1287P - Efficacy and safety of entrectinib in locally advanced/metastatic <italic>ROS1</italic> fusion-positive NSCLC: An updated integrated analysis

Background

Entrectinib is a potent, selective, CNS active, ROS1 tyrosine kinase inhibitor (TKI). In a preliminary analysis (data cut-off: 31 May 2018) of pts with ROS1 fusion-positive (ROS1-fp) NSCLC enrolled in phase 1/2 studies (ALKA-372-001, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88, NCT02097810, NCT02568267), treatment with entrectinib produced clinically meaningful and durable systemic responses with a manageable safety profile. We report on an updated integrated analysis in a larger patient population with longer follow-up (data cut-off: 1 May 2019).

Methods

Enrolled pts were ROS1 TKI naïve with measurable disease; most received entrectinib 600mg once daily. Tumours were assessed by blinded independent central review using RECIST v1.1, after 4 wks and every 8 wks thereafter. Primary endpoints were objective response rate (ORR) and duration of response (DoR). Progression-free survival (PFS), overall survival (OS), efficacy in pts with/without baseline CNS metastases, and safety were also assessed.

Results

The efficacy-evaluable population comprised 161 pts with ROS1-fp NSCLC; baseline characteristics are shown (Table). Median follow-up: 15.8 months (range 0.1–43.2). ORR, 67.1% (95% CI 59.3–74.3); 14 pts (8.7%) achieved complete response, 94 (58.4%) partial response, 14 (8.7%) stable disease, 15 (9.3%) disease progression. Median DoR, 15.7 months (95% CI 13.9–28.6); median PFS, 15.7 months (95% CI 11.0–21.1); median OS, not estimable (NE) (95% CI 28.3–NE). In the subgroup with prior immunotherapy (n=24), ORR, 70.8% (95% CI 48.9–87.4). In pts with investigator-assessed CNS metastases at baseline, ORR, 62.5% (95% CI 48.6–75.1). The safety profile was similar to that previously reported.

Conclusions

This updated analysis, using a larger dataset with longer follow-up, shows that entrectinib induces clinically meaningful responses in pts with ROS1-fp NSCLC, including pts with CNS metastases at baseline Table: 1287P

*Race not reported for 8 patients. ^†CNS metastases at baseline per investigator; ^‡Included tyrosine kinase inhibitors. Two pts from STARTRK-2 received previous crizotinib

Clinical trial identification

ALKA-372-001 (EudraCT 2012-000148-88); STARTRK-1 (NCT02097810); STARTRK-2 (NCT02568267).

Editorial acknowledgement

Third-party medical writing assistance, under the direction of the authors, was provided by Lucy Carrier, PhD, of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd.

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

M.G. Krebs: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Janssen; Advisory/Consultancy, Research grant/Funding (institution): Octimet; Advisory/Consultancy: Achilles Therapeutics; Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: BerGenBio; Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Blueprint; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Carrick; Research grant/Funding (institution): CellCentric; Research grant/Funding (institution): Chugai; Research grant/Funding (institution): Debiopharm; Research grant/Funding (institution): Genmab; Research grant/Funding (institution): Immutep; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Kymab; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): MedImmune; Research grant/Funding (institution): Merck; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Sierra; Research grant/Funding (institution): StarPharma; Research grant/Funding (institution): Taiho; Research grant/Funding (institution): Turning Point Therapeutics. F. De Braud: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Istituto Gentili; Advisory/Consultancy: Fondazione Internazionale Menarini; Advisory/Consultancy: Octomet Oncology; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Merck Sharp & Dohme; Advisory/Consultancy, Speaker Bureau/Expert testimony: Ignyta; Advisory/Consultancy: Bayer; Advisory/Consultancy: Noema; Advisory/Consultancy: ACCMED; Advisory/Consultancy, Speaker Bureau/Expert testimony: Dephaforum; Advisory/Consultancy: Nadirex; Advisory/Consultancy, Speaker Bureau/Expert testimony: Biotechspert; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Tiziana Life Sciences; Advisory/Consultancy: Pierre Fabre; Speaker Bureau/Expert testimony: prIME Oncology; Research grant/Funding (institution): Kymab; Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Research grant/Funding (institution): Tesaro. S. Siena: Advisory/Consultancy: Amgen; Advisory/Consultancy: Bayer; Advisory/Consultancy: BMS; Advisory/Consultancy: CheckMab; Advisory/Consultancy: Celgene; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Incyte; Advisory/Consultancy: Merck; Advisory/Consultancy: Novartis; Advisory/Consultancy: Roche; Advisory/Consultancy: Seattle Genetics. A. Drilon: Honoraria (institution): Ignyta/Roche/Genentech; Honoraria (institution): oxo, Bayer, Lilly; Honoraria (institution): TP Therapeutics; Honoraria (institution): AstraZeneca; Honoraria (institution), Research grant/Funding (institution): Pfizer; Honoraria (institution): Blueprint; Honoraria (institution): Takeda/Ariad/Millennium; Honoraria (institution): Helsinn; Honoraria (institution): BeiGene; Honoraria (institution): BerGenBio; Honoraria (institution): Hengrui; Honoraria (institution), Research grant/Funding (institution): Exelixis; Honoraria (institution): Tyra; Honoraria (institution): Verastem; Honoraria (institution): MORE Health; Honoraria (institution): Puma; Honoraria (institution): GlaxoSmithKline; Research grant/Funding (self): Foundation Medicine; Research grant/Funding (institution): Taiho; Research grant/Funding (institution): Teva; Research grant/Funding (institution): PharmaMar; Licensing/Royalties: Wolters Kluwer. R.C. Doebele: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, Licensing/Royalties, Includes patent and biologic material licensing fees: Ignyta; Advisory/Consultancy, Travel/Accommodation/Expenses, Licensing/Royalties, Includes patent and biologic material licensing fees: Genentech/Roche; Advisory/Consultancy, Research grant/Funding (institution), Licensing/Royalties, Includes patent and biologic material licensing fees: Loxo Oncology; Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Eli Lilly; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Travel/Accommodation/Expenses: Blueprint Medicines; Advisory/Consultancy: Anchiano; Advisory/Consultancy, Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Licensing/Royalties, Includes patent and biologic material licensing fees: Rain Therapeutics; Research grant/Funding (institution): Mirati; Research grant/Funding (institution): Strategia; Licensing/Royalties, Patent and biologic material licensing fees: Abbott Molecular; Licensing/Royalties, Patent and biologic material licensing fees: Chugai; Licensing/Royalties, Patent and biologic material licensing fees: Foundation Medicine; Licensing/Royalties, Patent and biologic material licensing fees: Black Diamond; Licensing/Royalties, Patent and biologic material licensing fees: Voronoi; Licensing/Royalties, Patent and biologic material licensing fees: Pearl River; Licensing/Royalties, Patent and biologic material licensing fees: Ariad. M.R. Patel: Advisory/Consultancy: Nektar Therapeutics; Research grant/Funding (self): Merck; Research grant/Funding (self): Vyriad; Research grant/Funding (self): Fate Therapeutics. B.C. Cho: Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Roche; Advisory/Consultancy: BMS; Advisory/Consultancy, Research grant/Funding (institution): Ono; Advisory/Consultancy, Research grant/Funding (institution): Yuhan; Advisory/Consultancy: Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy, Research grant/Funding (institution): Janssen; Advisory/Consultancy, Research grant/Funding (institution): Medpacto; Advisory/Consultancy, Research grant/Funding (institution): Blueprint Medicines; Advisory/Consultancy, Shareholder/Stockholder/Stock options: KANAPH Therapeutic; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): MOGAM Institute; Research grant/Funding (institution): Dong-A ST; Research grant/Funding (institution): Champions Oncology; Research grant/Funding (institution): Dizal Pharma; Research grant/Funding (institution): MSD; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): GI-Innovation; Shareholder/Stockholder/Stock options: TheraCanVac, Inc; Shareholder/Stockholder/Stock options: Gencurix Inc.; Shareholder/Stockholder/Stock options: Bridgebio Therapeutics; Officer/Board of Directors: Daan Biotherapeutics. S.V. Liu: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy: Catalyst; Advisory/Consultancy: Celgene; Advisory/Consultancy: G1 Therapeutics; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech/Roche; Advisory/Consultancy: Guardant Health; Advisory/Consultancy: Inivata; Advisory/Consultancy: Janssen; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy: Loxo; Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: PharmaMar; Advisory/Consultancy: Regeneron; Advisory/Consultancy: Takeda; Research grant/Funding (institution): Alkermes; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Blueprint; Research grant/Funding (institution): Corvus; Research grant/Funding (institution): Lycera; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Merus; Research grant/Funding (institution): Molecular Partners; Research grant/Funding (institution): Rain; Research grant/Funding (institution): RAPT; Research grant/Funding (institution): Spectrum; Research grant/Funding (institution): Turning Point Therapeutics. M-J. Ahn: Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Takeda; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: MSD; Advisory/Consultancy: Merck; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Ono Pharmaceutical; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Alpha Pharmaceutical; Advisory/Consultancy: Progeneer. C-H. Chiu: Honoraria (self): Pfizer; Honoraria (self), Advisory/Consultancy: AstraZeneca/MedImmune; Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Chugai Pharmaceuticals; Honoraria (self): Eli Lilly; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Ono Pharmaceutical; Honoraria (self), Advisory/Consultancy: Roche. A.F. Farago: Honoraria (self): DAVA Oncology; Honoraria (self): Clinical Care Options; Honoraria (self): Medical Learning Institute; Honoraria (self): Medscape; Honoraria (self): PeerView; Honoraria (self): Research to Practice; Advisory/Consultancy, Research grant/Funding (self): Bayer; Advisory/Consultancy, Research grant/Funding (self): Loxo Oncology; Advisory/Consultancy, Research grant/Funding (self): Genentech; Advisory/Consultancy, Research grant/Funding (self): Roche; Advisory/Consultancy, Research grant/Funding (self): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): AbbVie; Advisory/Consultancy, Research grant/Funding (self): PharmaMar; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (self): Merck; Advisory/Consultancy: H3 Biomedicine; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Syros; Research grant/Funding (self): Ignyta; Research grant/Funding (self): Amgen; Research grant/Funding (self): Novartis. C-C. Lin: Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self): Roche; Advisory/Consultancy: Blueprint Medicines; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Takeda; Travel/Accommodation/Expenses: BeiGene; Travel/Accommodation/Expenses: Eli Lilly. C.S. Karapetis: Honoraria (self): MSD; Honoraria (self), Advisory/Consultancy: Roche; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Eisai; Advisory/Consultancy: Merck; Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Amgen; Advisory/Consultancy: BMS. Y-C. Li: Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Roche Hong Kong; Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy, Travel/Accommodation/Expenses: Boehringer Ingelheim; Advisory/Consultancy: Lilly Oncology; Advisory/Consultancy: Merck; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Takeda; Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Travel/Accommodation/Expenses: Taiho; Travel/Accommodation/Expenses: Eisai; Travel/Accommodation/Expenses: Sanomics/Xcelom; Travel/Accommodation/Expenses: Mundipharma. F. Barlesi: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Bayer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly Oncology; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): F Hoffmann-La Roche; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pierre Fabre; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Takeda; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): ACEA; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Ipsen; Research grant/Funding (institution): Ignyta; Research grant/Funding (institution): Innate Pharma; Research grant/Funding (institution): Loxo; Research grant/Funding (institution): MedImmune; Research grant/Funding (institution): Sanofi-Aventis. B. Simmons: Shareholder/Stockholder/Stock options, Full/Part-time employment: Roche/Genentech. B. Pitcher: Full/Part-time employment: F. Hoffmann-La Roche . R. Dziadziuszko: Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy: Pfizer; Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Celon Pharm; Advisory/Consultancy: Merck; Advisory/Consultancy: MSD; Advisory/Consultancy: Takeda; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Novartis.