Aim: Chromosomal rearrangements of the ROS1 receptor tyrosine kinase gene define a distinct molecular subset of non-small cell lung cancer (NSCLC), which may be susceptible to therapeutic ROS1 inhibition. Crizotinib is a small molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1 and c-MET.
Methods: Fifty patients with advanced NSCLC harboring a ROS1 rearrangement were enrolled into an expansion cohort of the global phase 1 study of crizotinib. Local ROS1 testing was used, including break-apart fluorescence in situ hybridization (FISH) in 47 of 50 cases. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily, and assessed for safety and response to therapy. The primary endpoint was objective response rate (ORR). Duration of response (DR), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier method. ROS1 fusion partners (if tissue was available) were identified using next generation sequencing (NGS) or reverse-transcriptase-polymerase-chain reaction (RT-PCR) assays.
Results: At the time of data cutoff, median follow-up of the 50 ROS1 patients was 16.1 months. The majority of patients (86%) had received at least one prior line of standard therapy for advanced NSCLC. The ORR was 70% (95% CI, 55%, 82%), with 3 complete responses and 32 partial responses. Median DR was 75.9 weeks (95% CI, 61.6, NR). Median PFS was 19.2 months (95% CI, 14.6, NR), with 24 patients (48%) still in follow-up for PFS. Median OS has not been reached; 1-year OS was 85% (95% CI, 71%, 93%). Among 24 tumors tested (21 with NGS and 3 with RT-PCR), 7 different ROS1 fusion partners were identified, including 5 known and 2 novel partner genes. No correlation was observed between type of ROS1 rearrangement and clinical response to crizotinib. The safety profile of crizotinib in ROS1 patients was similar to that seen in patients with ALK-rearranged NSCLC.
Conclusions: Crizotinib exhibits robust antitumor activity in patients with advanced ROS1-rearranged NSCLC, with an ORR of 70% and a median PFS of 19.2 months. Responses were durable with a median DR of 75.9 weeks. In this trial ROS1 defines an additional distinct population of NSCLC patients for whom crizotinib is highly effective.
Disclosure: A. Shaw: Consultant/SAB: Pfizer, Novartis, Ariad, Chugai, Genentech, Ignyta; S.I. Ou: Advisory boards: Pfizer; Corporate-sponsored research: Pfizer; Y. Bang: Advisory boards: Pfizer; Corporate-sponsored research: Pfizer; B. Solomon: Advisory boards: Pfizer, Novartis, Roche, Clovis Oncology, AstraZeneca, Merck, BMS, Lilly; G.J. Riely: Advisory boards: Ariad, Celgene, Mersana; Corporate-sponsored research: Novartis, Pfizer, Millennium, Roche, GSK, Merck; M. Varella-Garcia: Advisory board: Exelixis; Corporate-sponsored research: Abbott Molecular; Other substantive relationships (Speaker engagement in educational seminars): Abbott Molecular; D. Costa: Other substantive relationships (Consultancy): Pfizer; R. Doebele: Advisory board: Pfizer, Boehringer-Ingelheim; Corporate-sponsored research: Pfizer, Mirati Therapeutics; L.P. Le: Stock ownership: Enzymatics; Other substantive relationships (Consulting with compensation): Enzymatics; Z. Zheng: Stock ownership: Enzymatics; P. Stephenson: Other substantive relationships (Consultancy): Pfizer; S.M. Shreeve: Stock ownership: Johnson and Johnson, Pfizer; Other substantive relationships (Employment): Janssen Pharmaceutical Companies of Johnson and Johnson; L. Tye: Employment and stock ownership: Pfizer; J. Christensen: Stock ownership: Pfizer; K. Wilner: Employment, stock ownership, advisory board and corporate-sponsored research: Pfizer; A. Iafrate: Advisory boards: Chugai, Constellation, Enzymatics; Stock ownership: Enzymatics. All other authors have declared no conflicts of interest.