Crizotinib in MET-Deregulated or ROS1-Rearranged Pretreated Non–Small Cell Lung Cancer (METROS): A Phase II, Prospective, Multicenter, Two-Arms Trial

Abstract

Purpose: MET-deregulated NSCLC represents an urgent clinical need because of unfavorable prognosis and lack of specific therapies. Although recent studies have suggested a potential role for crizotinib in patients harboring MET amplification or exon 14 mutations, no conclusive data are currently available. This study aimed at investigating activity of crizotinib in patients harboring MET or ROS1 alterations.Patients and Methods: Patients with pretreated advanced NSCLC and evidence of ROS1 rearrangements (cohort A) or MET deregulation (amplification, ratio MET/CEP7 >2.2 or MET exon 14 mutations, cohort B) were treated with crizotinib 250 mg twice daily orally. The coprimary endpoint was objective response rate in the two cohorts.Results: From December 2014 to March 2017, 505 patients were screened and a total of 52 patients (26 patients per cohort) were enrolled onto the study. At data cutoff of September 2017, in cohort A, objective response rate was 65%, and median progression-free survival and overall survival were 22.8 months [95% confidence interval (CI) 15.2-30.3] and not reached, respectively. In cohort B, objective response rate was 27%, median progression-free survival was 4.4 months (95% CI 3.0-5.8), and overall survival was 5.4 months (95% CI, 4.2-6.5). No difference in any clinical endpoint was observed between MET-amplified and exon 14-mutated patients. No response was observed among the 5 patients with cooccurrence of a second gene alteration. No unexpected toxicity was observed in both cohorts.Conclusions: Crizotinib induces response in a fraction of MET-deregulated NSCLC. Additional studies and innovative therapies are urgently needed.

<p>Incidence of <em>ROS1</em>-Rearranged Non-Small-Cell Lung Carcinoma in India and Efficacy of Crizotinib in Lung Adenocarcinoma Patients</p>

“…35 Similarly, the METROS phase II trial also showed a very high ORR of 65% and median PFS of 22.8 (95% CI 15.2--30.3 months with crizotinib therapy among 26 patients with ROS1-rearranged pretreated NSCLC. 36 Two studies from India have reported a good response to crizotinib therapy. 19,20 In one study, crizotinib therapy achieved an ORR of 93.8%, with 1-and 2-year OS of 72% and 54%, respectively.…”

First-in-Human Study of AT13148, a Dual ROCK-AKT Inhibitor in Patients with Solid Tumors

“…Importantly, this has led to drugs, which inhibit multiple targets being licensed for indications that are relevant to one target and not to the other. For example, sorafenib is licensed in renal cancer for its VEGFR inhibitory activity but not in melanoma for its RAF inhibitory activity (38,39), and crizotinib has been licensed in lung cancer for its ALK inhibitory activity but not as an MET inhibitor (40,41). AT13148 inhibited multiple AGC kinases and was found to cause cell death and apoptosis when compared with more selective AKT inhibitors in vitro.…”

Spectrum of Mesenchymal–Epithelial Transition Aberrations and Potential Clinical Implications: Insights From Integrative Pancancer Analysis

“…The juxtamembrane domain is encoded in part by MET exon 14 and contains several important regulatory elements, including the c-Cbl binding site, which contributed to the degradation of MET protein (41). MET X1010 splice alteration is known to be oncogenic, and LUAD patients harboring MET exon 14 alterations, such as MET X1010_splice, can be treated with the NCCN-compendium listed drug crizotinib (32,33). However, several recent reports have shown that many patients receiving these MET small molecule inhibitors showed progression, and further studies to understand the resistance mechanisms are required (42).…”