Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1–2 trials

Alexander Drilon, Salvatore Siena, Rafal Dziadziuszko, Fabrice Barlesi, Matthew G. Krebs, Alice T. Shaw, Filippo de Braud, Christian Rolfo, Myung Ju Ahn, Jürgen Wolf, Takashi Seto, Byoung Chul Cho, Manish R. Patel, Chao Hua Chiu, Thomas John, Koichi Goto, Christos S. Karapetis, Hendrick Tobias Arkenau, Sang We Kim, Yuichiro OheYu Chung Li, Young K. Chae, Christine H. Chung, Gregory A. Otterson, Haruyasu Murakami, Chia Chi Lin, Daniel S.W. Tan, Hans Prenen, Todd Riehl, Edna Chow-Maneval, Brian Simmons, Na Cui, Ann Johnson, Susan Eng, Timothy R. Wilson, Robert C. Doebele

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)261-270
Number of pages10
JournalThe Lancet Oncology
Volume21
Issue number2
DOIs
StatePublished - Feb 2020

Bibliographical note

Funding Information:
The studies were funded by Ignyta/F Hoffmann-La Roche. Third-party medical writing assistance, under the direction of the authors, was provided by Charlotte Kennerley and Caroline Loder of Gardiner-Caldwell Communications, Macclesfield, UK, and was funded by F Hoffmann-La Roche. The authors thank the patients, their families, and the participating study centres. Data and statistical analysis were overseen by Na Cui (Genentech, San Francisco, CA, USA). Salvatore Siena is supported by Fondazione Oncologia Niguarda Onlus. Matthew Krebs acknowledges support by National Institute of Health Research Manchester Biomedical Research Centre and NIHR Manchester Clinical Research Facility and Manchester Experimental Cancer Medicine Centre (Manchester, UK).

Funding Information:
AD has received honoraria and consulting fees for advisory boards from Ignyta/Roche/Genentech, Loxo/Bayer/Lily, TP Therapeutics, AstraZeneca, Pfizer, Blueprint, Takeda/Ariad/Millennium, Helsinn, BeiGene, BerGenBio, Hengrui, Exelixis, Tyra, Verastem, MORE Health, Puma, and GlaxoSmithKline; associated research funding paid to institution by Pfizer, Exelixis, Taiho, Teva, and Pharmamar; research funding from Foundation Medicine; and royalties from Wolters Kluwer. SS is an advisory board member for Amgen, Bayer, BMS, CheckMab, Celgene, Daiichi Sankyo, Incyte, Merck, Novartis, Roche, and Seattle Genetics. RCD has received consulting fees from Ignyta, Genentech and Roche, Loxo Oncology, Bayer, Eli Lilly, AstraZeneca, Pfizer, and Rain Therapeutics; sponsored research agreements from Ignyta, Loxo, Mirati, Pfizer, Eli Lilly, and Strategia; royalties or licensing fees for intellectual property from Ignyta, Loxo, Abbott Molecular, Genentech, Chugai, Foundation Medicine, and Black Diamond; and has stock ownership in Rain Therapeutics. FB has personal financial interests in AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F Hoffmann-La Roche, Novartis, Merck, MSD, Pierre Fabre, Pfizer, and Takeda; and institutional financial interests in AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eisai, Eli Lilly Oncology, F Hoffmann-La Roche, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, Merck Sharp and Dohme, Pierre Fabre, Pfizer, Sanofi-Aventis, and Takeda. MGK has received honoraria for advisory boards from Roche, Janssen, Octimet, and Achilles Therapeutics; travel grants from AstraZeneca and BerGenBio; and research funding from Roche and BerGenBio. ATS has served as a compensated consultant or received honoraria from ARIAD, Bayer, Blueprint Medicines, Chugai, Daiichi Sankyo, EMD Serono, Foundation Medicine, Genentech/Roche, Guardant, Ignyta, KSQ Therapeutics, LOXO, Natera, Novartis, Pfizer, Servier, Taiho Pharmaceutical, Takeda, and TP Therapeutics; has received research (institutional) funding from Daiichi Sankyo, Ignyta, Novartis, Pfizer, Roche/Genentech, and TP Therapeutics; and has received travel support from Pfizer and Genentech/Roche. FdB serves as an advisory board or board of directors member for Tiziana Life Sciences, Bristol-Myers Squibb, Celgene, Novartis, Servier, Pharm Research Associated, Daiichi Sankyo, Ignyta, Amgen, Pfizer, Octimet Oncology, Incyte, Teofarma, Pierre Fabre, Roche, and EMD Serono; and has received honoraria from Bristol-Myers Squibb, Eli Lilly, Roche, Amgen, AstraZeneca, Istituto Gentili, Fondazione Internazionale Menarini, Novartis, Merck Sharp & Dohme, Ignyta, Bayer, Noema, ACCMED, Dephaforum, Nadirex, Roche, Biotechspert, prIME Oncology, and Pfizer. CR is a speaker for Merck Sharp and Dohme, Novartis, and Guardant Health; a scientific advisor for Mylan, Oncompass, and AstraZeneca; and has research collaborations with OncoDNA and Guardant Health. M-JA has received consultant fees and honoraria from AstraZeneca, Lilly, Takeda, Roche, MSD, Merck, Boehringer Ingelheim, Ono Pharmaceutical, Bristol-Myers Squibb, and Alpha Pharmaceutical. JW is an advisory board member for AbbVie, AstraZeneca, Blueprint, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Ignyta, Janssen, Lilly, Loxo, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda; and has conducted research projects sponsored by Merck Sharp & Dohme, Novartis, Bristol-Myers Squibb, Janssen, and Pfizer. TS has received research grants from Bayer Yakuhin, Daiichi Sankyo, Eisai, LOXO Oncology, Merck Serono, and Chugai Pharmaceuticals; and grants and honoraria from Astellas Pharma, AstraZeneca, Chugai Pharmaceuticals, Eli Lilly Japan, Kissei Pharmaceutical, Merck Sharp & Dohme, Nippon Boehringer Ingelheim, Novartis Pharma, Pfizer Japan, Takeda Pharmaceutical, Bristol-Myers Squibb, Kyowa Hakko Kirin, Nippon Kayaku, Ono, Roche Singapore, Taiho Pharmaceutical, Thermo Fisher Scientific, and Yakult Honsha. BCC has received research funding from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, and Merck Sharp & Dohme; has had consulting roles for Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, and MSD; owns stocks from TheraCane Vac; and has received royalties from Champions Oncology. MRP is an advisory board member for Nektar Therapeutics, and has received research funding from Vyriad and Fate Therapeutics. C-HC has received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche, and Takeda. TJ has received advisory or consulting fees for advisory boards from Roche, Ignyta, Pfizer, AstraZeneca, Boehringer Ingelheim, Merck, Takeda, Novartis, and Bristol-Myers Squibb. KG has received research grants and personal fees from Chugai and personal fees from Roche. CSK has received personal fees from Roche, AstraZeneca, Eisai, MSD, and Merck. S-WK has received clinical research funding from AstraZeneca, Lilly, and Boehringer Ingelheim; and attended an advisory meeting for AstraZeneca, Lilly, and Boehringer Ingelheim. YO has received honoraria from AstraZeneca, Chugai, Lilly, Ono, BMS, Boehringer Ingelheim, Bayer, Pfizer, MSD, and Taiho; has had advisory or consultancy roles for AstraZeneca, Chugai, ONO, Bristol-Myers Squibb, Kyorin, Celltrion, and Amgen; and has received grants or research funding from AstraZeneca, Chugai, Lilly, ONO, Bristol-Myers Squibb, Kyorin, Dainippon Sumitomo, Pfizer, Taiho, Novartis, Ignyta, Takeda, Kissei, Daiichi Sankyo, and Janssen. Y-CL has received travel grants from Roche Hong Kong. YKC has received research grants from AbbVie, BMS, Biodesix, Lexent Bio, and Freenome; and honoraria for his participation as an advisory board member from Roche/Genentech, AstraZeneca, Foundation Medicine, Counsyl, NeoGenomics, Guardant Health, Boehringer Ingelheim, Biodesix, ImmuneOncia, Lilly Oncology, Merck, and Takeda. CHC received honoraria for ad-hoc scientific advisory boards from AstraZeneca, Bristol-Myers Squibb, Lilly, Celgene, Ignyta, and CUE Biopharma. GAO has received consulting fees from Pfizer, Genentech, AstraZeneca, Takeda, and Novocure; and research funding (to the institution) from AstraZeneca, Pfizer, Bristol-Myers Squibb, Genentech, Ignyta, and Merck. HM has received personal fees from AstraZeneca, Chugai, Lilly Japan, Merck Sharp & Dohme, Taiho Pharmaceutical, Bristol-Myers Squibb Japan, Ono Pharmaceutical, Boehringer Ingelheim, Pfizer, and Novartis. C-CL has received personal fees from Roche and Pfizer. DSWT has received grants from Novartis, Bayer, AstraZeneca, Pfizer, and GlaxoSmithKline; personal fees from Novartis, Bayer, Boehringer Ingelheim, Celgene, AstraZeneca, Eli Lilly, and Loxo; and non-financial support from Novartis, Boehringer Ingelheim, Celgene, Merck, Pfizer, Roche, and Takeda. HP has received honoraria and/or travel grants from Roche, Bayer, Amgen, Ipsen, Pfizer, Novartis, Sanofi, Merck, Vifor Pharma, Terumo, and Lilly. TR is employed by Genentech and has equity in Roche. EC-M and AJ were employees of Ignyta during the conduct of the study. BS, NC, SE, and TRW are employed by Genentech and have equity in Roche. RD reports personal fees from Roche during the conduct of the study; non-financial support from Roche and AstraZeneca; and personal fees from Roche, AstraZeneca, Novartis, Pfizer, Foundation Medicine, Bristol-Myers Squibb Merck, and Boehringer-Ingelheim. H-TA declares no competing interests.

Funding Information:
The studies were funded by Ignyta/F Hoffmann-La Roche. Third-party medical writing assistance, under the direction of the authors, was provided by Charlotte Kennerley and Caroline Loder of Gardiner-Caldwell Communications, Macclesfield, UK, and was funded by F Hoffmann-La Roche. The authors thank the patients, their families, and the participating study centres. Data and statistical analysis were overseen by Na Cui (Genentech, San Francisco, CA, USA). Salvatore Siena is supported by Fondazione Oncologia Niguarda Onlus. Matthew Krebs acknowledges support by National Institute of Health Research Manchester Biomedical Research Centre and NIHR Manchester Clinical Research Facility and Manchester Experimental Cancer Medicine Centre (Manchester, UK).

Funding Information:
The studies were designed by the funders and study investigators. Data were collected, analysed, and interpreted by the funders, with the authors and investigators. TR, EC-M, BS, NC, AJ, SE, and TRW had full access to the raw data. All authors contributed to the writing and approval of this report. Professional medical writing assistance was funded by F Hoffmann-La Roche. The lead (AD and SS) and corresponding (RCD) authors had full access to all the data and had final responsibility for the decision to submit for publication.

Publisher Copyright:
© 2020 Elsevier Ltd

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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