Updated efficacy and safety of entrectinib in patients with NTRK fusion-positive tumors: Integrated analysis of STARTRK-2, STARTRK-1 and ALKA-372-001

Abstract

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 tumours: 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 tumours 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. Tumours 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 tumours, 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 tumours. Clinical trial identification: ALKA, EudraCT: 2012-000148-88 STARTRK-1, NCT02097810 STARTRK-2, NCT02568267. Editorial acknowledgement: 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: Leadership role: Educational Committee Member: IALSC - Vice President; ISLB; Educational Chair: OLA Oncology Latin America Association - Faculty for ASCO International; Scientific COmmittee Member at ESO; Membership Committee Officer ESMO; Speaker Bureau / Expert testimony: MSD; GuardantHealth; Mylan; Research grant / Funding (institution): Antwerp University Hospital: Novartis; Sanofi; Non-remunerated activity/ies: Oncompass Steering scientific committee: OncoDNA; Research collaboration, no renumeration: Exesomes; Research collaboration no renumeration: GuardantHealth. R. Dziadziuszko: Advisory / Consultancy, Officer / Board of Directors: Roche, Bristol-Myers Squibb, Merck, AstraZeneca, Pfizer, Novartis; Research grant / Funding (self), 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: Ignyta, Loxo, Rain; Research grant / Funding (self): 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. He; Licensing / Royalties: Novartis; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: ICON plc; Advisory / Consultancy, Officer / Board of Directors: Blueprint Medicines; Speaker Bureau / Expert testimony, Officer / Board of Directors: Merrimack Pharmaceuticals; Shareholder / Stockholder / Stock options: Caris Life Sciences, Champions Oncology, Bessor Pharmaceuticals, Erasca Pharmaceuticals. B. Simmons: Full / Part-time employment: Roche (Genentech). X. Huang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech. C. Ye: Full / Part-time employment: Genentech. L. Paz-Ares: Honoraria (self): Lilly, MSD, BMS, Roche, Pharmamar, Merck, AstraZeneca, Novartis, Boehringer, Celgene, Servier, Sysmex, Celgene, Amgen, Incyte, Pfizer; Leadership role: Genomica; Research grant / Funding (institution): AstraZeneca, BMS, MSD; Non-remunerated activity/ies: Scientific Chair and Member of the Board of Asociación Española Contra el Cáncer (AECC; Major Spanish Anti-Cancer Charity); Spouse / Financial dependant: Spouse: (Rocio Garcia-Carbonero): 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.