Crizotinib in ROS 1-Rearranged Non – Small-Cell Lung Cancer

BACKGROUND—Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non–small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET. METHODS—We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase–polymerase-chain-reaction assays. RESULTS—The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to Copyright © 2014 Massachusetts Medical Society. Address reprint requests to Dr. Shaw at the Massachusetts General Hospital Cancer Center, Yawkey 7B, 32 Fruit St., Boston, MA 02114, or at ashaw1@mgh.harvard.edu. Drs. Shaw and Ou contributed equally to this article. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. NIH Public Access Author Manuscript N Engl J Med. Author manuscript; available in PMC 2015 May 20. Published in final edited form as: N Engl J Med. 2014 November 20; 371(21): 1963–1971. doi:10.1056/NEJMoa1406766. N IH -P A A uhor M anscript N IH -P A A uhor M anscript N IH -P A A uhor M anscript crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC. CONCLUSIONS—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. The ROS1 oncogene encodes an orphan receptor tyrosine kinase related to anaplastic lymphoma kinase (ALK), along with members of the insulin-receptor family.1 First discovered as the oncogene product of an avian sarcoma RNA tumor virus,2–4 ROS1 (ROS1 proto-oncogene receptor tyrosine kinase) is activated by chromosomal rearrangement in a variety of human cancers, including non–small-cell lung cancer (NSCLC), cholangiocarcinoma, gastric cancer, ovarian cancer, and glioblastoma multiforme.5–9 Rearrangement leads to fusion of a portion of ROS1 that includes the entire tyrosine kinase domain with 1 of 12 different partner proteins.10 The resulting ROS1 fusion kinases are constitutively activated and drive cellular transformation. Whether the various ROS1 fusion kinases may have different oncogenic properties is unknown. ROS1 rearrangements occur in approximately 1% of patients with NSCLC.11 Of the estimated 1.5 million new cases of NSCLC worldwide each year, approximately 15,000 may be driven by oncogenic ROS1 fusions. As with ALK rearrangements, ROS1 rearrangements are more commonly found in patients who have never smoked or have a history of light smoking and who have histologic features of adenocarcinoma.11,12 However, at the genetic level, ALK and ROS1 rearrangements rarely occur in the same tumor, with each defining a unique molecular subgroup of NSCLC.11 Several lines of evidence suggest that ROS1 may represent another therapeutic target of the ALK inhibitor crizotinib (Xalkori, Pfizer). First, the kinase domains of ALK and ROS1 share 77% amino acid identity within the ATP-binding sites. Crizotinib binds with high affinity to both ALK and ROS1, which is consistent with this homology.13 Second, in cellbased assays for inhibition of autophosphorylation of different kinase targets, both ALK and ROS1 are sensitive to crizotinib, with a half-maximal inhibitory concentration of 40 to 60 nM.14 Third, in cell lines expressing ROS1 fusions, crizotinib potently inhibits ROS1 signaling and cell viability.12,15,16 Finally, case reports have described marked responses to crizotinib in patients with ROS1-rearranged NSCLC.12,17 Here we report the efficacy and safety of crizotinib in patients with advanced, ROS1-rearranged NSCLC.