Phase III Study of Crizotinib Versus Pemetrexed or Docetaxel Chemotherapy in Patients with Advanced Alk-Positive Non-Small Cell Lung Cancer (NSCLC) (Profile 1007)

Abstract

ABSTRACT Background Chromosomal rearrangements of anaplastic lymphoma kinase (ALK) are associated with marked clinical responses to crizotinib, an orally available tyrosine kinase inhibitor targeting ALK. This global randomized phase III study compared the efficacy and safety of crizotinib (C) with standard chemotherapy (pemetrexed or docetaxel [P/D]) as 2nd-line therapy for patients (pts) with advanced ALK+ NSCLC. Methods Between Feb 2010 and Feb 2012, 347 pts with stage IIIB/IV ALK+ NSCLC previously treated with 1 prior platinum-based regimen were randomized to receive C 250 mg PO BID (n = 173) or either P 500 mg/m 2 or D 75 mg/m 2 IV q3w (n = 174; 58% P, 42% D). ALK was detected by FISH in a central lab. Pts with progressive disease on P/D were offered C on PROFILE 1005. The primary endpoint was progression-free survival (PFS) per independent radiologic review; secondary endpoints included objective response rate (ORR), overall survival (OS), safety, and patient-reported outcomes. Results The study met its primary objective by demonstrating the superiority of C over P/D in prolonging PFS (median 7.7 vs 3.0 mo; HR 0.49; 95% CI 0.37–0.64; P < 0.0001). ORR was significantly higher in pts treated with C (65% vs 20%; P < 0.0001). Interim analysis of OS (28% events) showed no statistically significant difference between C and P/D (preliminary median estimate 20.3 vs 22.8 mo; HR 1.02; 95% CI 0.68–1.5; P = 0.5394), but was not adjusted for crossover (108 pts [62%] crossed over to C). The most common treatment-related adverse events (TRAE) with C were visual disturbance (59%), diarrhea (53%), nausea (52%), vomiting (44%), and elevated transaminases (36%), and with P/D, nausea (35%), fatigue (29%), neutropenia (22%), decreased appetite (21%), and alopecia (20%). The incidence of grade 3/4 TRAE was the same for C vs P/D (31%). The incidence of TRAE leading to discontinuation was 6% for C vs 10% for P/D. Duration of treatment was longer for C vs P/D (median cycles started 11 vs 4). Conclusions C showed significant improvement in PFS and ORR compared with P/D and had an acceptable safety profile. These findings establish C as the standard of care for pts with previously treated advanced ALK+ NSCLC. Disclosure A.T. Shaw: Advisory relationship with Pfizer, Ariad, Chugai, Novartis and Daiichi-Sankyo. Research funding from AstraZeneca and Novartis. D.W. Kim: Advisory relationship with Pfizer. Honoraria from Pfizer. K. Nakagawa: Honoraria from Pfizer and Eli Lilly. B. Besse: Research funding from Pfizer. B. Solomon: Advisory relationship with Pfizer. Research funding from Pfizer. F.H. Blackhall: Advisory relationship with Pfizer. Honoraria from Pfizer. Research funding from Pfizer. Expert testimony for UK NICE scoping for crizotinib. Y. Wu: Honoraria from Pfizer, Roche, AstraZeneca, Eli Lilly, and Sanof-Aventis. Research funding from Pfizer, Roche, and AstraZeneca. M. Thomas: Advisory relationship with Pfizer. K.J. O'Byrne: Adivsory relationships with and honoraria, research funding, travel-cost remuneration from Pfizer and Eli Lilly. D. Moro-Sibilot: Honoraria from Pfizer. R. Camidge: Advisory relationship with Pfizer. Honoraria from Pfizer. V. Hirsh: Advisory relationship with Pfizer. Honoraria from Pfizer. T.S.K. Mok: Advisory relationships with and honoraria from Pfizer, AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene, AVEO, Taiho, GSK, and Boehringer Ingelheim. Research funding from AstraZeneca. V. Tassell: Employed by Pfizer. Holds Pfizer stock. A. Polli: Employed by Pfizer. Holds Pfizer stock. P. Jänne: Advisory relationships with Pfizer, Boehringer Ingelheim, Roche, Genentech, Abbott, AstraZeneca, Sanofi, and Teva. Renumeration from LabCorp. All other authors have declared no conflicts of interest.