• Alexander Drilon, D Ross Camidge, Jessica J Lin, Sang-We Kim, Benjamin J Solomon, Rafal Dziadziuszko, Benjamin Besse, Koichi Goto, Adrianus Johannes de Langen, Jürgen Wolf, Ki Hyeong Lee, Sanjay Popat, Christoph Springfeld, Misako Nagasaka, Enriqueta Felip, Nong Yang, Vamsidhar Velcheti, Shun Lu, Steven Kao, Christophe Dooms, Matthew G Krebs, Wenxiu Yao, Muhammad Shaalan Beg, Xiufeng Hu, Denis Moro-Sibilot, Parneet Cheema, Shanna Stopatschinskaja, Minal Mehta, Denise Trone, Armin Graber, Gregory Sims, Yong Yuan, Byoung Chul Cho, and TRIDENT-1 Investigators.
• From Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College (A.D.) and the NYU Perlmutter Cancer Center (V.V.) - all in New York; the University of Colorado, Anschutz Medical Campus, Aurora (D.R.C.); Massachusetts General Hospital, Harvard Medical School, Boston (J.J.L.); Asan Medical Center (S.-W.K.) and Yonsei Cancer Center, Yonsei University College of Medicine (B.C.C.), Seoul, and Chungbuk National University Hospital, Cheongju-si (K.H.L.) - all in South Korea; the Peter MacCallum Cancer Center, Melbourne, VIC (B.J.S.), and the Chris O'Brien Lifehouse, Camperdown, NSW (S.K.) - both in Australia; the Department of Oncology and Radiotherapy and Early Clinical Trials Center, Medical University of Gdansk, Gdansk, Poland (R.D.); Paris-Saclay University, Gustave Roussy Cancer Center, Villejuif (B.B.), and Centre Hospitalier Universitaire de Grenoble-Alpes, La Tronche (D.M.-S.) - both in France; National Cancer Center Hospital East, Kashiwa, Japan (K.G.); the Netherlands Cancer Institute, Amsterdam (A.J.L.); the Center for Integrated Oncology, University Hospital of Cologne, Cologne (J.W.), and the Department of Medical Oncology, Heidelberg University Hospital, National Center for Tumor Diseases, Heidelberg (C.S.) - both in Germany; the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London (S.P.), and the University of Manchester and the Christie NHS Foundation Trust, Manchester (M.G.K.) - all in the United Kingdom; the University of California, Irvine, School of Medicine, Orange (M.N.), and Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb, San Diego (S.S., M.M., D.T., A.G., G.S.) - both in California; Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona (E.F.); Hunan Cancer Hospital, Hunan (N.Y.), the Department of Oncology, Shanghai Chest Hospital, Shanghai (S.L.), Sichuan Cancer Hospital and Institute, Chengdu (W.Y.), and Henan Cancer Hospital, Zhengzhou (X.H.) - all in China; the Respiratory Oncology Unit, University Hospitals Leuven, Leuven, Belgium (C.D.); UT Southwestern Medical Center, Dallas (M.S.B.); William Osler Health System, University of Toronto, Toronto (P.C.); and Bristol Myers Squibb, Princeton, NJ (Y.Y.).
• N. Engl. J. Med. 2024 Jan 11; 390 (2): 118131118-131.

BackgroundThe early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for the treatment of ROS1 fusion-positive non-small-cell lung cancer (NSCLC) have antitumor activity, but resistance develops in tumors, and intracranial activity is suboptimal. Repotrectinib is a next-generation ROS1 TKI with preclinical activity against ROS1 fusion-positive cancers, including those with resistance mutations such as ROS1 G2032R.MethodsIn this registrational phase 1-2 trial, we assessed the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1 fusion-positive NSCLC. The primary efficacy end point in the phase 2 trial was confirmed objective response; efficacy analyses included patients from phase 1 and phase 2. Duration of response, progression-free survival, and safety were secondary end points in phase 2.ResultsOn the basis of results from the phase 1 trial, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in 56 of the 71 patients (79%; 95% confidence interval [CI], 68 to 88) with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI; the median duration of response was 34.1 months (95% CI, 25.6 to could not be estimated), and median progression-free survival was 35.7 months (95% CI, 27.4 to could not be estimated). Response occurred in 21 of the 56 patients (38%; 95% CI, 25 to 52) with ROS1 fusion-positive NSCLC who had previously received one ROS1 TKI and had never received chemotherapy; the median duration of response was 14.8 months (95% CI, 7.6 to could not be estimated), and median progression-free survival was 9.0 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (59%; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response. A total of 426 patients received the phase 2 dose; the most common treatment-related adverse events were dizziness (in 58% of the patients), dysgeusia (in 50%), and paresthesia (in 30%), and 3% discontinued repotrectinib owing to treatment-related adverse events.ConclusionsRepotrectinib had durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.).Copyright © 2024 Massachusetts Medical Society.

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