Crizotinib Highly Active in ROS1-Rearranged NSCLC
In a study reported in The New England Journal of Medicine, Shaw et al found that crizotinib (Xalkori) produced a high response rate in patients with ROS1-rearranged non–small cell lung cancer (NSCLC).
Chromosomal rearrangements in ROS1, which encodes the proto-oncogene receptor tyrosine kinase ROS1, define a distinct molecular subgroup in NSCLC. In addition to inhibiting ALK, crizotinib inhibits ROS1 and MET. As noted by the investigators, oncogenic ROS1 fusions may account for approximately 15,000 of the worldwide 1.5 million new cases of NSCLC each year. ALK and ROS1 rearrangements are infrequently found within the same tumor. Both are more common in patients with a history of never or light smoking and in adenocarcinoma.
Study Details
The study involved 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of a phase I study of crizotinib. Patients received crizotinib at the standard dose of 250 mg twice daily. Patients had a median age of 53 years, 56% were female, 54% were white and 42% were Asian, 78% were never-smokers, 98% had adenocarcinoma, Eastern Cooperative Oncology Group performance status was 0 in 44% and 1 in 54%, and 44% had received more than one prior regimen for advanced disease.
Responses
The objective response rate was 72% (95% confidence interval [CI] = 58%–84%), with 3 complete responses and 33 partial responses. Median duration of response was 17.6 months (95% CI = 14.5 months to not reached). Median progression-free survival was 19.2 months (95% CI = 14.4 months to not reached), with 25 patients (50%) still in follow-up for progression at data cutoff. Median follow-up for overall survival was 16.4 months; overall survival at 12 months was 85% (95% CI = 72%–93%), with the median not reached.
Fusion Partners
A total of 30 samples were tested by next-generation sequencing (n = 27) or reverse transcriptase polymerase chain reaction (n = 3). Of the 27 tested by next-generation sequencing, 22 had specific ROS1 rearrangements, 4 were negative for ROS1 rearrangement, and the assay failed in 1; 1 of the 4 negative samples was positive for EML4-ALK. ROS1 fusion partners consisted of the gene encoding CD74 (11 of 25 samples), SDC4 (4 samples), EZR (4 samples), SLC34A2 (3 samples), and TPM3 (1 sample); all of these have previously been identified as ROS1 fusion partners. Two new partners, LIMA1 (LIM domain and actin binding 1) and MSN (moesin), were identified by next-generation sequencing. There was no apparent association of type of ROS1 rearrangement and response to crizotinib.
The safety profile of crizotinib in the 50 patients was similar to that observed in patients with ALK-rearranged NSCLC.
The investigators concluded: “In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active.”
Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center, is the corresponding author for the article. Dr. Shaw and Sai-Hong I. Ou, MD, PhD, of the University of California at Irvine, contributed equally to the article.
The study was funded by Pfizer and others. For full disclosures of the study authors, visit www.nejm.org.
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