Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement.

7508 Background: Chromosomal rearrangements of the ROS1 receptor tyrosine kinase gene define a new molecular subset of NSCLC. In cell lines, ROS1 rearrangements lead to expression of oncogenic ROS1 fusion kinases and sensitivity to ROS kinase inhibition. We examined the efficacy and safety of crizotinib, a small molecule tyrosine kinase inhibitor of MET, ALK and ROS, in patients with advanced, ROS1-rearranged NSCLC. Methods: Patients with advanced NSCLC harboring ROS1 rearrangement, as determined using a break-apart FISH assay, were recruited into an expansion cohort of a phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg BID. The objective response rate (ORR) was determined based on RECIST 1.0. The disease control rate (DCR; stable disease [SD] + partial response [PR] + complete response [CR]) was evaluated at 8 weeks. Results: Thirteen patients within the ROS expansion cohort received crizotinib and all were evaluable for response. The median age was 47 yrs (range 31–72), and all but one of the patients were never-smokers. All patients had adenocarcinoma histology. 12/13 patients were tested for ALK rearrangement and all were negative. The median number of prior treatments was 1 (range 0–3). To date, the ORR is 54% (7/13), with 6 PRs and 1 CR, with 6 responses achieved by the first restaging scan at 7–8 wks. There was 1 additional unconfirmed PR at the time of data cut-off. The DCR at 8 wks was 85% (11/13). Median duration of treatment was 20 wks (range 4+–59+). All responses are ongoing, and 12 patients continue on study. One patient had disease progression at first restaging and was discontinued from the study. The pharmacokinetics and safety profile of crizotinib in this group of patients were similar to that observed in patients with ALK-positive NSCLC. Conclusions: Crizotinib demonstrates marked antitumor activity in patients with advanced NSCLC harboring ROS1 rearrangements. Like ALK, ROS defines a distinct subpopulation of NSCLC patients for whom crizotinib therapy may be highly effective. This study represents the first clinical validation of ROS as a therapeutic target in cancer.