Phase II study of crizotinib in Japanese patients with advanced non-small cell lung cancer harboring a MET gene alteration: Co-MET study

Abstract

Background: The majority of non‐small cell lung cancer (NSCLC) patients are diagnosed as metastatic disease for which no curative treatment is available. Phase III randomized trials of tyrosine kinase inhibitor (TKI) therapy for EGFR‐mutant and anaplastic lymphoma receptor tyrosine kinase (ALK)‐rearranged lung cancers have documented improvements in response and progression‐free survival (PFS), and TKIs are approved for the treatment of patients with oncogene‐driver mutations. c‐Met is the tyrosine kinase receptor for hepatocyte growth factor, and MET gene alterations including MET exon14 skipping mutation‐positive or MET high gene copy number are known to be an oncogene via activation of c‐MET signaling pathway. Crizotinib is a selective ATP‐competitive small‐molecule inhibitor of c‐Met, ALK and ROS1 tyrosine kinases. Durable responses to crizotinib were reported in patients with advanced NSCLC harboring MET exon 14 skipping mutation or high MET gene copy number. Therefore, we considered to assess the efficacy and safety of crizotinib in patients with advanced NSCLC harboring aMET gene alteration. Trial design: Co‐MET is an open‐label, multi‐center, 2 cohort single‐arm phase II trial of oral crizotinib in patients with advanced NSCLC harboring MET exon 14 skipping mutations without prior MET TKI treatment (cohort 1) or high MET gene copy number of 7 ormore (cohort 2). The status of MET gene alterations will be determined using a validated RT‐PCR assay and/or NGS. Crizotinib, 250 mg BID, will be administered orally continuously until disease progression or unacceptable toxicities. All tumor scans will be reviewed by an independent radiology committee according to RECIST version 1.1. The primary endpoint is objective response rate (ORR). Assuming a null hypothesis of a 20% ORR and an alternative hypothesis of a 50% ORR for cohort 1, and a one‐sided type I error of 0.05 (one‐side) and 80% power based on the exact binomial distribution, the required number of evaluable patients is 19. The sample size for cohort 2 is empirically set at 10 patients.