 90 inhibitor, against gastrointestinal stromal tumor-associated PDGFRAD842V mutation. Clin Cancer Res 14:5749–5758. Diaz LA Jr, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, Allen B, Bozic I, Reiter JG, and Nowak MA, et al. (2012) The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486:537–540. Dilling MB, Germain GS, Dudkin L, Jayaraman AL, Zhang X, Harwood FC, and Houghton PJ (2002) 4E-binding proteins, the suppressors of eukaryotic initiation factor 4E, are down-regulated in cells with acquired or intrinsic resistance to rapamycin. J Biol Chem 277:13907–13917. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, and Siena S, et al. (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26:5705–5712. Doebele RC, Lu X, Sumey C, Maxson DA, Weickhardt AJ, Oton AB, Bunn PA Jr, Barón AE, Franklin WA, and Aisner DL, et al. (2012a) Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer. Cancer 118:4502–4511. Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, Kondo KL, Linderman DJ, Heasley LE, and Franklin WA, et al. (2012b) Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 18:1472–1482. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, and Ohno-Jones S, et al. (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037. Dumaz N, Hayward R, Martin J, Ogilvie L, Hedley D, Curtin JA, Bastian BC, Springer C, and Marais R (2006) In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer Res 66:9483–9491. Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C, Chiao JH, Reilly JF, Ricker JL, and Richon VM, et al. (2007) Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 109:31–39. Ebos JML, Lee CR, Christensen JG, Mutsaers AJ, and Kerbel RS (2007) Multiple circulating proangiogenic factors induced by sunitinib malate are tumorindependent and correlate with antitumor efficacy. Proc Natl Acad Sci USA 104: 17069–17074. Ebos JML, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, and Kerbel RS (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15:232–239. Eiermann W; International Herceptin Study Group (2001) Trastuzumab combined with chemotherapy for the treatment of HER2-positive metastatic breast cancer: pivotal trial data. Ann Oncol 12 (Suppl 1):S57–S62. Emery CM, Vijayendran KG, Zipser MC, Sawyer AM, Niu L, Kim JJ, Hatton C, Chopra R, Oberholzer PA, and Karpova MB, et al. (2009) MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci USA 106: 20411–20416. Engelman JA, Zejnullahu K, Gale C-M, Lifshits E, Gonzales AJ, Shimamura T, Zhao F, Vincent PW, Naumov GN, and Bradner JE, et al. (2007a) PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 67:11924–11932. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale C-M, Zhao X, and Christensen J, et al. (2007b) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316: 1039–1043. Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, and Sneller V (2010) Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 28:2144–2150. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, and Desai AA, et al.; TARGET Study Group (2007b) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, and Bajetta E, et al.; AVOREN Trial investigators (2007a) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370:2103–2111. Faber AC, Corcoran RB, Ebi H, Sequist LV, Waltman BA, Chung E, Incio J, Digumarthy SR, Pollack SF, and Song Y, et al. (2011) BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. Cancer Discov 1:352–365. Falk AT, Poudenx M, Otto J, Ghalloussi H, and Barrière J (2012) Adenocarcinoma of the lung with miliary brain and pulmonary metastases with echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase translocation treated with crizotinib: a case report. Lung Cancer 78:282–284. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, and Shokat KM (2009) Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7:e38.
Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, and Boyle P (2007) Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 18:581–592. Ferrara N (2010) Role of myeloid cells in vascular endothelial growth factorindependent tumor angiogenesis. Curr Opin Hematol 17:219–224. Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, and De Mol M, et al. (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131: 463–475. Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, Epner E, Krishnan A, Leonard JP, and Lonial S, et al. (2006) Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 24:4867–4874. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, and Nolop K, et al. (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363:809–819. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, and Mohr P, et al.; METRIC Study Group (2012) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367:107–114. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285: 1182–1186. Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, and Wu JY, et al. (2013) Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 381:125–132. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WKA, Paleologos N, Nicholas MK, and Jensen R, et al. (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27: 4733–4740. Galanis E, Buckner JC, Maurer MJ, Kreisberg JI, Ballman K, Boni J, Peralba JM, Jenkins RB, Dakhil SR, and Morton RF, et al.; North Central Cancer Treatment Group (2005) Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 23: 5294–5304. Gallardo A, Lerma E, Escuin D, Tibau A, Muñoz J, Ojeda B, Barnadas A, Adrover E, Sánchez-Tejada L, and Giner D, et al. (2012) Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas. Br J Cancer 106:1367–1373. Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, Greninger P, Thompson IR, Luo X, and Soares J, et al. (2012) Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 483:570–575. Garrido-Laguna I, Hong DS, Janku F, Nguyen LM, Falchook GS, Fu S, Wheler JJ, Luthra R, Naing A, and Wang X, et al. (2012) KRASness and PIK3CAness in patients with advanced colorectal cancer: outcome after treatment with earlyphase trials with targeted pathway inhibitors. PLoS ONE 7:e38033. George S, Blay JY, Casali PG, Le Cesne A, Stephenson P, Deprimo SE, Harmon CS, Law CNJ, Morgan JA, and Ray-Coquard I, et al. (2009) Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer 45:1959–1968. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, JagielloGruszfeld A, Crown J, Chan A, and Kaufman B, et al. (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355: 2733–2743. Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, Untch M, Smith I, Baselga J, and Jackisch C, et al.; Herceptin Adjuvant (HERA) Trial Study Team (2011) Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 12:236–244. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, and Benson AB 3rd Eastern Cooperative Oncology Group Study E3200 (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25: 1539–1544. Gilman A (1963) The initial clinical trial of nitrogen mustard. Am J Surg 105: 574–578. Godin-Heymann N, Bryant I, Rivera MN, Ulkus L, Bell DW, Riese DJ 2nd, Settleman J, and Haber DA (2007) Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the T790M drug resistance mutation. Cancer Res 67:7319–7326. Gong Y, Somwar R, Politi K, Balak M, Chmielecki J, Jiang X, and Pao W (2007) Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas. PLoS Med 4:e294. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, and Sawyers CL (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–880. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, and Barone C, et al.; CORRECT Study Group (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381:303–312. Guo T, Agaram NP, Wong GC, Hom G, D’Adamo D, Maki RG, Schwartz GK, Veach D, Clarkson BD, and Singer S, et al. (2007) Sorafenib inhibits the imatinib-resistant KITT670I gatekeeper mutation in gastrointestinal stromal tumor. Clin Cancer Res 13:4874–4881. Gupta M, Ansell SM, Novak AJ, Kumar S, Kaufmann SH, and Witzig TE (2009) Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2. Blood 114:2926–2935.
Targeted Therapies in Cancer Gyrd-Hansen M and Meier P (2010) IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat Rev Cancer 10:561–574. Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB, Dakhil SR, Woda B, Fisher RI, and Peterson BA, et al. (2006) Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 24:3121–3127. Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, and von Grünhagen U, et al.; International Group of Investigators; ; German Chronic Lymphocytic Leukaemia Study Group (2010) Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 376:1164–1174. Hammerman PS, Fox CJ, Birnbaum MJ, and Thompson CB (2005) Pim and Akt oncogenes are independent regulators of hematopoietic cell growth and survival. Blood 105:4477–4483. Harris LN, You F, Schnitt SJ, Witkiewicz A, Lu X, Sgroi D, Ryan PD, Come SE, Burstein HJ, and Lesnikoski B-A, et al. (2007) Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer. Clin Cancer Res 13:1198–1207. Harrison C, Kiladjian J-J, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, McQuitty M, Hunter DS, Levy R, and Knoops L, et al. (2012) JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 366: 787–798. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJC, Stokoe D, Gloor SL, and Vigers G, et al. (2010) RAF inhibitors prime wildtype RAF to activate the MAPK pathway and enhance growth. Nature 464: 431–435. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, Hussain J, Reis-Filho JS, Springer CJ, and Pritchard C, et al. (2010) Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140:209–221. Heinrich MC, Corless CL, Blanke CD, Demetri GD, Joensuu H, Roberts PJ, Eisenberg BL, von Mehren M, Fletcher CDM, and Sandau K, et al. (2006) Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 24:4764–4774. Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen C-J, Van den Abbeele AD, and Druker BJ, et al. (2003b) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342–4349. Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen C-J, Joseph N, Singer S, Griffith DJ, Haley A, and Town A, et al. (2003a) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299:708–710. Heinrich MC, Maki RG, Corless CL, Antonescu CR, Harlow A, Griffith D, Town A, McKinley A, Ou W-B, and Fletcher JA, et al. (2008) Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinibresistant gastrointestinal stromal tumor. J Clin Oncol 26:5352–5359. Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J, Sirard C, and Mayer J (2007) Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 25:5616–5623. Hiwase DK, Saunders V, Hewett D, Frede A, Zrim S, Dang P, Eadie L, To LB, Melo J, and Kumar S, et al. (2008) Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implications. Clin Cancer Res 14:3881–3888. Hochhaus A, Druker B, Sawyers C, Guilhot F, Schiffer CA, Cortes J, Niederwieser DW, Gambacorti-Passerini C, Stone RM, and Goldman J, et al. (2008) Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment. Blood 111:1039–1043. Hochhaus A, Kantarjian HM, Baccarani M, Lipton JH, Apperley JF, Druker BJ, Facon T, Goldberg SL, Cervantes F, and Niederwieser D, et al. (2007) Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 109:2303–2309. Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, and Horning SJ (2009) Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol 27:1607–1614. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, and Hassel JC, et al. (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723. Horning SJ, Younes A, Jain V, Kroll S, Lucas J, Podoloff D, and Goris M (2005) Efficacy and safety of tositumomab and iodine-131 tositumomab (Bexxar) in B-cell lymphoma, progressive after rituximab. J Clin Oncol 23:712–719. Hoy SM (2012) Bendamustine: a review of its use in the management of chronic lymphocytic leukaemia, rituximab-refractory indolent non-Hodgkin’s lymphoma and multiple myeloma. Drugs 72:1929–1950. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, and Bodrogi I, et al.; Global ARCC Trial (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271–2281. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, and Holmgren E, et al. (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342. Ihle NT, Lemos R Jr, Wipf P, Yacoub A, Mitchell C, Siwak D, Mills GB, Dent P, Kirkpatrick DL, and Powis G (2009) Mutations in the phosphatidylinositol-3kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. Cancer Res 69:143–150. Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, Pirun M, Sander C, Socci ND, and Ostrovnaya I, et al. (2012) Genome sequencing identifies a basis for everolimus sensitivity. Science 338:221.
1391
Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, and Alsina M, et al. (2004) A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 127:165–172. Jahangiri A, De Lay M, Miller LM, Carbonell WS, Hu Y-L, Lu K, Tom MW, Paquette J, Tokuyasu TA, and Tsao S, et al. (2013). Gene expression profile identifies tyrosine kinase c-Met as a targetable mediator of antiangiogenic therapy resistance. Clin Cancer Res 19:1773–1783. Janes MR, Limon JJ, So L, Chen J, Lim RJ, Chavez MA, Vu C, Lilly MB, Mallya S, and Ong ST, et al. (2010) Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med 16:205–213. Janku F, Wheler JJ, Westin SN, Moulder SL, Naing A, Tsimberidou AM, Fu S, Falchook GS, Hong DS, and Garrido-Laguna I, et al. (2012) PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol 30:777–782. Jemal A, Siegel R, Xu J, and Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300. Jhawer M, Goel S, Wilson AJ, Montagna C, Ling Y-H, Byun D-S, Nasser S, Arango D, Shin J, and Klampfer L, et al. (2008) PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 68:1953–1961. Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J, Ramadori G, Hohenberger P, Duyster J, and Al-Batran S-E, et al. (2012) One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA 307:1265–1272. Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, Emery CM, Stransky N, Cogdill AP, and Barretina J, et al. (2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468:968–972. Johannsen M, Flörcken A, Bex A, Roigas J, Cosentino M, Ficarra V, Kloeters C, Rief M, Rogalla P, and Miller K, et al. (2009) Can tyrosine kinase inhibitors be discontinued in patients with metastatic renal cell carcinoma and a complete response to treatment? A multicentre, retrospective analysis. Eur Urol 55:1430–1438. Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au H-J, Berry SR, Krahn M, Price T, and Simes RJ, et al. (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040–2048. Judson I, Ma P, Peng B, Verweij J, Racine A, di Paola ED, van Glabbeke M, Dimitrijevic S, Scurr M, and Dumez H, et al.; EORTC Soft Tissue and Bone Sarcoma Group (2005) Imatinib pharmacokinetics in patients with gastrointestinal stromal tumour: a retrospective population pharmacokinetic study over time. Cancer Chemother Pharmacol 55:379–386. Kantarjian H, Cortes J, Kim D-W, Dorlhiac-Llacer P, Pasquini R, DiPersio J, Müller MC, Radich JP, Khoury HJ, and Khoroshko N, et al. (2009) Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15month median follow-up. Blood 113:6322–6329. Kantarjian H, Pasquini R, Hamerschlak N, Rousselot P, Holowiecki J, Jootar S, Robak T, Khoroshko N, Masszi T, and Skotnicki A, et al. (2007a) Dasatinib or highdose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood 109:5143–5150. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta D, Capdeville R, and Zoellner U, et al.; International STI571 CML Study Group (2002) Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346:645–652. Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, Moiraghi B, Shen Z, Mayer J, and Pasquini R, et al. (2010) Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 362:2260–2270. Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, Ossenkoppele GJ, Nicolini F-E, O’Brien SG, and Litzow M, et al. (2007b) Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 110:3540–3546. Kantarjian HM, Giles FJ, Bhalla KN, Pinilla-Ibarz J, Larson RA, Gattermann N, Ottmann OG, Hochhaus A, Radich JP, and Saglio G, et al. (2011) Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood 117:1141–1145. Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Undurraga MS, Wang J, Ipiña JJK, Kim D-W, and Ogura M, et al. (2012) Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 119:1123–1129. Katayama R., Shaw A.T., Khan T.M., Mino-Kenudson M., Solomon B.J., Halmos B., Jessop N.A., Wain J.C., Yeo A.T., and Benes C., et al. (2012). Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med 4: 120ra17. Khambata-Ford S, Garrett CR, Meropol NJ, Basik M, Harbison CT, Wu S, Wong TW, Huang X, Takimoto CH, and Godwin AK, et al. (2007) Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230–3237. Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, and Halmos B (2005) EGFR mutation and resistance of nonsmall-cell lung cancer to gefitinib. N Engl J Med 352:786–792. Kopetz S, Hoff PM, Morris JS, Wolff RA, Eng C, Glover KY, Adinin R, Overman MJ, Valero V, and Wen S, et al. (2010) Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 28: 453–459. Köstler WJ, Hudelist G, Rabitsch W, Czerwenka K, Müller R, Singer CF, and Zielinski CC (2006) Insulin-like growth factor-1 receptor (IGF-1R) expression does not predict for resistance to trastuzumab-based treatment in patients with Her-2/neu overexpressing metastatic breast cancer. J Cancer Res Clin Oncol 132: 9–18.
1392
Izar et al.
Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, and Camphausen K, et al. (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27:740–745. Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, and Franz DN (2010) Everolimus for subependymal giantcell astrocytomas in tuberous sclerosis. N Engl J Med 363:1801–1811. Kuiper JL and Smit EF (2013) High-dose, pulsatile erlotinib in two NSCLC patients with leptomeningeal metastases—one with a remarkable thoracic response as well. Lung Cancer 80:102–105. Kunkel P, Ulbricht U, Bohlen P, Brockmann MA, Fillbrandt R, Stavrou D, Westphal M, and Lamszus K (2001) Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2. Cancer Res 61:6624–6628. Kuroda J, Puthalakath H, Cragg MS, Kelly PN, Bouillet P, Huang DCS, Kimura S, Ottmann OG, Druker BJ, and Villunger A, et al. (2006) Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic. Proc Natl Acad Sci USA 103:14907–14912. Kwak EL, Bang Y-J, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou S-HI, Dezube BJ, Jänne PA, and Costa DB, et al. (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693–1703. Kwak EL, Clark JW, and Chabner B (2007) Targeted agents: the rules of combination. Clin Cancer Res 13:5232–5237. Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL, Driscoll DR, Fidias P, and Lynch TJ, et al. (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 102:7665–7670. Larson RA, Hochhaus A, Hughes TP, Clark RE, Etienne G, Kim D-W, Flinn IW, Kurokawa M, Moiraghi B, and Yu R, et al. (2012) Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia 26:2197–2203. Laurent C, Müller S, Do C, Al-Saati T, Allart S, Larocca LM, Hohaus S, Duchez S, Quillet-Mary A, and Laurent G, et al. (2011) Distribution, function, and prognostic value of cytotoxic T lymphocytes in follicular lymphoma: a 3-D tissue-imaging study. Blood 118:5371–5379. le Coutre P, Ottmann OG, Giles F, Kim D-W, Cortes J, Gattermann N, Apperley JF, Larson RA, Abruzzese E, and O’Brien SG, et al. (2008) Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood 111:1834–1839. le Coutre PD, Giles FJ, Hochhaus A, Apperley JF, Ossenkoppele GJ, Blakesley R, Shou Y, Gallagher NJ, Baccarani M, and Cortes J, et al. (2012) Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results. Leukemia 26:1189–1194. Lewis CE, De Palma M, and Naldini L (2007) Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res 67: 8429–8432. Liegl B, Kepten I, Le C, Zhu M, Demetri GD, Heinrich MC, Fletcher CDM, Corless CL, and Fletcher JA (2008) Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol 216:64–74. Lièvre A, Bachet J-B, Le Corre D, Boige V, Landi B, Emile J-F, Côté J-F, Tomasic G, Penna C, and Ducreux M, et al. (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992–3995. Lilly MB, Ottmann OG, Shah NP, Larson RA, Reiffers JJ, Ehninger G, Müller MC, Charbonnier A, Bullorsky E, and Dombret H, et al. (2010) Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: Results from a phase 3 study. Am J Hematol 85: 164–170. Linardou H, Dahabreh IJ, Kanaloupiti D, Siannis F, Bafaloukos D, Kosmidis P, Papadimitriou CA, and Murray S (2008) Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 9:962–972. Liu J, Stevens PD, and Gao T (2011) mTOR-dependent regulation of PHLPP expression controls the rapamycin sensitivity in cancer cells. J Biol Chem 286: 6510–6520. Liu LF (1989) DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem 58:351–375. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J-F, de Oliveira AC, Santoro A, Raoul J-L, and Forner A, et al.; SHARP Investigators Study Group (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359: 378–390. Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, Masi G, Stasi I, Canestrari E, and Rulli E, et al. (2009) KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer 101:715–721. Lu Y, Zi X, Zhao Y, Mascarenhas D, and Pollak M (2001) Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 93:1852–1857. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, and Haluska FG, et al. (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139. Mahalingam D, Medina EC, Esquivel JA 2nd, Espitia CM, Smith S, Oberheu K, Swords R, Kelly KR, Mita MM, and Mita AC, et al. (2010) Vorinostat enhances the activity of temsirolimus in renal cell carcinoma through suppression of survivin levels. Clin Cancer Res 16:141–153. Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, Inserra E, Diederichs S, Iafrate AJ, and Bell DW, et al. (2008) Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 359:366–377.
Mancuso MR, Davis R, Norberg SM, O’Brien S, Sennino B, Nakahara T, Yao VJ, Inai T, Brooks P, and Freimark B, et al. (2006) Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 116:2610–2621. Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J, Solal-Celigny P, Offner F, Walewski J, and Raposo J, et al. (2005) CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105:1417–1423. Margolin K, Longmate J, Baratta T, Synold T, Christensen S, Weber J, Gajewski T, Quirt I, and Doroshow JH (2005) CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer 104:1045–1048. McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, and Cabanillas F, et al. (1998) Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 16: 2825–2833. Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, Valtorta E, Schiavo R, Buscarino M, and Siravegna G, et al. (2012) Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486: 532–536. Miselli FC, Casieri P, Negri T, Orsenigo M, Lagonigro MS, Gronchi A, Fiore M, Casali PG, Bertulli R, and Carbone A, et al. (2007) c-Kit/PDGFRA gene status alterations possibly related to primary imatinib resistance in gastrointestinal stromal tumors. Clin Cancer Res 13:2369–2377. Mizukami Y, Jo W-S, Duerr E-M, Gala M, Li J, Zhang X, Zimmer MA, Iliopoulos O, Zukerberg LR, and Kohgo Y, et al. (2005) Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. Nat Med 11: 992–997. Mok TS, Wu Y-L, Thongprasert S, Yang C-H, Chu D-T, Saijo N, Sunpaweravong P, Han B, Margono B, and Ichinose Y, et al. (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957. Molina MA, Sáez R, Ramsey EE, Garcia-Barchino M-J, Rojo F, Evans AJ, Albanell J, Keenan EJ, Lluch A, and García-Conde J, et al. (2002) NH(2)-terminal truncated HER-2 protein but not full-length receptor is associated with nodal metastasis in human breast cancer. Clin Cancer Res 8:347–353. Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M, Salido M, Gallen M, Marsters S, and Tsai SP, et al. (2012) Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat Med 18:221–223. Montagut C, Sharma SV, Shioda T, McDermott U, Ulman M, Ulkus LE, Dias-Santagata D, Stubbs H, Lee DY, and Singh A, et al. (2008) Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res 68:4853–4861. Montemurro M, Gelderblom H, Bitz U, Schütte J, Blay JY, Joensuu H, Trent J, Bauer S, Rutkowski P, and Duffaud F, et al. (2013) Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumour and pretreatment including both imatinib and sunitinib, and nilotinib: A retrospective analysis. Eur J Cancer 49:1027–1031. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, and Wolff RA, et al.; National Cancer Institute of Canada Clinical Trials Group (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966. Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, and Shubina A, et al. (2011) Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 12: 431–440. Moroni M, Veronese S, Benvenuti S, Marrapese G, Sartore-Bianchi A, Di Nicolantonio F, Gambacorta M, Siena S, and Bardelli A (2005) Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 6:279–286. Morschhauser F, Radford J, Van Hoof A, Vitolo U, Soubeyran P, Tilly H, Huijgens PC, Kolstad A, d’Amore F, and Gonzalez Diaz M, et al. (2008) Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol 26:5156–5164. Motoyama AB, Hynes NE, and Lane HA (2002) The efficacy of ErbB receptortargeted anticancer therapeutics is influenced by the availability of epidermal growth factor-related peptides. Cancer Res 62:3151–3158. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, and Hollaender N, et al.; RECORD-1 Study Group (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449–456. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, and Kim ST, et al. (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124. Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, and DePrimo SE, et al. (2006b) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16–24. Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Merchan JR, and Wilding G, et al. (2006a) Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295:2516–2524. Müller MC, Cortes JE, Kim D-W, Druker BJ, Erben P, Pasquini R, Branford S, Hughes TP, Radich JP, and Ploughman L, et al. (2009) Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood 114:4944–4953. Mulloy R, Ferrand A, Kim Y, Sordella R, Bell DW, Haber DA, Anderson KS, and Settleman J (2007) Epidermal growth factor receptor mutants from human
Targeted Therapies in Cancer lung cancers exhibit enhanced catalytic activity and increased sensitivity to gefitinib. Cancer Res 67:2325–2330. Nagata Y, Lan K-H, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, and Nguyen NT, et al. (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6:117–127. Nahta R and Esteva FJ (2006) HER2 therapy: molecular mechanisms of trastuzumab resistance. Breast Cancer Res 8:215. Nahta R, Yuan LXH, Zhang B, Kobayashi R, and Esteva FJ (2005) Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res 65:11118–11128. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee M-K, Attar N, and Sazegar H, et al. (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468:973–977. Ng KP, Hillmer AM, Chuah CTH, Juan WC, Ko TK, Teo ASM, Ariyaratne PN, Takahashi N, Sawada K, and Fei Y, et al. (2012) A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat Med 18:521–528. Nishida T, Kanda T, Nishitani A, Takahashi T, Nakajima K, Ishikawa T, and Hirota S (2008) Secondary mutations in the kinase domain of the KIT gene are predominant in imatinib-resistant gastrointestinal stromal tumor. Cancer Sci 99: 799–804. Nishio M, Kiura K, and Nakagawa K, et al. (2012) A phase I/II study of ALK inhibitor CH5424802 in patients with ALK-positive NSCLC; safety and efficacy interim results of the phase II portion. Abstract presented at the 37th European Society for Medical Oncology Conference (EMSO 2012) (poster 4410); 28 Sept—2 Oct 2012; Vienna, Austria; Ann Oncol 23(Suppl. 9):ix153 (Abstract 4410). O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, and Hughes T, et al.; IRIS Investigators (2003) Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348:994–1004. Offersen BV, Pfeiffer P, Hamilton-Dutoit S, and Overgaard J (2001) Patterns of angiogenesis in nonsmall-cell lung carcinoma. Cancer 91:1500–1509. Ohashi K, Sequist LV, Arcila ME, Moran T, Chmielecki J, Lin Y-L, Pan Y, Wang L, de Stanchina E, and Shien K, et al. (2012) Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci USA 109:E2127–E2133. Olsen E, Duvic M, Frankel A, Kim Y, Martin A, Vonderheid E, Jegasothy B, Wood G, Gordon M, and Heald P, et al. (2001) Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol 19:376–388. Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, Frankel SR, Chen C, Ricker JL, and Arduino JM, et al. (2007) Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 25:3109–3115. Osborn MJ, Freeman M, and Huennekens FM (1958) Inhibition of dihydrofolic reductase by aminopterin and amethopterin. Proc Soc Exp Biol Med 97:429–431. Ottmann O, Dombret H, Martinelli G, Simonsson B, Guilhot F, Larson RA, RegeCambrin G, Radich J, Hochhaus A, and Apanovitch AM, et al. (2007) Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood 110: 2309–2315. Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT, Tura S, Fischer T, Deininger MW, and Schiffer CA, et al. (2002) A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100:1965–1971. Oxnard GR, Arcila ME, Sima CS, Riely GJ, Chmielecki J, Kris MG, Pao W, Ladanyi M, and Miller VA (2011) Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res 17:1616–1622. Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, and Boggon TJ, et al. (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500. Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, Inoue M, Bergers G, Hanahan D, and Casanovas O (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220–231. Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M, Zakowski MF, Heelan RT, Kris MG, and Varmus HE (2005) KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2:e17. Perrone F, Lampis A, Orsenigo M, Di Bartolomeo M, Gevorgyan A, Losa M, Frattini M, Riva C, Andreola S, and Bajetta E, et al. (2009) PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol 20:84–90. Pfreundschuh M, Trümper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, and Zinzani P-L, et al.; MabThera International Trial Group (2006) CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7:379–391. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, and Jackisch C, et al.; Herceptin Adjuvant (HERA) Trial Study Team (2005) Trastuzumab after adjuvant chemotherapy in HER2positive breast cancer. N Engl J Med 353:1659–1672. Piekarz RL, Frye R, Prince HM, Kirschbaum MH, Zain J, Allen SL, Jaffe ES, Ling A, Turner M, and Peer CJ, et al. (2011) Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood 117:5827–5834.
1393
Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH, Zain J, Prince HM, Leonard JP, and Geskin LJ, et al. (2009) Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 27:5410–5417. Piro LD, White CA, Grillo-López AJ, Janakiraman N, Saven A, Beck TM, Varns C, Shuey S, Czuczman M, and Lynch JW, et al. (1999) Extended Rituximab (antiCD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol 10:655–661. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, Shi H, Atefi M, Titz B, and Gabay MT, et al. (2011) RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480:387–390. Poulikakos PI, Zhang C, Bollag G, Shokat KM, and Rosen N (2010) RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464:427–430. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli A, and Bernards R (2012) Unresponsiveness of colon cancer to BRAF (V600E) inhibition through feedback activation of EGFR. Nature 483:100–103. Prenen H, Cools J, Mentens N, Folens C, Sciot R, Schöffski P, Van Oosterom A, Marynen P, and Debiec-Rychter M (2006) Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate. Clin Cancer Res 12:2622–2627. Prenen H, De Schutter J, Jacobs B, De Roock W, Biesmans B, Claes B, Lambrechts D, Van Cutsem E, and Tejpar S (2009) PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res 15:3184–3188. Prince HM, Duvic M, Martin A, Sterry W, Assaf C, Sun Y, Straus D, Acosta M, and Negro-Vilar A (2010) Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma. J Clin Oncol 28:1870–1877. Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL, Gore M, Desai AA, Patnaik A, and Xiong HQ, et al. (2006) Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 24:2505–2512. Ravandi F, Estey EH, Appelbaum FR, Lo-Coco F, Schiffer CA, Larson RA, Burnett AK, and Kantarjian HM (2012) Gemtuzumab ozogamicin: time to resurrect? J Clin Oncol 30:3921–3923. Raymond E, Dahan L, Raoul J-L, Bang Y-J, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, and Vinik A, et al. (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364:501–513. Rebocho AP and Marais R (2013) ARAF acts as a scaffold to stabilize BRAF:CRAF heterodimers. Oncogene 32:3207–3212. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, and Moore N, et al. (2009) Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 27:1227–1234. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, and Moore N, et al.; BO17704 Study Group (2010) Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol 21:1804–1809. Reichardt P and Montemurro M (2011) Clinical experience to date with nilotinib in gastrointestinal stromal tumors. Semin Oncol 38 (Suppl 1):S20–S27. Rezvani AR and Maloney DG (2011) Rituximab resistance. Best Pract Res Clin Haematol 24:203–216. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, and Alexanian R, et al. (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609–2617. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau J-L, Ben-Yehuda D, Lonial S, and Goldschmidt H, et al.; Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487–2498. Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, Harousseau J-L, Ben-Yehuda D, Lonial S, and Goldschmidt H, et al. (2007) Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 110:3557–3560. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, and Rusakov IG, et al. (2011) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378:1931–1939. Rini BI, Michaelson MD, Rosenberg JE, Bukowski RM, Sosman JA, Stadler WM, Hutson TE, Margolin K, Harmon CS, and DePrimo SE, et al. (2008) Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumabrefractory metastatic renal cell carcinoma. J Clin Oncol 26:3743–3748. Rini BI, Wilding G, Hudes G, Stadler WM, Kim S, Tarazi J, Rosbrook B, Trask PC, Wood L, and Dutcher JP (2009) Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol 27:4462–4468. Risau W (1997). Mechanisms of angiogenesis. Nature 386:671–674. Robak T, Dmoszynska A, Solal-Céligny P, Warzocha K, Loscertales J, Catalano J, Afanasiev BV, Larratt L, Geisler CH, and Montillo M, et al. (2010) Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 28:1756–1765. Robert C, Thomas L, Bondarenko I, O’Day S, M D JW, Garbe C, Lebbe C, Baurain J-F, Testori A, and Grob J-J, et al. (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526. Rodig SJ, Mino-Kenudson M, Dacic S, Yeap BY, Shaw A, Barletta JA, Stubbs H, Law K, Lindeman N, and Mark E, et al. (2009) Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res 15:5216–5223.
1394
Izar et al.
Rodon J, Dienstmann R, Serra V, and Tabernero J (2013) Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol 10: 143–153. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, and Kaufman PA, et al. (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353: 1673–1684. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, and Sanchez JM, et al.; Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica (2012) Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13:239–246. Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, Dietrich D, Biesmans B, Bodoky G, and Barone C, et al. (2010) Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol 28:466–474. Sáez R, Molina MA, Ramsey EE, Rojo F, Keenan EJ, Albanell J, Lluch A, GarcíaConde J, Baselga J, and Clinton GM (2006) p95HER-2 predicts worse outcome in patients with HER-2-positive breast cancer. Clin Cancer Res 12:424–431. Safaee Ardekani G, Jafarnejad SM, Tan L, Saeedi A, and Li G (2012) The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PLoS ONE 7:e47054. Saglio G, Hochhaus A, Goh YT, Masszi T, Pasquini R, Maloisel F, Erben P, Cortes J, Paquette R, and Bradley-Garelik MB, et al. (2010a) Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer 116:3852–3861. Saglio G, Kim D-W, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, and Hughes TP, et al.; ENESTnd Investigators (2010b) Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362: 2251–2259. Sakamoto H, Tsukaguchi T, Hiroshima S, Kodama T, Kobayashi T, Fukami TA, Oikawa N, Tsukuda T, Ishii N, and Aoki Y (2011) CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell 19:679–690. Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, and Brice P, et al. (2011) Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 377:42–51. Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, and Mayer RJ (2004) Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201–1208. Samuels BL, Chawla S, Patel S, von Mehren M, Hamm J, Kaiser PE, Schuetze S, Li J, Aymes A, and Demetri GD (2013) Clinical outcomes and safety with trabectedin therapy in patients with advanced soft tissue sarcomas following failure of prior chemotherapy: results of a worldwide expanded access program study. Ann Oncol 24:1703–1709. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, and Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for nonsmall-cell lung cancer. N Engl J Med 355:2542–2550. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, and Samoilova OS, et al.; VISTA Trial Investigators (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906–917. Sasaki T, Koivunen J, Ogino A, Yanagita M, Nikiforow S, Zheng W, Lathan C, Marcoux JP, Du J, and Okuda K, et al. (2011) A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res 71: 6051–6060. Sawaki A, Nishida T, Doi T, Yamada Y, Komatsu Y, Kanda T, Kakeji Y, Onozawa Y, Yamasaki M, and Ohtsu A (2011) Phase 2 study of nilotinib as third-line therapy for patients with gastrointestinal stromal tumor. Cancer 117:4633–4641. Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG, Schiffer CA, Talpaz M, Guilhot F, and Deininger MWN, et al. (2002) Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99:3530–3539. Scaltriti M, Rojo F, Ocaña A, Anido J, Guzman M, Cortes J, Di Cosimo S, MatiasGuiu X, Ramon y Cajal S, and Arribas J, et al. (2007) Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst 99:628–638. Scarpace SL (2012) Eribulin mesylate (E7389): review of efficacy and tolerability in breast, pancreatic, head and neck, and non-small cell lung cancer. Clin Ther 34:1467–1473. Schöffski P, Reichardt P, Blay J-Y, Dumez H, Morgan JA, Ray-Coquard I, Hollaender N, Jappe A, and Demetri GD (2010) A phase I-II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors. Ann Oncol 21:1990–1998. Schor-Bardach R, Alsop DC, Pedrosa I, Solazzo SA, Wang X, Marquis RP, Atkins MB, Regan M, Signoretti S, and Lenkinski RE, et al. (2009) Does arterial spin-labeling MR imaging-measured tumor perfusion correlate with renal cell cancer response to antiangiogenic therapy in a mouse model? Radiology 251:731–742. Schwartzberg LS, Franco SX, Florance A, O’Rourke L, Maltzman J, and Johnston S (2010) Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptorpositive metastatic breast cancer. Oncologist 15:122–129. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, Solomon JA, Yoo S, Arron ST, and Friedlander PA, et al. (2012) Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 366:2171–2179. Sequist LV, Besse B, Lynch TJ, Miller VA, Wong KK, Gitlitz B, Eaton K, Zacharchuk C, Freyman A, and Powell C, et al. (2010) Neratinib, an irreversible pan-ErbB
receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer. J Clin Oncol 28:3076–3083. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, and Cosper AK, et al. (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 3:75ra26. Shah NP, Kantarjian HM, Kim D-W, Réa D, Dorlhiac-Llacer PE, Milone JH, VelaOjeda J, Silver RT, Khoury HJ, and Charbonnier A, et al. (2008) Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 26:3204–3212. Shah NP, Kim D-W, Kantarjian H, Rousselot P, Llacer PED, Enrico A, Vela-Ojeda J, Silver RT, Khoury HJ, and Müller MC, et al. (2010) Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica 95:232–240. Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J, and Sawyers CL (2002) Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2:117–125. Shattuck DL, Miller JK, Carraway KL 3rd, and Sweeney C (2008) Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. Cancer Res 68:1471–1477. Shaw AT, Camidge DR, and Felip E, et al. (2012) Results of a first-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors. Abstract presented at the 37th European Society for Medical Oncology Conference (EMSO 2012) (poster 4400); 28 Sept—2 Oct 2012; Vienna, Austria; Ann Oncol 23(Suppl. 9):ix153 (Abstract 4400). Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, Solomon B, Stubbs H, Admane S, and McDermott U, et al. (2009) Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 27:4247–4253. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, and Martins R, et al.; National Cancer Institute of Canada Clinical Trials Group (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132. Shi H, Moriceau G, Kong X, Lee M-K, Lee H, Koya RC, Ng C, Chodon T, Scolyer RA, and Dahlman KB, et al. (2012) Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun 3:724. Shih J-Y, Gow C-H, and Yang P-C (2005) EGFR mutation conferring primary resistance to gefitinib in non–small-cell lung cancer. N Engl J Med 353:207–208. Shimamura T, Li D, Ji H, Haringsma HJ, Liniker E, Borgman CL, Lowell AM, Minami Y, McNamara K, and Perera SA, et al. (2008) Hsp90 inhibition suppresses mutant EGFR-T790M signaling and overcomes kinase inhibitor resistance. Cancer Res 68:5827–5838. Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, Fuh G, Gerber H-P, and Ferrara N (2007) Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol 25:911–920. Shojaei F, Wu X, Qu X, Kowanetz M, Yu L, Tan M, Meng YG, and Ferrara N (2009) G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci USA 106: 6742–6747. Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, Trudel S, Kukreti V, Bahlis N, and Alsina M, et al. (2012) A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 120:2817–2825. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, and Pawlicki M, et al.; Breast Cancer International Research Group (2011) Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365:1273–1283. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, and Pegram M, et al. (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792. Slobbe P, Poot AJ, Windhorst AD, and van Dongen GAMS (2012) PET imaging with small-molecule tyrosine kinase inhibitors: TKI-PET. Drug Discov Today 17: 1175–1187. Smith BL, Chin D, Maltzman W, Crosby K, Hortobagyi GN, and Bacus SS (2004) The efficacy of Herceptin therapies is influenced by the expression of other erbB receptors, their ligands and the activation of downstream signalling proteins. Br J Cancer 91:1190–1194. Smith-Jones PM, Solit DB, Akhurst T, Afroze F, Rosen N, and Larson SM (2004) Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors. Nat Biotechnol 22:701–706. Sos ML, Koker M, Weir BA, Heynck S, Rabinovsky R, Zander T, Seeger JM, Weiss J, Fischer F, and Frommolt P, et al. (2009) PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 69:3256–3261. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, and Flaherty KT, et al. (2012) Survival in BRAF V600mutant advanced melanoma treated with vemurafenib. N Engl J Med 366: 707–714. Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A, Iacobucci I, Amabile M, Abruzzese E, and Orlandi E, et al. (2006) Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia Clinical Cancer Research Office. J Am Assoc Cancer Res 12:7374–7379.
Targeted Therapies in Cancer Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, and Kavina A, et al. (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28:1061–1068. Takezawa K, Pirazzoli V, Arcila ME, Nebhan CA, Song X, de Stanchina E, Ohashi K, Janjigian YY, Spitzler PJ, and Melnick MA, et al. (2012) HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov 2: 922–933. Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F, Schiffer CA, Fischer T, Deininger MWN, and Lennard AL, et al. (2002) Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 99: 1928–1937. Teeling JL, Mackus WJM, Wiegman LJJM, van den Brakel JHN, Beers SA, French RR, van Meerten T, Ebeling S, Vink T, and Slootstra JW, et al. (2006) The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol 177:362–371. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, and Christian MC, et al. (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, and Atkins MB, et al. (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454. Turke AB, Zejnullahu K, Wu Y-L, Song Y, Dias-Santagata D, Lifshits E, Toschi L, Rogers A, Mok T, and Sequist L, et al. (2010) Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17:77–88. Van Cutsem E, Köhne C-H, Hitre E, Zaluski J, Chang Chien C-R, Makhson A, D’Haens G, Pintér T, Lim R, and Bodoky G, et al. (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360: 1408–1417. Van Cutsem E, Köhne C-H, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, and Tejpar S, et al. (2011) Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 29:2011–2019. Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon J-L, Van Laethem J-L, Maurel J, and Richardson G, et al. (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658–1664. van der Graaf WTA, Blay J-Y, Chawla SP, Kim D-W, Bui-Nguyen B, Casali PG, Schöffski P, Aglietta M, Staddon AP, and Beppu Y, et al.; EORTC Soft Tissue and Bone Sarcoma Group; PALETTE Study Group (2012) Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 379:1879–1886. van Oosterom AT, Judson I, Verweij J, Stroobants S, Donato di Paola E, Dimitrijevic S, Martens M, Webb A, Sciot R, and Van Glabbeke M, et al.; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (2001) Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 358:1421–1423. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh D-Y, Diéras V, and Guardino E, et al.; EMILIA Study Group (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783–1791. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer H-R, and Cupissol D, et al. (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116–1127. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, Knecht R, Amellal N, Schueler A, and Baselga J (2007) Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 25:2171–2177. Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger M, Miller C, and Silver RT, et al. (2012) A double-blind, placebocontrolled trial of ruxolitinib for myelofibrosis. N Engl J Med 366:799–807. Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay J-Y, Issels R, van Oosterom A, Hogendoorn PCW, and Van Glabbeke M, et al. (2004) Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364:1127–1134. Vikis H, Sato M, James M, Wang D, Wang Y, Wang M, Jia D, Liu Y, Bailey-Wilson JE, and Amos CI, et al. (2007) EGFR-T790M is a rare lung cancer susceptibility allele with enhanced kinase activity. Cancer Res 67:4665–4670. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, Wubbenhorst B, Xu X, Gimotty PA, and Kee D, et al. (2010) Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18:683–695. Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, Kehoe SM, Johannessen CM, MacConaill LE, and Hahn WC, et al. (2011) dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol 29:3085–3096 Walter AO, Tjin R, Haringsma H, Lin K, Dubrovskiy A, Lee K, St. Martin T, Karp R, Zhu Z, and Niu D, et al. (2011) Abstract C189: CO-1686, an orally available,
1395
mutant-selective inhibitor of the epidermal growth factor receptor (EGFR), causes tumor shrinkage in non-small cell lung cancer (NSCLC) with T790M mutations. Mol Cancer Ther 10:C189–C189. Wardelmann E, Thomas N, Merkelbach-Bruse S, Pauls K, Speidel N, Büttner R, Bihl H, Leutner CC, Heinicke T, and Hohenberger P (2005) Acquired resistance to imatinib in gastrointestinal stromal tumours caused by multiple KIT mutations. Lancet Oncol 6:249–251. Wells SA Jr, Gosnell JE, Gagel RF, Moley J, Pfister D, Sosa JA, Skinner M, Krebs A, Vasselli J, and Schlumberger M (2010) Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol 28: 767–772. Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, Elisei R, Jarzab B, and Vasselli JR, et al. (2012) Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 30:134–141. Weng W-K and Levy R (2003) Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 21:3940–3947. White DL, Dang P, Engler J, Frede A, Zrim S, Osborn M, Saunders VA, Manley PW, and Hughes TP (2010) Functional activity of the OCT-1 protein is predictive of long-term outcome in patients with chronic-phase chronic myeloid leukemia treated with imatinib. J Clin Oncol 28:2761–2767. White DL and Hughes TP (2009) Predicting the response of CML patients to tyrosine kinase inhibitor therapy. Curr Hematol Malig Rep 4:59–65. Whittaker SJ, Demierre M-F, Kim EJ, Rook AH, Lerner A, Duvic M, Scarisbrick J, Reddy S, Robak T, and Becker JC, et al. (2010) Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 28:4485–4491. Wierda WG, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, Robak T, Furman RR, Hillmen P, and Trneny M, et al.; Hx-CD20-406 Study Investigators (2010) Ofatumumab as single-agent CD20 immunotherapy in fludarabinerefractory chronic lymphocytic leukemia. J Clin Oncol 28:1749–1755. Wiseman GA, Gordon LI, Multani PS, Witzig TE, Spies S, Bartlett NL, Schilder RJ, Murray JL, Saleh M, and Allen RS, et al. (2002) Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: a phase II multicenter trial. Blood 99:4336–4342. Witzig TE, Flinn IW, Gordon LI, Emmanouilides C, Czuczman MS, Saleh MN, Cripe L, Wiseman G, Olejnik T, and Multani PS, et al. (2002b) Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol 20:3262–3269. Witzig TE, Gordon LI, Cabanillas F, Czuczman MS, Emmanouilides C, Joyce R, Pohlman BL, Bartlett NL, Wiseman GA, and Padre N, et al. (2002a) Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol 20:2453–2463. Xu L, Kikuchi E, Xu C, Ebi H, Ercan D, Cheng KA, Padera R, Engelman JA, Jänne PA, and Shapiro GI, et al. (2012) Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers codriven by mutant EGFR containing T790M and MET. Cancer Res 72:3302–3311. Yano S, Wang W, Li Q, Matsumoto K, Sakurama H, Nakamura T, Ogino H, Kakiuchi S, Hanibuchi M, and Nishioka Y, et al. (2008) Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptoractivating mutations. Cancer Res 68:9479–9487. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, and de Vries EGE, et al.; RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514–523. Yap TA, Vidal L, Adam J, Stephens P, Spicer J, Shaw H, Ang J, Temple G, Bell S, and Shahidi M, et al. (2010) Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol 28: 3965–3972. Yasuda H, Kobayashi S, and Costa DB (2012) EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol 13:e23–e31. Yerushalmi R, Gelmon KA, Leung S, Gao D, Cheang M, Pollak M, Turashvili G, Gilks BC, and Kennecke H (2012) Insulin-like growth factor receptor (IGF-1R) in breast cancer subtypes. Breast Cancer Res Treat 132:131–142. Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, Ramchandren R, Bartlett NL, Cheson BD, and de Vos S, et al. (2012) Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol 30:2183–2189. Yun C-H, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong K-K, Meyerson M, and Eck MJ (2008) The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA 105:2070–2075. Zama IN, Hutson TE, Elson P, Cleary JM, Choueiri TK, Heng DYC, Ramaiya N, Michaelson MD, Garcia JA, and Knox JJ, et al. (2010) Sunitinib rechallenge in metastatic renal cell carcinoma patients. Cancer 116:5400–5406. Zhang L, Bhasin M, Schor-Bardach R, Wang X, Collins MP, Panka D, Putheti P, Signoretti S, Alsop DC, and Libermann T, et al. (2011) Resistance of renal cell carcinoma to sorafenib is mediated by potentially reversible gene expression. PLoS ONE 6:e19144. Zhou W, Ercan D, Chen L, Yun C-H, Li D, Capelletti M, Cortot AB, Chirieac L, Iacob RE, and Padera R, et al. (2009) Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 462:1070–1074.