65PUpdated efficacy and safety of entrectinib in patients with NTRK fusion-positive tumours: Integrated analysis of STARTRK-2, STARTRK-1 and ALKA-372-001.

Background Entrectinib is a systemic and CNS-active, potent inhibitor of TRKA/B/C and ROS1. Primary data from integrated efficacy and safety analyses (6 months' follow-up) from entrectinib clinical trials have shown that entrectinib is a promising option for patients (pts) with NTRK fusion-positive (NTRK+) solid tumors: blinded independent central review (BICR) objective response rate (ORR) was 57.4% (95% CI 43.2–70.8). We show longer follow-up data from this integrated analysis. Methods Pts with locally advanced/metastatic NTRK+ solid tumors confirmed by nucleic acid-based methods and enrolled in global (>150 sites, 15 countries) phase 1/2 entrectinib trials (ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267) were included. Tumors were assessed after 4 wks (Cycle 1) then every 8 wks. Scans underwent BICR using RECIST v1.1. Primary endpoints were ORR and duration of response (DOR) by BICR. Secondary endpoints included overall survival (OS); ORR and DOR in pts with and without baseline CNS disease; intracranial (IC) ORR and DOR in pts with baseline CNS disease; safety. Results The efficacy-evaluable population comprises 54 adult pts with advanced/metastatic NTRK+ solid tumors, including pts with baseline CNS metastases. As of 30 Oct 2018 (additional 5 months' follow-up), BICR ORR was 59.3% (95% CI 45.0–72.4); complete responses n = 4 (7.4%). Median BICR DOR was 12.9 mo (95% CI 7.9–not estimable [NE]), median OS was 23.9 mo (95% CI 16.8–NE). Per baseline CNS status, BICR ORR was 58.3% (95% CI 27.7–84.8) and 59.5% (95% CI 43.3–74.4) and median DOR was NE (4.2–NE) and 12.9 mo (7.9–NE) for pts with (n = 12) and without (n = 42) CNS disease, respectively. IC ORR was 54.5% (95% CI 23.4–83.3) and median IC DOR by BICR was NE (6.7–NE). Entrectinib was well tolerated with a safety profile consistent with that previously reported; there were no new or unexpected safety findings. Conclusions In line with the primary data, these results at an additional 5 months of follow-up show that entrectinib induced clinically meaningful, durable systemic and intracranial responses in pts with NTRK+ solid tumors. Clinical trial identification ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267. Editorial acknowledgement Medical Writing support was provided by Laura Vergoz and Charlotte Kennerley, PhD of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche. Legal entity responsible for the study F. Hoffman-La Roche. Funding F. Hoffman-La Roche. Disclosure C. Rolfo: Speaker Bureau / Expert testimony: MSD, GuardantHealth, Mylan; Research grant / Funding (institution): Novartis, Sanofi; Non-remunerated activity/ies: Oncompass Steering scientific committee; OncoDNA: Research collaboration no renumerated for Exosomes (2017); GuarantHealth research collaboration (2019); Leadership role: IALSC, Educational Committee Member; ISLB, Vice President; Educational Chair, OLA Oncology Latin American Association; Scientific Committee Member at ESO; Membership Committee Officer, ESMO. R. Dziadziuszko: Advisory / Consultancy, Officer / Board of Directors: Roche, Bristol-Myers Squibb, Merck, AstraZeneca, Pfizer, Novartis; Research grant / Funding (institution): Roche, Bristol-Myers Squibb, Merck, AstraZeneca, Pfizer, Novartis, Boehringer Ingelheim, Clovis; Travel / Accommodation / Expenses: Roche, AstraZeneca. R.C. Doebele: Shareholder / Stockholder / Stock options: Rain Therapeutics; Advisory / Consultancy: Chair of Scientific Advisory Board for Rain Therapeutics; Honoraria (self): Guardant; Advisory / Consultancy: Pfizer, Trovagene, Ariad, Takeda, AstraZeneca, Genentech/Roche, Ignyta, Loxo, Rain.; Research grant / Funding (institution): Ignyta, Loxo, Mirati; Licensing / Royalties: Abbott Molecular, Rain Therapeutics, GVKbio, Chugai, Loxo, Ignyta, Genentech, Ariad, Foundation Medicine, Black Diamond. G. Demetri: Research grant / Funding (institution): Bayer, Novartis, Pfizer, Janssen Oncology, Ignyta (now Roche) , Roche/Genentech, Loxo Oncology, AbbVie, Epizyme, Adaptimmune, GlaxoSmithKline ; Advisory / Consultancy: Novartis, Pfizer, EMD-Serono , Sanofi Oncology, Janssen Oncology, Ignyta (now Roche), Roche/Genentech, Loxo Oncology, Mirati Therapeutics, Epizyme, PharmaMar, Daiichi-Sankyo, WIRB Copernicus Group/ Arsenal Capital, ZioPharm, Polaris Pharmaceuticals, M.J. ; Licensing / Royalties: Novartis ; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: c ICON plc ; Advisory / Consultancy, Officer / Board of Directors: Blueprint Medicines; Officer / Board of Directors: Merrimack Pharmaceuticals; Shareholder / Stockholder / Stock options: G1 Therapeutics, Caris Life Sciences, Champions Oncology, Bessor Pharmaceuticals, Erasca Pharmaceuticals. B. Simmons: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche (Genentech). A. Aziez: Full / Part-time employment: Roche. X. Huang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech. S. Osborne: Full / Part-time employment: Roche. L. Paz-Ares: Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly, MSD, BMS, Roche, PharmaMar, Merck, Astra-Zeneca, Novartis, Boehringer Ingelheim, Celgene, Servier, Sysmex, Celgene, Amgen, Incyte, Pfizer; Officer / Board of Directors: Genomica; Research grant / Funding (institution): Astra-Zeneca, BMS, MSD; Non-remunerated activity/ies: Scientific Chair and Member of the Board of Asociación Española Contra el Cáncer (AECC; Majoir Spanish Anti-Cancer Charity); Spouse / Financial dependant: My wife (Rocio Garcia-Carbonero): - She has been EMA SAG member untill June 2017 - She has received honoraria from July 2017 onwards from Ipsen, Novartis, Pfizer, Servier, Sanofi, Roche, Amgen and Merck. [ABSTRACT FROM AUTHOR]