Neurotrophic receptor tyrosine kinase (NTRK) gene fusions lead to the expression of chimeric TRK proteins with constitutively activated kinase function, conferring oncogenic potential across several tumour types. Entrectinib is a CNS-active, potent inhibitor of TRKA/B/C and ROS1. We present integrated efficacy and safety data for entrectinib in NTRK fusion-positive (NTRK-FP) solid tumours focusing on pts with NSCLC.
Pts with locally advanced/metastatic NTRK-FP tumours (with or without baseline CNS disease) confirmed by nucleic acid-based methods, enrolled in global (>150 sites, 15 countries) phase 1/2 entrectinib trials (ALKA-372-001 [EudraCT 2012-000148-88], STARTRK-1 [NCT02097810], STARTRK-2 [NCT02568267]) were included. Disease burden was assessed per BICR using RECIST v1.1, after cycle 1 (4 wks) then every 8 wks. Primary endpoints: ORR, DOR by BICR. Secondary endpoints: PFS, OS, and safety.
Outcomes in the total efficacy-evaluable population (n = 54; 10 tumour types, >19 histopathologies) are shown in the table; responses were seen in all tumour types, median PFS 11.2 mo. In the cohort of pts with NTRK-FP NSCLC (n = 10), BICR ORR was 70% (7/10). In NSCLC pts with CNS disease per investigator at baseline (n = 6), 4 had an intracranial response (2 complete, 2 partial); 1 had stable disease and 1 was not evaluable. In the safety population (68 pts with NTRK-FP solid tumors who received at least 1 dose of entrectinib), most treatment-related adverse events (TRAEs) were grade 1–2; grade 3: 32.4%, grade 4: 2.9%; no grade 5 TRAEs. TRAEs resulted in discontinuation in 4.4% and dose reduction in 39.7% of pts.
In this integrated analysis of global multicentre clinical trials, entrectinib was well tolerated and induced clinically meaningful, durable systemic and intracranial responses in pts with NTRK-FP solid tumours, including those with NSCLC. (Table).
ALKA-372-001 = EudraCT 2012-000148-88 – start date: 2015, trials ongoing STARTRK-1= NCT02097810 – start date: 2014, active, not recruiting (last update 2018) STARTRK-2 = NCT02568267 – start date: 2015, recruiting (last updated 2018).
Medical writing and editorial support was provided by Charlotte Kennerley, PhD of Gardiner-Caldwell Communications, Ashfield Healthcare Communications and sponsored by Roche in accordance with Good Publication Practice guidelines.
F. Hoffmann-La Roche.
Study Sponsor: Ignyta, Inc., a wholly owned subsidiary of F. Hoffmann-La Roche Ltd.
L. Paz-Ares: Honoraria: Lilly, MSD, BMS, Roche, PharmaMar, Merck, AstraZeneca, Novartis, BI, Celgene, Servier, Sysmex, Amgen, Incyte, Pfizer; Research: AZ, BMS, MSD; Advisory boards: Genomica; Scientific Chair/board member: Asociación Española Contra el Cáncer. R.C. Doebele: Sponsored research: Ignyta; Advisory boards: Roche, Ignyta, Takeda, AstraZeneca, Bayer; Stock ownership: Rain Therapeutics; Patent or biological material licensing fees: Ignyta, Abbott Molecular, Rain Therapeutics. A.F. Farago: Honoraria: Foundation Medicine, Clinical Care Options Oncology, Medical Learning Institute; Research: Ignyta, Loxo, AbbVie/Stemcentrx, PharmaMar, AZ, Novartis, Merck, BMS, Amgen; Consultant: Loxo, PharmaMar, AbbVie/Stemcentrx, Genentech, AZ, Bayer, Millennium. S.V. Liu: Research: Ignyta, Genentech, Pfizer, Threshold, Clovis, Corvus, Esanex, Bayer, OncoMed, Merck, Lycera, AZ, Molecular Partners, Rain Therapeutics; Advisory boards: Ignyta, Genentech, Pfizer, Takeda, Celgene, Lilly, Taiho, BMS, AZ, Regeneron, Merck. S.P. Chawla: Honoraria/research/Advisory boards: Amgen, Roche, GSK, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, Sarc, Janssen. D. Tosi: Research funding: Novartis, Astellas, Janssen, Ipsen. C.M. Blakely: Research funding: Ignyta, Mirati, Novartis, Medimmune, Clovis. J.C. Krauss: Research funding: Boston Biomedical, AbbVie, Amgen, Isofol. D. Sigal: Advisory boards: Molecular Stethoscopye, Celularity, Curematch, Bayer; Research funding: Halozyme; Speakers bureau member: Celgene, Bayer; Stock ownership: BMS, Novartis, Halozyme. L. Bazhenova: Research funding: Beyongspring pharma; Stock ownership: EPIC Sciences; Advisory boards: Genentech, Takeda, AbbVie, Eli Lilly, Pfizer, AstraZeneca. T. John: Advisory boards: BMS, AstraZeneca, Boehringer Ingelheim, Takeda, Pfizer, Novartis, Merck, Ignyta, Roche. B. Besse: Research funding: AbbVie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma. J. Wolf: Advisory boards: AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Ignyta, Lilly MSD, Novartis, Pfizer, Roche; Corporate sponsorship for research: BMS, MSD, Novartis, Pfizer. T. Seto: Honoraria/research: Astellas, AZ, Bayer, BMS, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Kissei, Kyowa HakkoKirin, Merck Serono, Mochida, MSD, Nippon, Novartis, BI, NipponKayakuOno, Pfizer, Roche, Sanofi, ShowaYakuhinKako, Taiho, Takeda, YakultHonsha, Verastem. E. Chow-Maneval: Employee: Ignyta. C. Ye, B. Simmons: Employee: Genentech. G.D. Demetri: Advisory boards: Blueprint Medicines, Merrimack Pharmaceuticals, G1 Therapeutics, Caris Life Sciences, Champions Oncology; Consultant: Novartis, Pfizer, EMD-Serono, Sanofi Oncology, Janssen Oncology, Ignyta, Roche, Loxo Oncology, Mirati Therapeutics, Epizyme, PharmaMar, Daiichi Sankyo, WIRB Copernicus Group, ZioPharm, Polaris Pharmaceuticals, M.J.Hennessey/OncLive, G1 Therapeutics, Caris Life Sciences, Champions Oncology, Bessor Pharmaceuticals, Erasca Pharmaceuticals; Consulting fees: Novartis, Pfizer, EMD-Serono, Sanofi Oncology, Janssen Oncology, Ignyta, Roche, Loxo Oncology, Mirati Therapeutics, Epizyme, PharmaMar, Daiichi Sankyo, WIRB Copernicus Group, ZioPharm, Polaris Pharmaceuticals, M.J.Hennessey/OncLive, Blueprint Medicines, Merrimack Pharmaceuticals, G1 Therapeutics, Caris Life Sciences, Champions Oncology; Research support: Bayer, Novartis, Pfizer, Janssen Oncology, Ignyta, Roche, Loxo Oncology, AbbVie, Epizyme, Adaptimmune, GlaxoSmithKline; Patent licensing fees: Novartis; Equity: Blueprint Medicines, Merrimack Pharmaceuticals, G1 Therapeutics, Caris Life Sciences, Champions Oncology, Bessor Pharmaceuticals, Erasca Pharmaceuticals.