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

Abstract

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.

Identification of ROS1 rearrangement in gastric adenocarcinoma

“…NCT00858195). 12 Currently, in addition to crizotinib, 3 different ROS1 inhibitors (AP26311 [NCT01449461], ASP3062 [NCT1284192], and AZD1480 [NCT01 12397 and NCT01219543]) are in early phase clinical trials (available at: www.clinicaltrials.gov; accessed August 31, 2012). It remains to be determined whether SLC34A2-ROS1 is a driver mutation in GC.…”

A genomic and clinicopathological study of non‐small‐cell lung cancers with discordant ROS1 gene status by fluorescence in‐situ hybridisation and immunohistochemical analysis

“…[2][3][4] Preclinical experiments indicate that cell lines harbouring ROS1 fusions are sensitive to the ROS1 kinase inhibitor crizotinib. 5,6 The latest results from Phase I trials of crizotinib also indicate that median progression-free survival in patients with advanced ROS1-rearranged NSCLC was 19.2 months. 7 Scheffler et al found that advanced patients with the ROS1 rearrangement had the best overall survival of all subgroups, including those with EGFR-mutated and ALK-rearranged NSCLCs; these authors estimate that the mean overall survival (OS) of patients receiving chemotherapy and crizotinib is 5.3 years.…”

Clinical next‐generation sequencing in patients with non–small cell lung cancer

“…2,3 More recently, targeted therapies directed at tumor cells harboring anaplastic lymphoma kinase (ALK) fusions and ROS1 fusions have produced impressive results. 4,5 In addition to EGFR, ALK, and ROS1, there are several other abnormalities that could potentially be treated with drugs already approved for other malignancies or investigational agents. 6 Molecular analysis to support personalized therapeutics has historically been obtained with several methods.…”