Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers of various tumour types, including salivary gland tumours (SGTs). Secretory carcinoma of the salivary gland, a rare subset of SGTs, is characterised by an ETV6-NTRK3 gene fusion found in ≥80% of cases. Larotrectinib is a highly selective, central nervous system-active, tropomyosin receptor kinase (TRK) inhibitor with an objective response rate (ORR) of 92% across 24 evaluable patients (pts) with a variety of SGTs, as of July 2020 (Le et al. Oncologist 2022 [in press]). We report updated efficacy and safety of larotrectinib in pts with TRK fusion SGTs with longer follow-up.
Pts with TRK fusion SGTs were identified from two larotrectinib clinical trials (NCT02122913, NCT02576431). Pts received larotrectinib 100 mg twice a day (BID) except for one pt who received 150 mg BID in the phase 1 trial (NCT02122913). Response was assessed by independent review committee (per Response Evaluation Criteria in Solid Tumours v1.1).
As of July 2021, 25 pts with TRK fusion SGTs were identified, including 24 with an additional year of follow-up. Median age was 59.0 years (range 28–80). All pts had ETV6-NTRK3 gene fusions. ORR was 84% (95% CI 64–95%): 8 complete responses, 13 partial responses, 2 stable disease and 2 progressive disease. Median time to response was 1.8 months. Median duration of response (DoR) was not reached; median follow-up was 39.6 months. Median progression-free survival (PFS) was 56.0 months (95% CI 30.8–not estimable) at a median follow-up of 41.3 months. Median overall survival (OS) was not reached at a median follow-up of 43.7 months. The 36-month DoR, PFS, and OS rates were 71%, 64%, and 82%. Duration of treatment ranged from 1.0 to 68.0 months. At data cut-off, 8 pts had progressed, with 5 pts continuing treatment post-progression for ≥4 weeks. Treatment-related adverse events (TRAEs) were mostly Grade 1–2. Grade 3–4 TRAEs were reported in 6 pts (24%). There were no treatment discontinuations due to TRAEs.
Larotrectinib demonstrated rapid and durable efficacy with a favourable safety profile in pts with TRK fusion SGTs. These data highlight the importance of identifying NTRK gene fusions in pts with SGTs.
NCT02122913, NCT02576431.
Medical writing assistance was provided by Anastasija Pesevska, PharmD, of Scion Medica, London, UK.
Bayer HealthCare Pharmaceuticals, Inc.
These studies were funded by Bayer HealthCare Pharmaceuticals, Inc. and Loxo Oncology, Inc., a wholly owned subsidiary of Eli Lilly and Company.
L. Shen: Financial Interests, Institutional, Research Grant: Beijing Xiantong Biomedical Technology Co., Ltd., Qilu Pharmaceutical Co., Ltd., Zaiding Pharmaceutical (Shanghai) Co., Ltd., Yaojie Ankang (Nanjing) Technology Co., Ltd., Baiji Shenzhou (Beijing) Biotechnology Co., Ltd.; Financial Interests, Personal, Advisory Role: MSD, BMS, Merck, AstraZeneca, Daiichi Sankyo, Roche, Minji biopharmaceutical, Harbour BioMed; Financial Interests, Personal, Speaker’s Bureau: Hutchison Whampoa, MSD. D.S. Hong: Financial Interests, Personal, Other, Travel, accommodations, expenses: AACR, ASCO, Bayer, Genmab, Gilead, SITC, Telperian; Financial Interests, Personal, Other, Consulting, Speaker, or Advisory Role: AbbVie, Adaptimmune, Alpha Insights, Acuta, Alkermes, Amgen, Aumbiosciences, Axiom, Baxter, Bayer, Boxer Capital, BridgeBio, COR2ed, COG, Cowen, Ecor1, Gennao Bio, Genentech, Gilead, GLG, Group H, Guidepoint, HCW Precision, Immunogen, Infinity, Janssen, Liberium, MedaCorp, Medscape, Numab, Oncologia Brasil, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, RAIN, SeaGen, ST Cube, Takeda, Tavistock, Trieza Therapeutics, Turning Point Therapeutics, WebMD, YingLing Pharma, Ziopharm; Financial Interests, Personal, Ownership Interest, Advisor: Molecular Match; Financial Interests, Personal, Ownership Interest, Founder, Advisor: OncoResponse, Telperian; Financial Interests, Institutional, Research Grant: AbbVie, Adaptimmune, Adlai-Nortye, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi-Sankyo, Deciphera, Eisai, Eli Lilly, Endeavor, Erasca, F. Hoffmann-LaRoche, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa Kirin, Loxo, Merck, Medimmune, Mirati, Mologen, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, SeaGen, Takeda, TCR2, Teckro, Turning Point Therapeutics, VM Oncology. M. Tahara: Financial Interests, Personal, Advisory Board: Merck Biopharma, Ono pharma, Bristol Myers Squibb, MSD, Pfizer, Bayer, Lilly, Rakuten Medical, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Institutional, Invited Speaker: MSD, AstraZeneca, Ono Pharma, Novartis, Pfizer, Bristol Myers Squibb, Loxo, GlaxoSmithKline, Lilly, Rakuten Medical; Financial Interests, Institutional, Research Grant: Bayer. C.S. Baik: Financial Interests, Personal, Other, External consultant: AstraZeneca; Financial Interests, Personal, Other, External Consultant: Blueprint Medicines, Daiichi, Takeda, TurningPoint Therapeutics, Guardant Health, Regeneron, Silverback Therapeutics; Financial Interests, Institutional, Research Grant: Loxo, AstraZeneca, Pfizer, Spectrum Phaemaceuticals, Blueprint Medicines, Daiichi Sankyo, Rain Therapeutics, Abbive, TP Therapeutics, Lilly Oncology, Janssen. J.R. Bauman: Financial Interests, Personal, Advisory Board: Kura, Janssen, Pfizer, Blueprint Medicine, Lilly, Merck, Mirati, Turning Point Therapeutics, BeiGene. J. Gilbert: Financial Interests, Personal, Advisory Board: Exelixis, Loxo, HRA Pharma, Bayer, Cue; Financial Interests, Personal, Other, Editor of fellowship magazine: OncLive; Financial Interests, Institutional, Invited Speaker, Money to institution to run trial: Pfizer, Exelixis; Non-Financial Interests, Personal, Invited Speaker, Local affiliate of ASCO: Tennessee Oncology Practice Society. M.S. Brose: Financial Interests, Institutional, Research Grant: Bayer, Loxo Oncology, Genentech, Eisai, Blueprint Medicines, Lilly, Novartis; Financial Interests, Personal, Advisory Role: Bayer, Loxo Oncology, Genentech, AstraZeneca, Lilly; Financial Interests, Personal, Other, Honoraria: Clinical Care Options, Medscape, OncLive, PeerView. J.E. Grilley-Olson: Financial Interests, Personal, Other, Consulting/honoraria: SpringWorks, Sorrento. T. Patil: Financial Interests, Personal, Other, Honoraria: Roche/Genentech, AstraZeneca, PRIME Oncology, Aptitude Health, LLC; Financial Interests, Personal, Other, Consultancy fees: Guidepoint, Axiom. R.S. McDermott: Financial Interests, Personal, Advisory Board: Pfizer, Amgen, BMS, Bayer, Janssen, Clovis; Financial Interests, Personal, Invited Speaker: MSD, Ipsen, Astellas; Financial Interests, Institutional, Invited Speaker: MSD, Clovis, BMS, Regeneron, Bayer, Astellas. L.E. Raez: Financial Interests, Personal, Research Grant: LOXO, BMS, Pfizer, AstraZeneca, Syndax, Mirati, Nanth Health, Liquid Genomics, Guardant Health, Lilly Oncology, Merck. J.M. Johnson: Financial Interests, Personal, Research Grant: BMS, AstraZeneca, Merck; Financial Interests, Personal, Other, Consulting: Foundation Medicine, Rakuten. R. Norenberg, L. Dima, C.E. Mussi: Financial Interests, Personal, Full or part-time Employment: Bayer. X. Le: Financial Interests, Personal, Other, Consulting/advisory fees: EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Boehringer Ingelheim, AbbVie, Novartis, Janssen, Hengrui Therapeutics, Daiichi Sankyo, Eli Lilly; Financial Interests, Institutional, Research Grant: Eli Lilly, Boehringer Ingelheim. A. Drilon: Financial Interests, Personal, Advisory Board: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millennium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, BeiGene, BerGenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem Oncology, MORE Health, AbbVie, 14ner/Elevation Oncology, Remedica Ltd., ArcherDX, Monopteros, Novartis, EMD Serono, Melendi, Liberum, Repare RX, Amgen, Janssen; Financial Interests, Personal, Other, CME: Medscape, Onclive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, PeerView Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Medscape, Clinical Care Options; Financial Interests, Personal, Other, CME, Consulting: Axis; Financial Interests, Personal, Other, Consulting: Nuvalent, Merus, mBrace, EPG Health, Harborside Nexus, Ology, TouchIME, Entos, Treeline Bio, Prelude, Applied Pharmaceutical Science, Inc; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, Remedica Ltd., RV More; Financial Interests, Personal, Stocks/Shares: Treeline Biosciences; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Institutional, Funding, Research funding: Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, PharmaMar; Financial Interests, Personal, Funding, Research: Foundation Medicine; Other, Personal, Other, Food/Beverage: Merck, PUMA, Merus; Other, Personal, Other, Other: Boehringer Ingelheim.