February 2013, Vol 2, No 1
Resistance to Targeted Molecular Therapies in NSCLCLung Cancer
Over the past decade, there has been enormous progress in our understanding of the molecular pathogenesis of non–small cell lung cancer (NSCLC), in particular among patients with lung adenocarcinoma. Approximately 60% of these patients’ tumors will be oncogene addicted.1 Those with mutated EGFR and ALK rearrangements can be treated with targeted inhibitors of the offending oncogene. While the success of the tyrosine kinase inhibitors (TKIs) – erlotinib and gefitinib directed against the epidermal growth factor receptor (EGFR) and crizotinib targeting the anaplastic lymphoma kinase (ALK) – has catalyzed significant changes in the treatment of patients with NSCLC, it has also introduced a new challenge: resistance that develops after TKI treatment (acquired resistance). Here, we review current understanding of EGFR- and ALK-driven lung adenocarcinoma, the mechanisms of acquired resistance in both groups of patients, and newer therapies being investigated for patients after the development of acquired resistance.
EGFR Mutations and EGFR-Targeted Therapies
EGFR is a receptor tyrosine kinase (RTK) that stimulates cellular growth, proliferation, and survival mediated by PI3K-AKT-mTOR and RAS-RAF-MEK-ERK pathways (Figure).2-5 Aberrant expression of EGFR is a well-established mechanism causing development of NSCLC tumors, in particular for the 10% to 15% of patients with activating mutations in the kinase domain of EGFR.6-9 The EGFR-TKIs gefitinib and erlotinib inhibit tumor growth by competing for the ATP- binding site of the kinase domain of EGFR.2 Although EGFR-TKIs have demonstrated modest antitumor activity in unselected patients with advanced NSCLC harboring EGFR mutations (response rates [RRs] 8%-9%10,11), these agents are capable of producing far greater responses (RRs 55%-91%, as reviewed by Pao and Chmielecki12 and Nguyen et al13). Female patients, never-smokers, and patients of East Asian ethnicity are more likely to respond to gefitinib or erlotinib, as discovered in early studies, and were subsequently found to be more likely to harbor activating mutations in EGFR.14-16
The IPASS study was the first randomized phase 3 trial to demonstrate gefitinib to be superior to standard platinum chemotherapy in East Asian, never- or light-smoker patients with advanced adenocarcinoma of the lung.17 Preplanned subgroup analysis showed that patients with EGFR mutations had longer progression-free survival (PFS) when treated with gefitinib (hazard ratio [HR] 0.48; P<.001), while those patients whose tumors were EGFR wild-type had shorter PFS when treated with gefitinib (HR 2.85; P<.001). First-SIGNAL, a second study of gefitinib in never-smoker patients conducted in Korea, demonstrated similar results to IPASS, where the presence of an EGFR mutation was predictive of higher overall RRs (84.6% [22/26] vs 25.9% [7/27]; P<.001) and longer PFS (HR; 0.377; 95% CI, 0.210-0.674; P<.001) among patients who received gefitinib.18 In addition to IPASS and First-SIGNAL, 2 phase 3 trials confirmed the superior efficacy of gefitinib versus chemotherapy in selected Japanese patients with lung adenocarcinoma and EGFR mutations (NEJ002 and WJTPG3405),19,20 and a third study verified the same results using erlotinib in Chinese patients (OPTIMAL).21 The EURTAC trial confirmed erlotinib was better than standard chemotherapy in a European Caucasian population with EGFR mutations (HR 0.37; P<.001).22 Erlotinib has been adopted into both the National Comprehensive Cancer Network and the American Society of Clinical Oncology guidelines for initial treatment of patients with EGFR-mutated lung cancer.23,24
Acquired Resistance to EGFR-TKIs
Acquired resistance occurs after initial favorable response to EGFR-TKI therapy and develops despite active treatment with erlotinib or gefitinib. Jackman and colleagues have defined criteria to help identify acquired resistance to TKIs.25 These criteria require an initial objective clinical benefit – either disease shrinkage or stable disease for at least 6 months – followed by progressive disease despite continuous TKI therapy within the last 30 days prior to development of progression. Using cell lines and mouse models with EGFR mutations treated with continuous EGFR-TKIs, several mechanisms of acquired resistance have been elucidated in the laboratory. Below we focus our discussion on those that have also been encountered clinically in patient specimens after rebiopsy.
T790M “Gatekeeper” Mutations
The most common mechanism of acquired resistance to EGFR-TKIs is a secondary mutation in exon 20 of EGFR, a single amino acid substitution at position 790 (methionine for threonine), first reported in 2005 in patients with advanced NSCLC previously treated with gefitinib or erlotinib.26,27 Analogous to the “gatekeeper” mutations that develop in other oncogene-addicted cancers (Table), the T790M mutation confers drug resistance by altering drug binding within the ATP-binding pocket of EGFR; this mechanism accounts for roughly 50% of patients with acquired resistance to EGFR-TKIs.26,27,33 While other single-site mutations in EGFR, such as D761Y, L747S, and T854A, have also been identified as causing TKI resistance, they occur in less than 5% of patients. The mechanisms of resistance for these mutations remain unclear, but in vitro studies demonstrate that, unlike T790M, these less common mutations may exhibit weaker resistance that may be overcome with increasing doses of EGFR-TKIs.13
Despite developing resistance to TKI therapy, patients harboring T790M appear to have indolent, less aggressive clinical courses (19 months postprogression survival compared with 12 months in patients without T790M; P=.036) and seem more likely to progress within an existing site of disease rather than progressing to a new metastatic site.34 In a cohort of patients with acquired resistance who underwent repeat biopsies and molecular analysis (n=37), Sequist and colleagues reported 18 patients (49%) with T790M mutations, and a subset of these (n=3) were reported to have overamplification of EGFR, specifically the T790M allele.35
A second mechanism causing acquired resistance to EGFR-TKIs is the upregulation of an alternative signaling pathway, or “bypass track,” capable of activating the same intracellular pathways as EGFR.36,37 For example, upregulation of MET, an alternative RTK capable of activating the PI3K pathway and downstream effectors including AKT, provides the tumor an alternative means of signaling despite suppression of EGFR by EGFR-TKIs. MET amplification in combination with EGFR T790M occurs in 20% of EGFR-driven NSCLC with acquired resistance, but in isolation of the gatekeeper mutation, only about 5% of acquired resistance cases have MET amplification alone35,38 Insulin-like growth factor-1 receptor may be another RTK able to create a bypass track in the setting of acquired resistance to EGFR-TKIs, although this has only been suggested by preclinical data.39
Approximately 5% of patients with acquired resistance develop secondary mutations in PI3KCA.35 PI3KCA mutations were also reported in 2% of patients whose tumors were genotyped as part of the Lung Cancer Mutation Consortium, but these patients had not received prior EGFR-TKIs.1 PI3KCA mutations have been reported in another small cohort of TKI-naive patients to coexist with other driver mutations besides EGFR, such as KRAS and ALK, and predict inferior patient outcomes when expressed concurrently with one of these oncogenes.40
Rarely, patients whose tumors have acquired resistance to EGFR-TKIs will exhibit histologic transformation of their primary tumor from adenocarcinoma to small cell or neuroendocrine differentiation, although the original EGFR mutation is preserved. This phenomenon has been observed in patient samples with a frequency ranging from 2% to 14%.35,38 Interestingly, these patients can be treated with small cell lung cancer chemotherapy regimens with favorable responses. The mechanism that triggers this change in histology is unclear but may be explained by a hypothesis that proposes that a pluripotent cancer stem cell underlies EGFR-mutant lung cancer development and resistance.35,41
Strategies for Overcoming EGFR-TKI Resistance
There is no standard treatment for patients once resistance to erlotinib or gefitinib develops, despite exhaustive attempts to identify an effective second-generation EGFR inhibitor (as reviewed by Oxnard et al42). One of the most heralded agents is afatinib, an irreversible inhibitor that forms a covalent bond in the ATP- binding site of EGFR, allowing inhibition of EGFR even in the presence of a secondary T790M resistance mutation. Gefitinib-resistant NSCLC cell lines are sensitive to afatinib in vitro and result in reduced EGFR pathway signaling and increased cellular apoptosis.43,44 This finding launched a series of clinical trials, named the LUX-Lung studies, to evaluate the efficacy of afatinib in EGFR-driven lung cancers. In the LUX-Lung 1 study, patients with advanced NSCLC and prior treatment with chemotherapy and EGFR-TKIs were found to have an improved PFS when treated with afatinib compared with those who received best supportive care (HR 0.38; P<.0001),45 although RRs were only 7% and there was no improvement in overall survival (OS), the primary end point. While outcomes for patients with EGFR mutations and T790M-mediated resistance were not available, 34% of enrolled patients did meet Jackman criteria for acquired resistance.45
Importantly, afatinib and other quinazoline inhibitors of EGFR, such as erlotinib, bind wild-type and mutant EGFR, thereby causing well-known toxicities of skin rash and diarrhea. These dose-limiting toxicities may prevent afatinib and other irreversible EGFR-TKIs from reaching concentrations necessary to effectively inhibit T790M-mediated resistance. The discovery of novel covalent pyrimidine EGFR inhibitors that are more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, has led to an exciting new area of investigation against secondary resistance to EGFR-TKIs using mutant-selective inhibitors that do not cause the expected toxicities.46 One such “third-generation” EGFR-TKI, CO-1686, is currently being studied in a phase 1/2 clinical trial for patients previously treated with EGFR-mutant NSCLC (NCT01526928).
AP26113 is another novel TKI with potent activity against both mutated EGFR and EGFR T790M without affecting wild-type EGFR. AP26113 also inhibits NSCLC tumors driven by ALK rearrangements (described below). Preliminary results from a phase 1/2 study of AP26113 demonstrated it to be well tolerated with favorable antitumor activity.47 The ongoing phase 2 study is enrolling 4 cohorts: patients with NSCLC and acquired resistance to EGFR-TKIs, patients with ALK-rearranged NSCLC who are either treatment naive or have developed acquired resistance to ALK-targeted therapy, and patients with other cancers with ALK-rearrangements (NCT01449461).
Cetuximab and Afatinib
Studies evaluating the EGFR-directed monoclonal antibody cetuximab have shown mixed results in NSCLC – meager improvements in OS when combined with first-line chemotherapy (11.3 months vs 10.1 months; HR 0.871; P=.044), and RRs of only 5% when used as a single agent.48-50 In addition, the combination of erlotinib and cetuximab failed to lead to significant radiographic responses in patients with acquired resistance.51 However, preclinical mouse models of lung adenocarcinoma harboring T790M mutations have shown surprisingly potent synergy when combining cetuximab with the irreversible EGFR inhibitor afatinib.52 Early results of a phase 1b multicenter international trial testing this combination presented in 2011 showed a 31% confirmed partial response (PR) rate and 94% clinical benefit rate in patients with T790M-mutated NSCLC who had clinically defined acquired resistance to first-generation TKIs.53 Because of these promising results, enrollment was expanded to patients in a phase 2 study, which has recently closed to accrual (NCT01090011).
Direct targeting of MET is another possible therapeutic approach for overcoming resistance to
EGFR-TKIs. Preclinical data suggest that inhibition of MET signaling in cell lines with EGFR resistance and MET amplification may restore sensitivity to EGFR inhibitors.37 Tivantinib (ARQ 197) and MetMAb have been combined with erlotinib and studied in large numbers of unselected patients. These data suggest that such a combination can be safely given, but there have been no tests of MET inhibitors with or without erlotinib in acquired resistance to EGFR-TKIs.54,55
There is extensive preclinical rationale for the use of HSP90 inhibitors in acquired resistance to EGFR-TKIs. HSP90 chaperone proteins stabilize many oncoproteins important in NSCLC, including EGFR and MET, and when lung cancer cell lines are treated with HSP90 inhibitors, mutated EGFR can be effectively degraded.56 Mouse models harboring EGFR L858R and T790M mutations also undergo tumor regression when treated with HSP90 inhibitors.52
Two HSP90 inhibitors (IPI-504 and STA-9090) have been evaluated in phase 2 trials that included patients with EGFR mutations previously treated with erlotinib. In both of these studies, response rates were low among patients with EGFR mutations, although patients whose tumors were EGFR wild-type had impressive tumor shrinkage and were found retrospectively to harbor ALK rearrangements (described in more detail below).57,58
However, 2 additional studies investigating a third HSP90 inhibitor, AUY922, have recently been presented with more promising results for patients with EGFR mutations. Garon and colleagues reported the results of a single-agent phase 2 study evaluating AUY922 in previously treated patients with advanced NSCLC stratified by mutation subtype. Of 33 patients with EGFR mutations, 6 sustained a PR (18%).59 We reported the preliminary results of a phase 1 trial designed specifically for patients with acquired resistance to EGFR-TKIs in which patients were treated with the combination of AUY922 and erlotinib (to avoid disease flare associated with discontinuation of erlotinib in patients who develop acquired resistance).60 This drug combination was well tolerated, and 1 patient treated at the highest dose level achieved a PR. A phase 2 study evaluating the efficacy of erlotinib and AUY922 is ongoing.
ALK and Crizotinib
Gene rearrangements involving ALK, most often with the echinoderm microtubule-associated protein-like 4, are found in 3% to 5% of patients with NSCLC. In these fusion genes, ALK is constitutively activated and drives tumor development through upregulation of cell survival pathways including PI3K-AKT and MEK-ERK (Figure).61,62 Patients harboring ALK rearrangements in their lung cancer tumors tend to be younger, never or light smokers with adenocarcinoma histology.63
ALK is the second molecular target to be validated in NSCLC64 and is targeted with crizotinib, a TKI with RRs of approximately 60% and a disease control rate of 80% in ALK-positive tumors.31,63 Based on phase 1 and 2 studies, the FDA granted crizotinib accelerated approval for the treatment of patients with NSCLC and ALK rearrangements in August 2011. Although most patients with ALK rearranged lung cancers will initially respond to crizotinib, a few cases of primary resistance have also been reported.65 Nevertheless, all patients develop acquired resistance at a median of 9 months,31 similar to EGFR-mutant lung cancer.26
Acquired Resistance to Crizotinib
Several groups have reported molecular analysis of posttreatment tumors obtained from patients after development of acquired resistance to crizotinib,65-68 revealing multiple mechanisms of resistance including secondary mutations in ALK, increased ALK copy number gain, upregulation of parallel signaling pathways including EGFR and KIT, and acquisition of secondary oncogene mutations.
Choi and colleagues66 identified an acquired L1196M point mutation within ALK, analogous to gatekeeper mutations described in EGFR and BCR-ABL (Table). In addition to the L1196M point mutation, a second mutation, C1156Y, was also identified in the same patient’s sample. In the 2 largest series of postbiopsy specimen obtained from patients treated with crizotinib, additional mutations in the ALK kinase were reported. Katayama and colleagues observed 3 missense mutations (L1196M, G1202R, and S1206Y) and 1 insertion mutation (1151Tins) in 4 of 18 patients with acquired resistance to crizotinib; all of these were associated with crizotinib resistance in vivo.68 Doebele and colleagues identified 2 L1196M and 2 G1269A point mutations in 4 of 11 patients.65 All secondary mutations in ALK reported in these 2 series were noted to be located within or near the binding pocket for ATP and crizotinib. In contrast to the T790M gatekeeper mutation, which accounts for the vast majority of secondary resistance mutations in EGFR, the varied secondary mutations reported in ALK all occur at a relatively low prevalence (22%-36%).
ALK Copy Number Gain
ALK copy number gain, defined as a more than 2-fold increase in the mean of the rearranged gene per cell, has been identified as a mechanism of acquired resistance to crizotinib. Two of 11 patients in the series reported by Doebele et al exhibited a marked increase in both the number of the ALK rearrangements per cell as well as the number of cells with EML4-ALK rearrangements. One patient demonstrated ALK copy number gain in addition to an ALK mutation, while the second patient had only ALK copy number gain, suggesting that ALK copy number gain may be the primary event in developing resistance, followed by the accumulation of mutations within the ALK kinase.65
Analogous to the development of MET amplification in EGFR-resistant tumors, parallel signaling pathways that activate effectors downstream of ALK in the presence of crizotinib can also lead to the development of acquired resistance in ALK-positive patients.32 Upregulation of EGFR and KIT signaling have been identified as 2 potential bypass track signaling pathways.67,68 Using a cell line created from a patient with acquired resistance to crizotinib due to an acquired L1152R point mutation, tumor cells were found to secrete the EGFR ligand amphiregulin, indicating that dependence on EGFR signaling had developed in the setting of resistance to crizotinib.67 When comparing matched samples pretreatment and posttreatment with crizotinib, Katayama et al reported that increased EGFR expression measured by immunohistochemical staining was observed in 4 of 9 patients with ALK rearrangements, although no activating EGFR mutations were found.68 One of these patients had a secondary mutation in ALK in addition to increased EGFR activation. In the same study, marked KIT amplification by fluorescence in situ hybridization was measured in another patient’s tumor, suggesting a second avenue by which bypass signaling might develop. Finally, 1 additional patient was found to have both focal KIT amplification and a secondary ALK mutation, illustrating once again that multiple mechanisms of resistance may be encountered in a single patient’s tumor specimen.68
Methods for Overcoming Crizotinib Resistance
Several second-generation ALK inhibitors are currently in clinical development for use in patients with acquired resistance to crizotinib, including CH5424802 (Chugai Pharmaceutical), LDK378 (Novartis), and AP26113 (ARIAD). Preliminary results from the phase 1 study of CH5424802 in ALK-positive NSCLC patients who were ALK inhibitor naive were recently reported.69 Although the phase 1 portion did not identify a maximum tolerated dose (MTD), at dose levels of 240 mg twice daily or higher, all 15 patients (100%) with measurable disease had a PR to treatment. The phase 2 study will enroll patients who are crizotinib resistant and ALK inhibitor naive to separate arms (NCT01588028).
Interim results from the phase 1 trial of LDK378 in patients with ALK-positive NSCLC and prior exposure to crizotinib have also been reported.70 The MTD was determined to be 750 mg orally daily. In patients who received doses greater than 400 mg daily, 21 of 26 (81%) had PRs to treatment, and responses within the central nervous system were reported in patients treated with 750 mg daily. The phase 2 portion of this study will enroll several cohorts, including patients who are crizotinib naive, patients with acquired resistance to crizotinib, and patients with other ALK-positive solid tumors (NCT01283516).
Preliminary results from a phase 1/2 clinical trial of AP26113, a dual inhibitor with activity in ALK-positive patients with acquired resistance to crizotinib as well as patients with resistance to EGFR-TKIs, were also recently reported. Of 11 patients with ALK rearrangements, 8 achieved a PR to treatment with AP26113, including 6 with acquired resistance to prior crizotinib.47 As described above, expansion of the phase 2 portion into 4 distinct molecular cohorts is ongoing (NCT01449461).
In addition to ALK inhibitors, HSP90 inhibitors are another drug class to show preferential activity in patients with ALK-rearranged NSCLC. Relevant HSP90 client proteins including KIT, EGFR, BRAF, AKT, and MET are key effectors of signaling pathways that may be upregulated in acquired resistance to crizotinib.71,72 A phase 2 trial investigating HSP90 inhibitor IPI-504 in patients with previously treated advanced NSCLC showed that the patients with the highest responses rates and longest PFS outcomes harbored ALK rearrangements in their tumors.57 Subsequent preclinical studies verified HSP90 inhibitors to be effective against ALK-positive NSCLC cell lines and mouse models, and perhaps more potent inhibitors against ALK-positive NSCLC than EGFR-mutant lung cancers.73 In another phase 2 trial evaluating HSP90 inhibitor STA-9090 in advanced NSCLC, responses were seen in 7 of 8 ALK-positive patients, with confirmed objective responses in 4 of 8 ALK-positive patients.58 HSP90 inhibitors have been shown effective in several models of crizotinib-mediated acquired resistance, and the combination of crizotinib and HSP90 inhibitors has synergistic antitumor activity in vitro.62,67,68 A trial of crizotinib and STA-9090 in the first-line setting is ongoing (NCT01579994).
While the discovery of oncogenes such as EGFR and ALK has allowed important therapeutic advances for patients with lung adenocarcinoma, it has also catalyzed the development of tumor-mediated treatment resistance. Reversing acquired resistance, or preventing its development, has become the focus of research efforts, first to identify the variable mechanisms by which TKI resistance begins, and subsequently to identify novel small-molecule inhibitors capable of circumventing this phenomenon. Combination therapies, for example those that block both oncogene and bypass track signaling pathways, may prove to be effective for treating acquired resistance in NSCLC.
Dr Johnson: research funding (Novartis); consultant (Genentech); spouse contracted employee as Governmental Affairs lobbyist (Astellas). Dr Gentzler: no disclosures. Dr Yu: no disclosures. Dr Riely: research funding (Pfizer, Chugai 2012); consultant (Novartis, Daiichi Sankyo, Tragara, Chugai 2011, ARIAD, Celgene, Foundation Medicine, Abbott Molecular).
1. Kris MG, Johnson BE, Kwiatkowski DJ. Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: the NCI’s Lung Cancer Mutation Consortium (LCMC). J Clin Oncol. 2011;29(suppl). Abstract CRA7506.
2. Lurje G, Lenz HJ. EGFR signaling and drug discovery. Oncology. 2009;77:400-410.
3. Bunn PA Jr, Franklin W. Epidermal growth factor receptor expression, signal pathway, and inhibitors in non-small cell lung cancer. Semin Oncol. 2002;29(suppl 14):38-44.
4. Kosaka T, Yatabe Y, Endoh H, et al. Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res. 2004;64:8919-8923.
5. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359:1367-1380.
6. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol. 2003;21:3798-3807.
7. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129-2139.
8. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497-1500.
9. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101:13306-13311.
10. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:
11. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005;366:1527-1537.
12. Pao W, Chmielecki J. Rational, biologically based treatment of EGFR- mutant non-small-cell lung cancer. Nat Rev Cancer. 2010;10:760-774.
13. Nguyen KS, Kobayashi S, Costa DB. Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clin Lung Cancer. 2009;10:281-289.
14. Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non–small-cell lung cancer. J Clin Oncol. 2003;21:2237-2246.
15. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003;290:2149-2158.
16. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer – molecular and clinical predictors of outcome. N Engl J Med. 2005;353:133-144.
17. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-
paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957.
18. Han JY, Park K, Kim SW, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012;30:1122-1128.
19. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380-2388.
20. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121-128.
21. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735-742.
22. Rosell R, Carcereny E, Gervais R, et al. 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. 2012;13:
23. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Non-Small Cell Lung Cancer. Version 2.2013. www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed January 20, 2013.
24. Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol. 2011;29:2121-2127.
25. Jackman D, Pao W, Riely GJ, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol. 2010;28:357-360.
26. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786-792.
27. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73.
28. Hochhaus A. Chronic myelogenous leukemia (CML): resistance to tyrosine kinase inhibitors. Ann Oncol. 2006;17(suppl 10):x274-x279.
29. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708-710.
30. Costa DB, Kobayashi S, Tenen DG, et al. Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non-small cell lung cancers. Lung Cancer. 2007;58:95-103.
31. Camidge DR, Bang Y, Kwak EL, et al. 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. 2011;29(suppl). Abstract 2501.
32. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707-714.
33. Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008;105:2070-2075.
34. Oxnard GR, Arcila ME, Sima CS, et al. 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. 2011;17:1616-1622.
35. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26.
36. Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A. 2007;104:20932-20937.
37. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039-1043.
38. Arcila ME, Oxnard GR, Nafa K, et al. 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. 2011;17:1169-1180.
39. Guix M, Faber AC, Wang SE, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest. 2008;118:2609-2619.
40. Chaft JE, Arcila ME, Paik PK, et al. Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma – rationale for comprehensive mutation profiling. Clin Cancer Res. 2012;11:485-491 .
41. Tatematsu A, Shimizu J, Murakami Y, et al. Epidermal growth factor receptor mutations in small cell lung cancer. Clin Cancer Res. 2008;14:6092-6096.
42. Oxnard GR, Arcila ME, Chmielecki J, et al. New strategies in overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer. Clin Cancer Res. 2011;17:5530-5537.
43. Kwak EL, Sordella R, Bell DW, et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A. 2005;102:7665-7670.
44. Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008;27:4702-4711.
45. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012;13:528-538.
46. Zhou W, Ercan D, Chen L, et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature. 2009;462:1070-1074.
47. Gettinger S, Weiss G, Salgia R, et al. A first-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies. Paper presented at: ESMO Congress 2012; September 28-October 2, 2012; Vienna, Austria. Abstract 4390.
48. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-
label randomised phase III trial. Lancet. 2009;373:1525-1531.
49. Lynch TJ, Patel T, Dreisbach L, et al. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol. 2010;28:911-917.
50. Hanna N, Lilenbaum R, Ansari R, et al. Phase II trial of cetuximab in patients with previously treated non-small-cell lung cancer. J Clin Oncol. 2006;24:5253-5258.
51. Janjigian YY, Azzoli CG, Krug LM, et al. Phase I/II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib. Clin Cancer Res. 2011;17:2521-2527.
52. Regales L, Gong Y, Shen R, et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest. 2009;119:3000-3010.
53. Horn L, Smit EF, Janjigian YY, et al. Activity and tolerability of combined EGFR targeting with afatinib (BIBW 2992) and cetuximab in T790M+ NSCLC patients. J Thorac Oncol. 2011;6:S361.
54. Sequist LV, von Pawel J, Garmey EG, et al. Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J Clin Oncol. 2011;29:3307-3315.
55. Spigel DR, Ervin TJ, Ramlau R, et al. Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC. J Clin Oncol. 2011;29(suppl). Abstract 7505.
56. Ueno T, Tsukuda K, Toyooka S, et al. Strong anti-tumor effect of NVP-AUY922, a novel Hsp90 inhibitor, on non-small cell lung cancer. Lung Cancer. 2012;76:26-31.
57. Sequist LV, Gettinger S, Senzer NN, et al. Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. J Clin Oncol. 2010;28:4953-4960.
58. Wong K, Koczywas M, Goldman JW, et al. An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) as monotherapy in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2011;29(suppl). Abstract 7500.
59. Garon EB, Moran T, Barlesi F, et al. Phase II study of the HSP90 inhibitor AUY922 in patients with previously treated, advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2012;30(suppl). Abstract 7543.
60. Chaft JE, Oxnard GR, Sima CS, et al. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clin Cancer Res. 2011;17:6298-6303.
61. Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 2008;14:4275-4283.
62. Katayama R, Khan TM, Benes C, et al. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A. 2011;108:7535-7540.
63. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247-4253.
64. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561-566.
65. Doebele RC, Pilling AB, Aisner D, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012;18:1472-1482.
66. Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010;363:1734-1739.
67. Sasaki T, Koivunen J, Ogino A, et al. A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res. 2011;71:6051-6060.
68. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4:120ra117.
69. Kiura K, Seto T, Yamamoto N, et al. A first-in-human phase I/II study of ALK inhibitor CH5424802 in patients with ALK-positive NSCLC.
J Clin Oncol. 2012;30(suppl). Abstract 7602.
70. Mehra R, Camidge DR, Sharma S, et al. First-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors. J Clin Oncol. 2012;30(suppl). Abstract 3007.
71. Neckers L. Chaperoning oncogenes: Hsp90 as a target of geldanamycin. Handb Exp Pharmacol. 2006;(172):259-277.
72. Workman P, Burrows F, Neckers L, et al. Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann N Y Acad Sci. 2007;1113:202-216.
73. Normant E, Paez G, West KA, et al. The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models. Oncogene. 2011;30:2581-2586.
Molecular subtyping of early breast cancers using MammaPrint and BluePrint allows precise and accurate prediction of the molecular phenotype of the disease, which has the potential to guide selection of personalized therapy if the tests are used prospectively. A retrospective study of 208 tumor samples found that molecular subtyping with [ Read More ]
The preferred screening test for HER2 status in surgical esophageal adenocarcinoma specimens is immunohistochemistry (IHC), with fluorescence in situ hybridization (FISH) restricted to cases with an indeterminate (2+) IHC score, according to investigators from the Mayo Clinic, Rochester, MN, who proposed a testing algorithm at the 2013 GI Cancers Symposium. [ Read More ]