Alexander Drilon1, Salvatore Siena2, Rafal Dziadziuszko3, Fabrice Barlesi4, Matthew G Krebs5, Alice T Shaw6, Filippo de Braud7, Christian Rolfo8, Myung-Ju Ahn9, Jürgen Wolf10, Takashi Seto11, Byoung Chul Cho12, Manish R Patel13, Chao-Hua Chiu14, Thomas John15, Koichi Goto16, Christos S Karapetis17, Hendrick-Tobias Arkenau18, Sang-We Kim19, Yuichiro Ohe20, Yu-Chung Li21, Young K Chae22, Christine H Chung23, Gregory A Otterson24, Haruyasu Murakami25, Chia-Chi Lin26, Daniel S W Tan27, Hans Prenen28, Todd Riehl29, Edna Chow-Maneval30, Brian Simmons29, Na Cui29, Ann Johnson30, Susan Eng29, Timothy R Wilson29, Robert C Doebele31. 1. Weill Cornell Medical College, New York, NY, USA; Memorial Sloan Kettering Cancer Center, New York, NY, USA. 2. Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy; Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. 3. Institute of Cancer Sciences, Medical University of Gdansk, Gdansk, Poland. 4. Aix Marseille University, INSERM, CNRS, CRCM, Assistance Publique-Hôpitaux de Marseille, Marseille, France. 5. Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK; The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. 6. Institute of Cancer Sciences, Massachusetts General Hospital, Boston, MA, USA. 7. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Oncology and Hemato-Oncology, Università deli Studi di Milano, Milan, Italy. 8. Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA. 9. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 10. Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 11. National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan. 12. Yonsei Cancer Center, Seoul, South Korea. 13. University of Minnesota, Department of Medicine, Minneapolis, MN, USA. 14. Taipei Veterans General Hospital, Taipei, Taiwan. 15. Olivia Newton John Cancer Research Institute, Austin Health, Melbourne, VIC, Australia. 16. National Cancer Center Hospital East, Kashiwa, Japan. 17. Flinders Medical Centre and Flinders University, Adelaide, SA, Australia. 18. Sarah Cannon Research Institute and Cancer Institute University College London, London, UK. 19. Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 20. National Cancer Center Hospital, Tokyo, Japan. 21. Hong Kong United Oncology Centre, Hong Kong Special Administrative Region, China. 22. Department of Medicine, Northwestern University, Chicago, IL, USA. 23. Moffitt Cancer Center, Tampa, FL, USA. 24. Arthur G James Cancer Hospital and Richard J Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. 25. Shizuoka Cancer Center, Tokyo, Japan. 26. National Taiwan University Hospital, Taipei, Taiwan. 27. National Cancer Centre, Singapore. 28. University Hospital Antwerp, Edegem, Belgium. 29. Genentech, South San Francisco, CA, USA. 30. Ignyta, San Diego, CA, USA. 31. School of Medicine, University of Colorado, Aurora, CO, USA. Electronic address: robert.doebele@cuanschutz.edu.
Abstract
BACKGROUND: Recurrent gene fusions, such as ROS1 fusions, are oncogenic drivers of various cancers, including non-small-cell lung cancer (NSCLC). Up to 36% of patients with ROS1 fusion-positive NSCLC have brain metastases at the diagnosis of advanced disease. Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the CNS. We explored the use of entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive NSCLC. METHODS: We did an integrated analysis of three ongoing phase 1 or 2 trials of entrectinib (ALKA-372-001, STARTRK-1, and STARTRK-2). The efficacy-evaluable population included adult patients (aged ≥18 years) with locally advanced or metastatic ROS1 fusion-positive NSCLC who received entrectinib at a dose of at least 600 mg orally once per day, with at least 12 months' follow-up. All patients had an Eastern Cooperative Oncology Group performance status of 0-2, and previous cancer treatment (except for ROS1 inhibitors) was allowed. The primary endpoints were the proportion of patients with an objective response (complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1) and duration of response, and were evaluated by blinded independent central review. The safety-evaluable population for the safety analysis included all patients with ROS1 fusion-positive NSCLC in the three trials who received at least one dose of entrectinib (irrespective of dose or duration of follow-up). These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001). FINDINGS: Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018), 41 (77%; 95% CI 64-88) of 53 patients in the efficacy-evaluable population had an objective response. Median follow-up was 15·5 monhts (IQR 13·4-20·2). Median duration of response was 24·6 months (95% CI 11·4-34·8). In the safety-evaluable population, 79 (59%) of 134 patients had grade 1 or 2 treatment-related adverse events. 46 (34%) of 134 patients had grade 3 or 4 treatment-related adverse events, with the most common being weight increase (ten [8%]) and neutropenia (five [4%]). 15 (11%) patients had serious treatment-related adverse events, the most common of which were nervous system disorders (four [3%]) and cardiac disorders (three [2%]). No treatment-related deaths occurred. INTERPRETATION: Entrectinib is active with durable disease control in patients with ROS1 fusion-positive NSCLC, and is well tolerated with a manageable safety profile, making it amenable to long-term dosing in these patients. These data highlight the need to routinely test for ROS1 fusions to broaden therapeutic options for patients with ROS1 fusion-positive NSCLC. FUNDING: Ignyta/F Hoffmann-La Roche.
BACKGROUND: Recurrent gene fusions, such as ROS1 fusions, are oncogenic drivers of various cancers, including non-small-cell lung cancer (NSCLC). Up to 36% of patients with ROS1 fusion-positive NSCLC have brain metastases at the diagnosis of advanced disease. Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the CNS. We explored the use of entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive NSCLC. METHODS: We did an integrated analysis of three ongoing phase 1 or 2 trials of entrectinib (ALKA-372-001, STARTRK-1, and STARTRK-2). The efficacy-evaluable population included adult patients (aged ≥18 years) with locally advanced or metastatic ROS1 fusion-positive NSCLC who received entrectinib at a dose of at least 600 mg orally once per day, with at least 12 months' follow-up. All patients had an Eastern Cooperative Oncology Group performance status of 0-2, and previous cancer treatment (except for ROS1 inhibitors) was allowed. The primary endpoints were the proportion of patients with an objective response (complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1) and duration of response, and were evaluated by blinded independent central review. The safety-evaluable population for the safety analysis included all patients with ROS1 fusion-positive NSCLC in the three trials who received at least one dose of entrectinib (irrespective of dose or duration of follow-up). These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001). FINDINGS:Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018), 41 (77%; 95% CI 64-88) of 53 patients in the efficacy-evaluable population had an objective response. Median follow-up was 15·5 monhts (IQR 13·4-20·2). Median duration of response was 24·6 months (95% CI 11·4-34·8). In the safety-evaluable population, 79 (59%) of 134 patients had grade 1 or 2 treatment-related adverse events. 46 (34%) of 134 patients had grade 3 or 4 treatment-related adverse events, with the most common being weight increase (ten [8%]) and neutropenia (five [4%]). 15 (11%) patients had serious treatment-related adverse events, the most common of which were nervous system disorders (four [3%]) and cardiac disorders (three [2%]). No treatment-related deaths occurred. INTERPRETATION:Entrectinib is active with durable disease control in patients with ROS1 fusion-positive NSCLC, and is well tolerated with a manageable safety profile, making it amenable to long-term dosing in these patients. These data highlight the need to routinely test for ROS1 fusions to broaden therapeutic options for patients with ROS1 fusion-positive NSCLC. FUNDING: Ignyta/F Hoffmann-La Roche.
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