The efficacy of the oral ALK inhibitor crizotinib (C) compared with pemetrexed-platinum chemotherapy (PPC) has been demonstrated in the first-line setting in patients with advanced ALK+ non–small-cell lung cancer (NSCLC). The primary objective, progression-free survival (PFS), for this phase 3 study (PROFILE 1014; supported by Pfizer [NCT01154140]) was met and was previously published in 20141 (data cutoff 30 Nov 2013) along with an interim analysis of the secondary endpoint of overall survival (OS), which was not mature at that time, with approximately 17 months of follow-up and 26% of OS events. Here, we report the final analysis of OS based on the last patient visit of 30 Nov 2016.
Between Jan 2011 and Jul 2013, 343 patients with previously untreated, advanced nonsquamous ALK+ NSCLC were randomized 1:1 to receive oral C 250 mg twice daily (n = 172) or PPC (n = 171). Of patients who received PPC, 144 (84%) were treated with second-line C (crossover patients).
Median follow-up duration for OS was 46 months in both arms, and 41% and 47% of patients reported OS events in the C and PPC arms, respectively. There was a numerical improvement in OS with C compared with PPC (hazard ratio [HR], 0.760; 95% confidence interval [CI] 0.548, 1.053; 1-sided P = 0.0489) that did not reach statistical significance. The median OS was not reached [NR] (95% CI 45.8, NR) with C and was 47.5 months (95% CI 32.2, NR) with PPC. However, after adjusting for crossover (for both arms) with the rank-preserving structural failure time model, the HRs for OS were 0.346 (95% bootstrap CI 0.081, 0.718) and 0.353 (95% bootstrap CI 0.102, 0.739) based on the stratified log-rank test and stratified Wilcoxon test, respectively.
In this randomized study, which allowed crossover from PPC to C, there was long OS in both treatment arms. There was no statistically significant difference between C and PPC arms in the final OS analysis, which was impacted by the high percentage of patients randomized to PPC who received subsequent C. After adjusting for crossover, OS in the C arm was significantly longer than in the PPC arm. Reference: 1. Solomon BJ, et al. N Engl J Med. 2014;371:2167–2177.
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T.S.K. Mok: Honoraria from AstraZeneca, Roche/Genentech, Eli Lilly and Co., Bristol-Myers Squibb Co., Boehringer Ingelheim, Novartis Pharmaceuticals, MSD, and Pfizer, fees for serving on advisory boards from AstraZeneca, Roche/Genentech, Eli Lilly and Co., Merck Serono, Bristol-Myers Squibb Co., Pfizer, Boehringer Ingelheim, Novartis, Clovis Oncology, Vertex Pharmaceuticals, SFJ, ACEA BioSciences, MSD, geneDecode Oncogenex, Celgene, and Ignyta, and research funding from AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, SFJ, Roche/Genentech, MSD, Clovis Oncology, Bristol-Myers Squibb Co., Taiho Pharmaceutical Co., Ltd., and Eisai Co., Ltd., and holding stock in Sanomics Ltd. K. Nakagawa: Honoraria from Astellas Pharma Inc., AstraZeneca K.K., EPS Holdings Inc, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd, Showa Yakuhin Kako Co., Ltd, SymBio Pharmaceuticals Ltd., Daiichi Sankyo Co., Ltd, Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., Bristol-Myers Squibb Co., Novartis Pharma K.K., Kissei Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., MSD K.K., and Ayumi Pharmaceutical Corporation, and research funding from Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., EPS Associates Co., Ltd., Quintiles Inc., Daiichi Sankyo Co., Ltd, Japan Clinical Research Operations, Eisai Co., Ltd., PPD-SNBL K.K., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Taiho Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co., GlaxoSmithKline K.K., AstraZeneca K.K., Kyowa Hakko Kirin Co., Ltd, AbbVie Inc., Novartis Pharma K.K., Eli Lilly Japan K.K., Yakult Honsha Co., Ltd., PAREXEL International Corp., Otsuka Pharmaceutical Co., Ltd., Astellas Pharma Inc., AC Medical Inc., and Merck Serono Co., Ltd, Y-L. Wu: Honoraria from AstraZeneca, Roche, and Eli Lilly and Co. T. Mekhail: Fees from Pfizer and Eli Lilly. E. Felip: Fees from serving on advisory boards for Eli Lilly, Pfizer, Roche, MSD, Boehringer Ingelhrim and receiving lecture fees from AstraZeneca, BMS and Novartis. F. Cappuzzo: Advisory board: Pfizer. J. Paolini, T. Usari, K. Wilner: Employee of and owning stock in Pfizer. F. Blackhall: Honoraria from Pfizer, Astra-Zeneca, Medivation, having consulting/advisory roles with Pfizer, Medivation, Amgen, Astra-Zeneca, receiving research funding from Pfizer, Astra-Zeneca, Novartis and receiving lecture fees from Pfizer. B.J. Solomon: Fees for serving on advisory boards from Pfizer, Novartis, Roche-Genentech, AstraZeneca, Merck, Bristol-Myers Squibb. All other authors have declared no conflicts of interest.