Evolving Treatment Paradigms in Non-Small Cell Lung Cancer

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1 PRINTER-FRIENDLY VERSION AT PHARMACYPRACTICE NEWS.COM Evolving Treatment Paradigms in Non-Small Cell Lung Cancer CALEB T. CHU, MD, MPH Postdoctoral Fellow Department of Thoracic/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas MARGARET E. M. VAN METER, MD Medical Oncology Fellow Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, Texas EDWARD S. KIM, MD Associate Professor of Medicine Department of Thoracic/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas Lung cancer is the leading cause of cancer-related death in the United States, accounting for 30% and 26% of all cancer deaths in men and women, respectively, and exceeding the predicted death rates for breast and colorectal cancers combined. 1 Non-small cell lung cancer (NSCLC) is the most common histologic subtype and accounts for more than 80% of lung cancers. Although locally resectable NSCLC can be cured with surgical intervention, very few patients present with early-stage disease. Unfortunately, the majority present with advanced (stages IIIB and IV) disease; surgery and radiotherapy are not routinely part of care for these patients. Overall survival (OS) for these groups of patients has improved only modestly over the past few decades through advances in chemotherapy; median OS has improved by approximately 2 months, providing 1-year survival rates of about 30% for patients receiving chemotherapy compared with 10% for those receiving supportive care. More recently, the advent of newer chemotherapy regimens has increased median survival times from 8 to 11 months in patients treated with standard doublet chemotherapy regimens. 2 The addition of biologic agents and efforts to focus their use PHAMACY PRACTICE NEWS JUNE

2 in specific patient populations have further increased efficacy, with median survival times in some studies exceeding 12 months. 3 Although previous studies of cytotoxic chemotherapy demonstrated no improvement in outcome when regimens were administered for more than 4 to 6 cycles, recent studies in the maintenance setting indicate that more prolonged therapy may be desirable. 4 As treatment strategies evolve and chemotherapies and biologic therapies are being increasingly integrated, a more personalized approach should be used to provide the most effective and least toxic treatments to patients with advanced NSCLC. Conventional Chemotherapy Platinum-based doublet regimens are the mainstay of chemotherapy in patients with advanced NSCLC and a good performance status (PS). The survival benefit of cisplatin in the treatment of NSCLC was established in 1995, based on a meta-analysis that included 52 clinical trials with more than 9,000 patients; in the trials involving patients with advanced disease, cisplatin-based chemotherapy showed a 27% reduction in the risk for death at 1 year. 5 Thus, in 1997, the American Society of Clinical Oncology (ASCO) issued guidelines recommending the use of cisplatin-based chemotherapy for patients with advanced NSCLC and a good PS. Given the toxicity of cisplatin-based regimens, much effort over the past decade has been directed toward developing better-tolerated, equally efficacious treatments. To this end, trials have evaluated the use of newer agents, either as monotherapy or in combination regimens, as well as the use of carboplatin in lieu of cisplatin in doublet regimens. In comparisons of platinum-based doublets, 2 variables must be considered: the platinum agent used (cisplatin or carboplatin) and the agent combined with the platinum agent. The principal drugs combined with a platinum agent in the third-generation doublets are gemcitabine (Gemzar, Lilly), vinorelbine, docetaxel (Taxotere, Sanofi-aventis), paclitaxel, and pemetrexed (Alimta, Lilly). A large trial comparing cisplatin-paclitaxel with 3 other regimens carboplatin-paclitaxel, cisplatin-docetaxel, and cisplatin-gemcitabine in 1,155 patients with advanced NSCLC showed no significant difference in OS (median 7.9 months) among the 4 regimens. 6 It is notable, however, that patients in the carboplatin-paclitaxel arm had a slightly lower rate of serious toxicities and that the study was limited to patients with an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1; initial analysis showed a higher rate of adverse events in patients with a PS of 2. The largest Phase III study ever performed in the first-line treatment of advanced NSCLC (N=1,725) compared cisplatin-pemetrexed with cisplatin-gemcitabine. 7 A statistically significant survival advantage was demonstrated for patients with adenocarcinoma or large-cell carcinoma histology treated with cisplatin-pemetrexed compared with cisplatin-gemcitabine (median OS, 11.8 and 10.4 months, respectively; hazard ratio [HR], 0.81; 95% confidence interval [CI], ; P=0.005). In contrast, patients with squamous cell histology had a shorter median survival when treated with cisplatin-pemetrexed (OS, 9.4 vs 10.8 months; HR, 1.23; 95% CI, ; P=0.05). This was the first Phase III trial to prospectively show a survival difference based on NSCLC histology. Newer Targeted Therapies With the advent of new targeted therapies, first-line chemotherapy for advanced NSCLC is changing. Given the limited ability of current chemotherapy regimens to prolong OS, new drug development has focused on improving tolerance, quality of life, and ease of administration while maintaining at least comparable efficacy to standard first-line therapy. The Phase III ECOG 4599 trial evaluated first-line platinum doublet therapy (carboplatin-paclitaxel) with and without the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab (Avastin, Genentech) in patients with advanced nonsquamous NSCLC. 3 Treatment in the experimental arm included bevacizumab combined with chemotherapy every 3 weeks for 6 cycles, followed by maintenance bevacizumab every 3 weeks until progressive disease or intolerable side effects occurred. Median OS, the primary end point, increased by 2 months (12.3 vs 10.3 months; HR, 0.79; 95% CI, ; P=0.003) with the addition of bevacizumab. Statistically significant improvements in response rate (35% vs 15%) and progression-free survival (PFS; 6.2 vs 4.5 months) also were observed. The pivotal FLEX (First-Line Erbitux in Lung Cancer) trial compared the cisplatin-vinorelbine doublet plus the anti-epidermal growth factor receptor (EGFR) antibody cetuximab (Erbitux, Bristol-Myers Squibb) with cisplatin-vinorelbine alone in patients with EGFRexpressing advanced NSCLC. 8 Cetuximab was given together with doublet chemotherapy for 6 cycles and continued as maintenance therapy until progressive disease or intolerable side effects developed. For the entire intention-to-treat population, median OS was 11.3 months in the cisplatin-vinorelbine-cetuximab arm and 10.1 months in those treated with cisplatin-vinorelbine alone (HR, 0.871; 95% CI, ; P=0.044). Prespecified subgroup analysis showed that the survival benefit of treatment that included cetuximab persisted across most subgroups. However, gender, PS, histology, smoking status, and geographic region all had prognostic significance. Specifically, women had longer survival times than men (12.7 vs 9.3 months), Asians had a longer survival than whites (19.5 vs 9.6 months), and patients with a higher PS and those who had never smoked had better prognoses than patients with lower PS and smokers. Data presented at the ASCO meeting in 2009 expanded on prognostic factors and molecular predictors of OS from the FLEX trial. In one analysis, KRAS 2

3 mutational status was found not to be predictive for cetuximab efficacy, but patients taking cetuximab who developed an acne-like rash had a longer median OS than those without the rash (15 vs 8.8 months; HR, 0.63; 95% CI, ; P<0.001). 9 Improvements in OS seen with molecular-targeted therapies against VEGF and EGFR in combination with platinum doublets in patients with advanced NSCLC 3,8 have led to further investigation of the combined effects. The SWOG (Southwest Oncology Group) 0536 Phase II study combined 4 drugs cetuximab, bevacizumab, carboplatin, and paclitaxel for up to 6 cycles, followed by maintenance bevacizumab weekly until disease progression. 10 The primary end point was the frequency and severity of hemorrhagic toxicities that were grade 4 or higher in patients with advanced-stage nonsquamous NSCLC. Combining carboplatin, paclitaxel, cetuximab, and bevacizumab resulted in a tolerable safety profile, with a 2% incidence of hemorrhage that was grade 4 or higher (95% CI, 0%-7%). An ongoing Phase III trial (SWOG 0819) is comparing the 4-drug regimen used in SWOG 0536 with the 3-drug regimen used in ECOG 4599 (carboplatin-paclitaxel-bevacizumab). The studies described above have evaluated biologic targeted agents in combination with cytotoxic chemotherapy. Two additional Phase III studies, INTEREST (Iressa NSCLC Trial Evaluating Response and Survival against Taxotere) and IPASS (First-line Iressa versus Carboplatin/ Paclitaxel in Asia), compared single-agent biologic therapy using the oral EGFR tyrosine kinase inhibitor (TKI) gefitinib (Iressa, AstraZeneca) with traditional chemotherapeutic agents, with favorable outcomes. INTEREST is a randomized Phase III trial comparing gefitinib with docetaxel in patients with advanced NSCLC who had previously received at least 1 platinum-based chemotherapy regimen. 11 Patients received either gefitinib daily or docetaxel every 3 weeks until disease progression or unacceptable toxicity. The primary end point was OS, analyzed via noninferiority in the overall population and superiority in patients with a high EGFR copy number. Results for all 1,433 patients confirmed noninferiority of gefitinib compared with docetaxel for OS (7.6 vs 8 months; HR, 1.020; 95% CI, ). However, in the 174 patients with a high number of EGFR gene copies, gefitinib did not show superiority for OS (8.4 vs 7.5 months; HR, 1.09; 95% CI, ; P=0.62). Subsequent biomarker analysis of EGFR and KRAS in tumor biopsies from the INTEREST trial showed similar OS in patients treated with gefitinib and docetaxel, regardless of biomarker subgroup. However, patients with EGFR mutations had longer PFS and higher objective response rate (ORR), and patients with high EGFR copy numbers had higher ORR when treated with gefitinib compared with docetaxel. 12 Recent data from the IPASS trial have shown that gefitinib also is a valid first-line therapy for a subset of patients. 13 This study included patients in East Asia with advanced NSCLC of adenocarcinoma histology who had a World Health Organization PS of 0 to 2 and were never smokers or former light smokers. The primary end point was PFS; median PFS was similar in those treated with gefitinib and those treated with carboplatin-paclitaxel (5.7 vs 5.8 months), but the Kaplan- Meier curves crossed at this point, and patients treated with gefitinib had a significantly higher rate of PFS at 12 months (24.9% vs 6.7%), with an overall HR of 0.74 (95% CI, ; P<0.0001). Preliminary OS (28% maturity with follow-up ongoing) was similar for gefitinib and carboplatin-paclitaxel, but gefitinib demonstrated improved quality-of-life ratings and a more favorable tolerability profile. In the IPASS trial, EGFR mutational status appeared to be a strong biomarker for gefitinib efficacy. 13 Similar analysis has shown that EGFR mutations also are associated with responsiveness to erlotinib (Tarceva, OSI Pharmaceuticals). 14 These findings indicate that genetic screening of patients prior to therapy may be warranted to allow clinicians to tailor therapy to individual patients. The study results also highlight a need for a paradigm shift toward molecular profiling in the treatment of advanced NSCLC to improve tolerability of therapy. Maintenance Therapy Debate continues about delayed (second- or thirdline) versus immediate (maintenance) chemotherapy in patients who already have received first-line therapy. Multiple trials have examined the role of maintenance chemotherapy after completion of initial chemotherapy in advanced NSCLC (Table). 4,15-21 Maintenance chemotherapy could be either continuation of 1 or more of the initial chemotherapy agents or the addition of a new chemotherapeutic or targeted agent. In one multicenter Phase III trial, patients with advanced NSCLC who did not have evidence of disease progression after first-line treatment with 4 cycles of carboplatin-gemcitabine were randomized to receive docetaxel either immediately or at disease progression. 19 Maintenance docetaxel was associated with a statistically significant improvement in PFS (5.7 vs 2.7 months; P=0.0001) and a trend toward improvement in OS (median 12.3 vs 9.7 months; P=0.0853). Several large Phase III trials of maintenance therapy reported at the 2009 ASCO annual meeting used erlotinib, erlotinib plus bevacizumab, or pemetrexed as maintenance therapy. The large Phase III SATURN trial tested erlotinib maintenance versus placebo after platinum-based doublet chemotherapy in 1,949 patients with advanced NSCLC. The SATURN trial met its primary end point of PFS, with results showing significantly increased PFS with erlotinib in all patients (HR, 0.71; 95% CI, ; P<0.0001), and improved OS (12 vs 11 months). 20 In exploratory analysis, an even greater benefit was seen in a subset of patients who had EGFR mutations. Based on this information, in April 2010, the FDA approved erlotinib for maintenance treatment of patients with advanced or metastatic NSCLC whose disease has not progressed after 4 cycles of 3

4 Table. Selected Trials of Maintenance Therapy in Advanced NSCLC Clinical Trial Treatment Arms N PFS, mo Median OS, mo Fidias et al 19 GC, then immediate docetaxel GC, then delayed docetaxel (P=0.001) (P=0.0853) 9.7 Capuzzo et al 20 (SATURN) CT, then E CT, then P PFS was significantly prolonged with E versus P in all patients (HR, 0.71; 95% CI, ; P<0.0001) Ciuleanu et al 4 Pemetrexed + BSC P + BSC Overall/NSQ/SQ 4.3/4.5/ /2.6/2.6 Overall/NSQ/SQ 13.4/15.5/ /10.3/10.8 Miller et al 21 (ATLAS) CT + B, then B + P CT + B, then B + E (P=0.0012) 4.8 NA B, bevacizumab; BSC, best supportive care; CI, confidence interval; CT, first-line platinum-based chemotherapy; E, erlotinib; GC, gemcitabine-carboplatin; HR, hazard ratio; NA, not available; NSCLC, non-small cell lung cancer; NSQ, nonsquamous histology; OS, overall survival; P, placebo; PFS, progression-free survival; SQ, squamous cell histology platinum-based first-line chemotherapy. Another Phase III trial evaluated pemetrexed and led to its July 2009 FDA approval as maintenance therapy (in patients with locally advanced or metastatic nonsquamous NSCLC whose disease has not progressed after 4 cycles of platinum-based first-line chemotherapy). This trial included 663 patients with advanced NSCLC who did not progress on an initial platinum-based doublet and showed that pemetrexed maintenance resulted in significantly better OS (13.4 vs 10.6 months; HR, 0.79; 95% CI, ; P=0.012) and PFS (4.3 vs 2.6 months; HR, 0.50; 95% CI, ; P<0.0001) than placebo. 4 Pemetrexed s efficacy, favorable tolerability profile, ease of administration, and OS benefit make it appealing as a maintenance drug in advanced NSCLC. Although most studies discussing maintenance options at the ASCO 2009 annual meeting tested non cross-resistant regimens, the ATLAS Phase III trial evaluated bevacizumab with or without erlotinib after completion of chemotherapy with bevacizumab for first-line treatment of advanced NSCLC. 21 This study, the first to evaluate combination versus singleagent maintenance therapy options, showed significant improvement in PFS in the group receiving combination therapy (4.8 vs 3.7 months; HR, 0.722; 95% CI, ; P=0.0012). Biomarkers and Therapy As discussed above, many of the recent advances in the treatment of NSCLC have involved the integration of targeted therapeutics and can more accurately define the subset of patients who are most likely to benefit from a given treatment. Thus, it is more important now than ever before to explore predictors of efficacy to help direct the best therapy for each patient. In clinical practice, factors such as smoking history, histology, gender, or ethnicity may help determine the choice of therapy. Genotypic correlates to response are being actively pursued. HISTOLOGY The importance of histology has been highlighted clearly for the use of pemetrexed in the treatment of advanced NSCLC in multiple settings. The large study by Scagliotti et al described above found that patients with nonsquamous tumors had a survival advantage when treated first-line with cisplatin-pemetrexed compared with those treated with cisplatin-gemcitabine, whereas those with squamous cell histology had a shorter median survival when treated with cisplatin-pemetrexed. 7 This was the first prospective study to show survival differences based on histology. A study by Hanna et al comparing pemetrexed and docetaxel in the second-line setting 22 was subsequently analyzed retrospectively using subset histology data 23 ; patients with nonsquamous NSCLC had a significant improvement in OS when treated with pemetrexed compared with those treated with docetaxel (9.3 vs 8.0 months; HR, 0.778; P=0.048). When pemetrexed was used as maintenance therapy by Ciuleanu et al, the improvements in PFS and OS were documented primarily in patients with nonsquamous histology. 4 One possible explanation for the observed differential efficacy of pemetrexed is that baseline thymidylate synthase (TS) levels are higher in squamous cell carcinoma than in adenocarcinoma. 24 Data on TS expression recently have been broadened to include undifferentiated large cell carcinoma. In a study presented at the ASCO meeting in 2009, significantly higher median mrna and protein TS levels were detected in large cell and squamous cell carcinoma 4

5 Adenocarcinoma or nonsquamous Squamous EGFR mutation- positive EGFR mutation- negative or unknown Chemotherapy doublet with or without cetuximab a Gefitinib Erlotinib Bevacizumab + chemotherapy doublet a Non-bevacizumab chemotherapy doublet (pemetrexed-based) a Maintenance therapy Pemetrexed a Erlotinib with or without bevacizumab Docetaxel Disease progression Salvage therapy Consider clinical trial Figure. Proposed algorithm for treatment of NSCLC. a FDA-approved regimens EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer samples compared with adenocarcinoma samples (large cell carcinoma: P<0.001 for both mrna and protein values; squamous cell carcinoma: P=0.002 for mrna, P<0.001 for protein). 25 EGFR, VEGF, AND KRAS Somatic mutations in the tyrosine kinase domains of two erbb genes the EGFR and HER-2 (human epidermal growth factor receptor 2) genes have been found in lung adenocarcinomas. EGFR mutations, particularly those in exon 19, are associated with sensitivity to the TKIs gefitinib and erlotinib. 29 However, markers of resistance to EGFR inhibitors also have been identified, including the T790M mutation in exon ,31 Approximately 15% to 30% of lung adenocarcinomas contain activating mutations in the KRAS gene and may be associated with unfavorable outcomes. 32 Unlike in colon cancer, mutations in KRAS in lung cancer are not associated with a lack of sensitivity to either of the EGFR TKIs. 33 Thus, although patients with EGFR mutations had improved PFS when treated with maintenance erlotinib in the SATURN trial, KRAS mutations had no predictive value. 20 BROADER GENOTYPE TESTING With the emergence of EGFR mutations as an important target for therapy, strategies for treating patients harboring other mutations that make them refractory to treatment are being tested. EML4-ALK is a novel fusion oncogene in NSCLC. 34 The fusion results from a small inversion within chromosome 2p, leading to expression of a constitutively activated, chimeric tyrosine kinase. Shaw et al have shown that the presence of EML4-ALK results in a similar clinical profile to that seen in patients with EGFR mutations and is particularly frequent in light or never smokers; however, unlike EGFR mutations, EML4-ALK is found more often in men. 35 Patients with EML4-ALK tumors did not benefit from EGFR TKIs; there were no responses in the EML4- ALK cohort. A promising Phase I trial testing the ALK inhibitor PF showed an ORR of 57% (47 of 82 patients; 46 partial responses and 1 complete response) and 33% stable disease in patients with ALK rearrangements, with mainly grade 1 or 2 gastrointestinal side effects. 36 This has allowed for the early development of several Phase III trials of ALK inhibitors as single agents, as well as with chemotherapy as second-line therapy. 5

6 Another active area of research centers on mechanisms of resistance to EGFR TKIs, including amplification of the MET oncogene and secondary mutations in EGFR, such as the T790M mutation. Molecular testing for these abnormalities may eventually play a role in treatment selection. A recent Phase II study comparing the effects of the MET inhibitor METMAb plus erlotinib with placebo plus erlotinib showed nearly a 50% increase in OS and PFS in patients with high MET expression who received the MET combination therapy. 37 However, patients with a low expression of MET fared worse on combination MET-erlotinib versus erlotinib alone, leading to future investigations into the possible interference of METMAb with erlotinib s effectiveness. ARQ 197 is another MET-inhibiting targeted therapy that has showed promise in patients with nonsquamous histology, EGFR wild-type, and KRAS mutations. 38 Preliminary results from a Phase II study comparing erlotinib plus ARQ 197 to erlotinib plus placebo indicated a greater median PFS in the experimental arm (16.1 vs 9.7 weeks), with similar adverse effects between the 2 arms. On another molecular front, there has been increasing interest involving irreversible EGFR inhibitors, mainly through the discovery of the small-molecule EGFR TKI BIBW Differing from its predecessors, BIBW 2992 binds irreversibly to both EGFR and HER-2 and is active against both wild-type and multiple mutant forms of EGFR. Preliminary results from an ongoing Phase II study of patients with NSCLC who had tumors with EGFR-activating mutations and progressive or recurrent disease following chemotherapy showed a 78% to 94% disease control rate, depending on the mutation subset, when BIBW 2992 alone was used. 39 Additional Phase II/III studies are under way investigating use of BIBW 2992 in NSCLC patients in other treatment settings. demonstrated that different lung cancers respond differently to therapy. Efforts must continue to be made to understand the biology of individual tumors by emphasizing tissue-based clinical trials to create patient-specific therapy. 40 References 1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2): Breathnach OS, Freidlin B, Conley B, et al. Twenty-two years of Phase III trials for patients with advanced non-small-cell lung cancer; sobering results. J Clin Oncol. 2001;19(6): Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24): Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009;374: Non-small Cell Lung Cancer Collaborative Group (NSCL-CG). Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ. 1995;311(7010): Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346(2): Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21): 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(9674): Pirker R, Rodrigues-Pereira J, Szczesna A, et al. Prognostic factors in advanced NSCLC: experience from the FLEX trial. J Clin Oncol. 2009;27(15 suppl): Abstract Conclusion Paradigms in first-line and maintenance settings of advanced NSCLC are evolving toward targeted molecular therapies with better tolerability profiles. Based on recent studies, new standards of management in advanced NSCLC must be considered, evaluating the roles of histology, maintenance therapy, and testing for mutations in EGFR (Figure). Each patient with NSCLC presents a unique challenge, and therapy should be directed by more than simply PS. Agents targeting EGFR, VEGF, and ALK pathways in NSCLC have 10. Kim ES, Herbst RS, Moon J, et al. S0536: Carboplatin, paclitaxel, cetuximab and bevacizumab followed by cetuximab and bevacizumab maintenance in advanced non-small cell lung cancer (NSCLC), a SWOG phase II study. PD Presented at: 2009 IASLC World Congress on Lung Cancer; July 31-August 4, 2009; San Francisco, CA. 11. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small cell lung cancer (INTEREST): a randomized Phase III trial. Lancet. 2008;372(9652): Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized Phase III INTEREST trial. J Clin Oncol. 2009;28(5):

7 13. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10): Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10): Socinski MA, Schell MJ, Peterman A, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non small-cell lung cancer. J Clin Oncol. 2002;20(5): Park JO, Kim SW, Ahn JS, et al. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007;25(33): Westeel V, Quoix E, Moro-Sibilot D, et al. Randomized study of maintenance vinorelbine in responders with advanced non-small cell lung cancer. J Natl Cancer Inst. 2005;97(7): Sculier JP, Lafitte JJ, Lecomte J, et al. A phase III randomised trial comparing sequential chemotherapy using cisplatin-based regimen and paclitaxel to cisplatin-based chemotherapy alone in advanced non-small-cell lung cancer. Ann Oncol. 2007;18(6): Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27(4): Cappuzzo F, Ciuleanu T, Stelmakh L, et al. SATURN: A doubleblind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. J Clin Oncol. 2009;27:(15 suppl): Abstract Miller VA, O Connor P, Soh C, et al. A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2009;27:(18 suppl): Abstract LBA Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non smallcell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22(9): Peterson P, Park K, Fossella F, et al. Is pemetrexed more effective in adenocarcinoma and large cell carcinoma than in squamous cell carcinoma? A retrospective analysis of a phase III trial of pemetrexed vs docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC): P J Thorac Oncol. 2007;2(8):S851: Abstract P Ceppi P, Volante M, Saviozzi S, et al. Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer. 2006;107(7): , PMID: Scagliotti G, Monica V, Ceppi P, et al. Baseline thymidylate synthase expression according to histological subtypes of non-small cell lung cancer. J Clin Oncol. 2009;27:(15 suppl): Abstract 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(21): Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676): 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(36): Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer molecular and clinical predictors of outcome. N Engl J Med. 2005;353(2): 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(8): Morgillo F, Kim WY, Kim ES, Ciardello F, Waun KH, Lee HY. Implication of the insulin-like growth factor-ir pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res. 2007;13(9): Rodenhuis S, Slebos RJ. The ras oncogenes in human lung cancer. Am Rev Respir Dis. 1990;142(6 pt 2):S27-S Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005;2(1):e 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(7153): 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: Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363: Spigel D, Ervin T, Ramlau R, et al. MetMAb added to erlotinib improves survival in a subset of patients with lung cancer. Presented at: the ESMO 35th Congress; October 8-12, 2010; Milan, Italy; Abstract LBA Schiller JH, Akerley WL, Brugger W, et al. Results from ARQ : a global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naïve patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2010;28:(18 suppl): Abstract LBA Yang CH, Shih JY, Su WC, et al. A phase II study of BIBW 2992 in patients with adenocarcinoma of the lung and activating EGFR mutations (LUX-Lung 2). J Clin Oncol. 2010;28:(15 suppl): Abstract Kim ES, Herbst RS, Wistuba II, et al. The BATTLE Trial: Personalizing Therapy for Lung Cancer. Cancer Discovery 2011;1:OF42-OF51. 7

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