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Title: Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials.
Austin Authors: Drilon, Alexander;Siena, Salvatore;Dziadziuszko, Rafal;Barlesi, Fabrice;Krebs, Matthew G;Shaw, Alice T;de Braud, Filippo;Rolfo, Christian;Ahn, Myung-Ju;Wolf, Jürgen;Seto, Takashi;Cho, Byoung Chul;Patel, Manish R;Chiu, Chao-Hua;John, Thomas ;Goto, Koichi;Karapetis, Christos S;Arkenau, Hendrick-Tobias;Kim, Sang-We;Ohe, Yuichiro;Li, Yu-Chung;Chae, Young K;Chung, Christine H;Otterson, Gregory A;Murakami, Haruyasu;Lin, Chia-Chi;Tan, Daniel S W;Prenen, Hans;Riehl, Todd;Chow-Maneval, Edna;Simmons, Brian;Cui, Na;Johnson, Ann;Eng, Susan;Wilson, Timothy R;Doebele, Robert C
Affiliation: University Hospital Antwerp, Edegem, Belgium
Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Austin Health, Heidelberg, Victoria, Australia
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
Institute of Cancer Sciences, Massachusetts General Hospital, Boston, MA, USA
Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
University of Minnesota, Department of Medicine, Minneapolis, MN, USA
Department of Medicine, Northwestern University, Chicago, IL, USA
Moffitt Cancer Center, Tampa, FL, USA
Arthur G James Cancer Hospital and Richard J Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
Genentech, South San Francisco, CA, USA
Ignyta, San Diego, CA, USA
Flinders Medical Centre and Flinders University, Adelaide, SA, Australia
Hong Kong United Oncology Centre, Hong Kong Special Administrative Region, China
Aix Marseille University, INSERM, CNRS, CRCM, Assistance Publique-Hôpitaux de Marseille, Marseille, France
Weill Cornell Medical College, New York, NY, USA
Memorial Sloan Kettering Cancer Center, New York, NY, USA
Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Yonsei Cancer Center, Seoul, South Korea
Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
Institute of Cancer Sciences, Medical University of Gdansk, Gdansk, Poland
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Oncology and Hemato-Oncology, Università deli Studi di Milano, Milan, Italy
Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany
National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
Taipei Veterans General Hospital, Taipei, Taiwan
National Cancer Center Hospital East, Kashiwa, Japan
Sarah Cannon Research Institute and Cancer Institute University College London, London, UK
National Cancer Center Hospital, Tokyo, Japan
Shizuoka Cancer Center, Tokyo, Japan
National Taiwan University Hospital, Taipei, Taiwan
National Cancer Centre, Singapore
School of Medicine, University of Colorado, Aurora, CO, USA
Issue Date: Feb-2020
Date: 2019-12-11
Publication information: The Lancet. Oncology 2020; 21(2): 261-270
Abstract: 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. 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, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001). 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. 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. Ignyta/F Hoffmann-La Roche.
DOI: 10.1016/S1470-2045(19)30690-4
ORCID: 0000-0003-3399-5342
Journal: The Lancet. Oncology
PubMed URL: 31838015
Type: Journal Article
Appears in Collections:Journal articles

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