Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer
By A. Shaw, S. Ou, Y. Bang, D. Camidge, B. Solomon, Ravi Salgia, Gregory Riely, M. Varella-Garcia, G. Shapiro, D. Costa and 11 more. New England Journal of Medicine, 2014
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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 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.
Subfields: Hematology, Oncology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/b2414c93b4a339278cdfc242c1a62eb79edacf38
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Citations in the corpus
- Safety and Antitumor Activity of the Multi-Targeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib (RXDX-101): Combined Results from Two Phase 1 Trials (ALKA-372-001 and STARTRK-1) (2017, neutral): “Prior systemic therapies, n (%) 0 0 6 (9) 6 (5) 1–2 0 15 (23) 15 (13) 3–4 3 (6) 25 (39) 28 (24) >4 51 (94) 19 (29) 70 (59)”
- Proteogenomic characterization reveals therapeutic vulnerabilities in lung adenocarcinoma (2020, neutral): “, 2010),ROS1 (Shaw et al., 2014), andRET fusions (Gautschi et al.”
- Understanding and targeting resistance mechanisms in NSCLC (2017, background): “Discovery of (10R)-7-amino-12fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure”
- Accurate and efficient detection of gene fusions from RNA sequencing data (2021, background): “nomas with ALK or ROS1 fusions are sensitive to treatment with crizotinib and other, second- and third-generation inhibitors (Shaw et al. 2014).”