Abstract
Crizotinib treatment elicited objective responses in 72% of patients with ROS1-rearranged NSCLC.
Major finding: Crizotinib treatment elicited objective responses in 72% of patients with ROS1-rearranged NSCLC.
Approach: Patients with ROS1-rearranged NSCLC were enrolled in an expansion cohort of the crizotinib phase I study.
Impact: ROS1 rearrangements distinguish a second subgroup of patients with NSCLC in which crizotinib is active.
The small-molecule ALK inhibitor crizotinib, which has been approved for the treatment of patients with ALK-rearranged non–small cell lung cancer (NSCLC), also potently inhibits ROS1, which is activated by chromosomal translocation in 1% of patients with NSCLC. Preclinical studies have indicated that NSCLC cells harboring ROS1 rearrangements are highly sensitive to crizotinib, and marked responses to crizotinib have been described in case studies of patients with ROS1-rearranged NSCLC. Shaw, Ou, and colleagues report the results from an expansion cohort of the phase I trial of crizotinib that included 50 patients with advanced NSCLC that tested positive for ROS1 rearrangement. Objective responses were observed in 72% of patients, including 3 complete responses (6%) and 33 partial responses (66%), and 9 patients (18%) had stable disease. As in patients with ALK-rearranged NSCLC, crizotinib was well-tolerated, and the vast majority of treatment-related adverse events were grade 1 or 2. Characterization of ROS1 rearrangements in a subset of patients identified known ROS1 fusion partners as well as previously uncharacterized fusions with LIMA1 and MSN, but responses to crizotinib occurred regardless of the fusion partner. Interestingly, the median duration of response (17.6 months) and the median progression-free survival (19.2 months) were longer in the trial's ROS1 expansion cohort than in the ALK expansion cohort (49.1 weeks and 9.7 months, respectively), possibly because crizotinib is a more potent inhibitor of ROS1 than of ALK. Although 46% of patients with ROS1-rearranged NSCLC ultimately developed resistance to crizotinib as of the data cutoff date, indicating that next-generation inhibitors will be needed to overcome crizotinib resistance in this patient population, these phase I findings demonstrate that crizotinib has significant, durable antitumor activity in patients with ROS1-rearranged NSCLC and identify an additional NSCLC molecular subgroup in which crizotinib may be effective.
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