Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions lead to the transcription of chimeric TRK proteins with overexpressed kinase function; this confers oncogenic potential across several tumor types. Entrectinib is a central nervous system (CNS)-active, potent inhibitor of TRKA/B/C and ROS1. We show integrated efficacy and safety analyses from entrectinib clinical trials.
Patients (pts) with locally advanced/metastatic NTRK-fusion positive (fp) 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 cycle 1 (4 wk) then every 8 wk. Scans underwent blinded independent central review (BICR) using RECISTv1.1. Primary endpoints: overall response rate (ORR); duration of response (DOR) by BICR. Secondary endpoints: progression-free survival (PFS), overall survival (OS) in pts with and without baseline CNS disease; safety.
The efficacy-evaluable population comprises 54 adult pts with advanced/metastatic NTRK-fp solid tumors (10 tumor types, >19 histopathologies), including pts with baseline CNS metastases. After 15.5 mo follow-up, BICR ORR was 57.4% (95% CI 43.2–70.8), complete responses n = 4 (7.4%); responses seen in all tumor types. Median BICR DOR: 10.4 mo (95% CI 7.1–NR); median BICR PFS: 11.2 mo (95% CI 8.0–14.9); median OS: 20.9 mo (95% CI 14.9–NR). Per baseline CNS status (investigator assessed), median BICR PFS was 12.0 mo (95% CI 8.7–15.7) and 7.7 mo (95% CI 4.7–NR) for patients without (n = 42) and with CNS disease (n = 12), respectively. In the safety population (355 pts who received entrectinib across clinical trials), most treatment-related AEs were grade 1–2 and managed with dose reduction (27.3%); few pts discontinued (3.9%) due to treatment-related AEs.
In this multicenter, pooled analysis of global clinical trials, entrectinib was well tolerated overall and induced clinically meaningful, durable systemic responses in pts with NTRK-fp solid tumors, type agnostic, with and without CNS disease.
Charlotte Kennerley at Gardiner Caldwell Communications.
EudraCT 2012-000148-88; NCT02097810; NCT02568267.
F. Hoffmann-La Roche Ltd.
Ignyta, Inc., a wholly owned subsidiary of F. Hoffmann-La Roche Ltd.
G.D. Demetri: Advisory board or board of directors: Blueprint Medicines, Merrimack Pharmaceuticals, G1 Therapeutics, Caris Life Sciences, Champions Oncology, Bessor Pharmaceuticals. A.F. Farago: Corporate sponsored research: Research funding (to institution): Ignyta, Loxo Oncology, AbbVie, AbbVie/Stemcentrx, Pharmamar, AstraZeneca, Novartis, Merck, BMS. S.V. Liu: Advisory board or board of directors: Ignyta, Genentech, Pfizer, Takeda, Celgene, Lilly, Taiho, Bristol-Myers Squibb, AstraZeneca. C.M. Blakely: Corporate sponsored research: Ignyta, Mirati, Novartis, Medimmune, Clovis. B. Besse: Corporate sponsored research: AstraZeneca, BMS, Boehringer-Ingelheim, Lilly, Pfizer, Roche-Genentech, Sanofi-Aventis, Servier, Onxeo, OncoMed, Inivata, OSE Pharma, Loxo. J. Wolf: Corporate sponsored research: BMS, MSD, Novartis, Pfizer. T. Seto: Corporate sponsored research: Astellas Pharma Inc., AstraZeneca K.K., Bayer Yakuhin, Ltd, Chugai Pharmaceutical Co., Ltd. Daiichi Sankyo Co. Ltd., Eisai Co., Ltd. E. Chow-Maneval, P.S. Multani: Employment at Ignyta A. Johnson: Corporate sponsored research: Ignyta. R.C. Doebele: Corporate sponsored research: Ignyta; Patent or Biological material licensing fees: Ignyta, Abbott Molecular, Rain Therapeutics. All other authors have declared no conflicts of interest.