Background

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in multiple tumour types. Larotrectinib, a highly selective TRK inhibitor, demonstrated an investigator-assessed objective response rate (ORR) of 75% across 206 pts with non-central nervous system (CNS) primary, TRK fusion-positive cancers (Hong et al, ASCO 2021). To better determine outcomes in a more mature dataset with a longer follow-up, we report on the first 164 pts enrolled as of February 2019 with a data cut-off of July 2021.

Methods

Data were pooled from three clinical trials (NCT02576431, NCT02122913, and NCT02637687) of larotrectinib-treated pts with non-CNS primary, TRK fusion cancer. ORR was assessed by independent review committee (IRC) per RECIST v1.1.

Results

A total of 164 pts were evaluable for efficacy by IRC. There were 17 different cancer types; the most common were soft tissue sarcoma (42%), thyroid (16%), salivary gland (13%), and lung (8%). Fifty-five (34%) pts were <18 years. Fourteen (9%) pts had CNS metastases at baseline. The overall best ORR was 74% (95% confidence interval [CI] 67–81): 50 (30%) complete response (CR), including 10 (6%) pathological CR, 72 (44%) partial response, 22 (13%) stable disease, 13 (8%) progressive disease and seven (4%) not determined. After longer follow-up, 17 pts (10%) had an improved best overall response over that from the July 2019 data cut. Median time to response was 1.8 months (range 0.9–16.2). Median duration of response was 34.5 months (95% CI 27.6–43.3); median follow-up was 34.1 months. Median progression-free survival was 32.0 months (95% CI 23.4–40.2); median follow-up was 35.8 months. Median overall survival (OS) was not reached; median follow-up was 38.0 months. The 48-month OS rate was 66% (95% CI 57–75). Treatment duration ranged from 0.1 to 67.9 months. Treatment-related adverse events (TRAEs) were mainly Grade 1–2; 32 (20%) pts had Grade 3–4 TRAEs.

Conclusions

With an extended follow-up, larotrectinib demonstrated durable and deepening responses, extended survival benefit and a favourable safety profile. This highlights the importance of identifying NTRK gene fusions in cancer pts.

Editorial acknowledgement

Medical writing assistance was provided by Anastasija Pesevska, PharmD, of Scion Medica, London, UK.

Legal entity responsible for the study

The authors.

Funding

These studies were funded by Bayer HealthCare Pharmaceuticals, Inc. and Loxo Oncology, Inc., a wholly owned subsidiary of Eli Lilly and Company.

Disclosure

R.S. McDermott: Financial Interests, Personal, Advisory Board: Amgen, Bayer, BMS, Clovis, Janssen, and Pfizer; Financial Interests, Personal, Invited Speaker: Astellas, Ipsen, and MSD; Financial Interests, Personal, Other, research interests: Astellas, Bayer, BMS, Clovis, MSD, and Regeneron; Financial Interests, Personal, Other: Stella, Bayer, BMS, Clovis, MSD, and Regeneron.

C. van Tilburg: Financial Interests, Personal, Advisory Board: Bayer and Novartis. J.J. Lin: Financial Interests, Personal, Other, personal fees and other: Pfizer, Genentech, C4 Therapeutics, Nuvalent, and Blueprint Medicines, Turning Point Therapeutics, Elevation Oncology, and Roche/Genentech, Hengrui Therapeutics, Neon Therapeutics, Relay Therapeutics, Novartis, and Bayer. S. Kummar: Financial Interests, Personal, Other, Editor in Chief of Current Problems in Cancer: Elsevier; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim, Springworks Therapeutics, Gilead, EcoR1, Mirati, Mundibiopharma Ltd, Bayer, Genome & Company and HarbourBiomed, Oxfordbiotherapeutics; Financial Interests, Personal, Other, Co-founder and equity holder for PathomlQ, spouse is a scientific advisor for Cadila Pharmaceuticals ltd and founder of Arxeon Inc.: PathomlQ, Cadila Pharmaceuticals Ltd, Arxeon Inc. D.S.W. Tan: Financial Interests, Personal, Advisory Role: Novartis, Merck, Loxo, AstraZeneca, Roche, Pfizer; Financial Interests, Personal, Other, Travel: Pfizer, Boehringer Ingelheim, Roche; Financial Interests, Personal, Other, Honoraria: BMS, Takeda, Novartis, Roche, Pfizer; Financial Interests, Personal, Research Grant: Novartis, GSK, AstraZeneca. J.D. Berlin: Financial Interests, Personal, Research Grant: Bayer, Astellas, Atreca, Lilly, Pfizer, BMS, Dragonfly, Boston Biomedical, AbbVie, Novartis, Transcenta, I-Mab, Sumitomo Dainippon Pharma Oncology, Karyopharm, Incyte; Financial Interests, Personal, Advisory Board: Bayer, Ipsen, Mirati, QED, Insemd, Oxford Biotherapeutics, Biosapiens. DSMB: Novocure, Karyopharm, AstraZeneca. U.N. Lassen: Financial Interests, Personal, Advisory Board: Bayer, Pfizer, Novartis; Financial Interests, Personal, Funding: BMS, GSK, Pfizer and Roche. F. Doz: Financial Interests, Personal, Advisory Board: Bayer, BMS, Roche, Celgene, LOXO Oncology, Servier, Tesaro; Financial Interests, Personal, Other, Travel: Bayer, BMS, and Roche; Financial Interests, Institutional, Advisory Role: Servier. B. Geoerger: Financial Interests, Personal, Advisory Role: Bayer. L. Mascarenhas: Financial Interests, Personal, Advisory Role: Bayer, Lilly, Salarius; Financial Interests, Personal, Funding: Pfizer, Loxo, Lilly, Salarius, AstraZeneca, Merck, Novartis, Amgen, Turning Point. N. Federman: Financial Interests, Personal, Stocks/Shares: Genmab, Reata Pharmaceuticals, BlueBird Bio; Financial Interests, Personal, Advisory Role: Zelda Pharmaceuticals, Loxo Oncology, Bayer; Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Royalties: NanoValent Ltd. R. Norenberg: Financial Interests, Personal, Full or part-time Employment: Bayer. L. Dima: Financial Interests, Personal, Full or part-time Employment: Bayer. C. Mussi: Financial Interests, Personal, Full or part-time Employment: Bayer. E.A. De La Cuesta: Financial Interests, Personal, Full or part-time Employment: Bayer. T. Laetsch: Financial Interests, Personal, Advisory Role: Novartis, Cellectis, Bayer, Loxo Oncology, Lilly, Deciphera, Jumo Health, Y-mAbs Therapeutics; Financial Interests, Institutional, Funding: Pfizer, Novartis, Bayer, Loxo Oncology, AbbVie, Amgen, Atara Biotherapeutics, BMS, Lilly, Epizyme, GSK, Janssen, Jubilant Pharmaceuticals, Novella Clinical, and Servier. D.S. Hong: Financial Interests, Institutional, Funding: AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, Loxo Oncology, Merck, MedImmune, Mirati, MiRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfize; Financial Interests, Personal, Other, Travel: Loxo Oncology, MiRNA, ASCO, AACR, SITC, and Genmab; Financial Interests, Personal, Advisory Role: Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, and Trieza Therapeutics; Financial Interests, Personal, Other, advisor: Molecular Match, Presagia Inc; founder: OncoResponse: Molecular Match, Presagia Inc, OncoResponse. A.E. Drilon: Financial Interests, Personal, Advisory Board: Ignyta/Genentech/Roche, Loxo Oncology/Bayer/Lilly, Takeda/Ariad/Millennium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn Therapeutics, Beigene, BerGenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, AbbVi; Financial Interests, Institutional, Other, associated research paid to institution: Pfizer, Exelixis, GSK, Teva, Taiho, and PharmaMar; Financial Interests, Institutional, Research Grant: Foundation Medicine; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Other, Food/Beverage: Merck, Puma, Merus, Boehringer Ingelheim; Financial Interests, Personal, Other, CME Honoraria: Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Medscape, and Clinical Care O. All other authors have declared no conflicts of interest.