Abstract 668P
Background
Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in a variety of tumour types. Larotrectinib is a highly selective, central nervous system-active TRK inhibitor, approved to treat pts with TRK fusion cancer. We report updated efficacy and safety data in an expanded dataset of pts with longer follow-up.
Methods
Data were pooled from 3 clinical trials (NCT02576431, NCT02122913, NCT02637687) of pts with TRK fusion cancer treated with larotrectinib. Responses were assessed by independent review committee (IRC) per RECIST v1.1.
Results
As of 20 July 2022, a total of 289 pts (median age 44 years [range 0–90]) were included. There were 26 different tumour types, including soft tissue sarcoma (24%), infantile fibrosarcoma (17%), thyroid (10%), and lung (10%). Pts received a median of 1 prior line of systemic therapy, with 124 (43%) pts receiving ≥2. Among 274 IRC-eligible pts, the objective response rate was 66% (95% CI 60–72): 75 (27%) complete response (CR), including 13 (5%) pathological CR (pCR); 107 (39%) partial response (PR); 49 (18%) stable disease; 26 (9%) progressive disease; and 17 (6%) not evaluable. Median duration of response was 43.3 months (mo; 95% CI 31.4–54.7) at a median follow-up of 31.5 mo. Median progression-free survival was 30.8 mo (95% CI 22.5–36.1) at a median follow-up of 31.3 mo. Median overall survival (OS) was not reached; 48-mo OS rate was 65%. Pts were treated for up to 75+ mo. At data cut-off, 108 pts had progressed; 46 continued treatment post-progression for ≥4 weeks due to continued clinical benefit. Treatment-related adverse events (TRAEs) were mainly Grade 1/2; 59 (20%) pts had Grade 3/4 TRAEs. Five (2%) pts discontinued due to TRAEs. In a 5-year long-term follow-up analysis of the original 55 pts from the July 2018 primary data cut-off, 8 pts had an improved best overall response from PR to CR (or pCR), with a total CR rate of 27%.
Conclusions
Larotrectinib continued to demonstrate rapid and durable responses, extended survival benefit, and a favourable safety profile. This supports the wider adoption of next-generation sequencing panels that include NTRK gene fusions to identify pts who may benefit from treatment.
Clinical trial identification
NCT02576431, NCT02122913, NCT02637687.
Editorial acknowledgement
Medical writing assistance was provided by Anastasija Pesevska, PharmD, and editorial assistance was provided by Melissa Ward, BA, both of Scion Medica, London, UK.
Legal entity responsible for the study
Bayer HealthCare Pharmaceuticals, Inc. and Loxo Oncology, Inc., a wholly owned subsidiary of Eli Lilly and Company.
Funding
These studies were funded by Bayer HealthCare Pharmaceuticals, Inc. and Loxo Oncology, Inc., a wholly owned subsidiary of Eli Lilly and Company.
Disclosure
A. Drilon: Financial Interests, Personal, Other, Honorarium/advisory board: Ignyta, Genentech, Roche, Loxo, Bayer, Lilly, Takeda, Ariad, Millenium, Turning Point Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, BeiGene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, AbbVie, 14ner/Elevation Oncology, ArcherDX, Monopteros, Novartis, EMD Serono, Medendi, Repare RX, Nuvalent, Merus, Chugai Pharmaceutical, Remedica Ltd., mBrace, AXIS, EPG Health, Harborside Nexus, Liberum, RV More, Ology, Amgen, TouchIME, Janssen, Entos, Treeline Bio, Prelude, Applied Pharmaceutical Science, Inc., AiCME, i3 Health, MonteRosa; Financial Interests, Personal, Stocks or ownership, Equity: Treeline Bio; Financial Interests, Personal, Stocks or ownership, Copyright (filed/pending): Selpercatinib-Osimertinib; Financial Interests, Institutional, Other, Associated research paid to institution: Pfizer, Exelixis, GSK, Teva, Taiho, PharmaMar; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Other, Food/beverage expenses: Merck, Puma, Merus; Financial Interests, Personal, Other: Boehringer Ingelheim; Financial Interests, Personal, Other, CME honorarium: 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, Clinical Care Options, EPG Health, JNCC/Harborside, Liberum, Remedica Ltd. L. Shen: Financial Interests, Personal, Funding: Beijing Xiantong Biomedical Technology Co., Ltd., Qilu Pharmaceutical Co., Ltd., Zaiding Pharmaceutical (Shanghai) Co., Ltd., Jacobio Pharmaceuticals Co., Ltd., Beihai Kangcheng (Beijing) Medical Technology Co. Ltd.; Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy: MSD, Merck, Boehringer Ingelheim, Harbour; Financial Interests, Personal, Speaker, Consultant, Advisor, Speaker: Hutchison Whampoa, Hengrui Therapeutics, ZaiLab, CStone. C. van Tilburg: Financial Interests, Personal, Advisory Board: Alexion, Bayer, Novartis. F. Doz: Financial Interests, Institutional, Advisory Board: Bayer, BMS, Roche, Loxo Oncology, Servier, Tesaro; Financial Interests, Personal, Other, Travel expenses: Bayer, BMS, Roche; Financial Interests, Institutional, Speaker, Consultant, Advisor, Consultancy: Servier. D.S.W. Tan: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy: Novartis, Merck, Loxo Oncology, AstraZeneca, Roche, Pfizer; Financial Interests, Personal, Other, Travel expenses: Pfizer, Boehringer Ingelheim, Roche; Financial Interests, Personal, Other, Honorarium: BMS, Takeda, Novartis, Roche, Pfizer; Financial Interests, Personal, Research Funding: Novartis, GSK, AstraZeneca. J.J. Lin: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy: Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Novartis, Mirati Therapeutics, Turning Point Therapeutics, Elevation Oncology, Regeneron, CLaiM Therapeutics; Financial Interests, Personal, Other, Honorarium: Pfizer; Financial Interests, Personal, Other, Travel expenses: Pfizer; Financial Interests, Institutional, Research Funding: Roche, Genentech, Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Linnaeus Therapeutics, Nuvalent, Novartis; Financial Interests, Personal, Other, CME funding: OncLive, MedStar Health, PeerView Institute, Northwell Health. S. Kummar: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, SpringWorks Therapeutics, Gilead, EcoR1, Seagen, Mundibiopharma Ltd., Bayer, Mirati, Genome Insight, Genome & Company, Harbour Biomed; Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy: Boehringer Ingelheim, SpringWorks Therapeutics, Gilead, EcoR1, Seagen, Mundibiopharma Ltd., Bayer, Mirati, Genome Insight, Genome & Company, Harbour Biomed; Financial Interests, Personal, Ownership Interest, Co-founder and equity holder: PathomlQ; Other, Personal, Other, Spouse is a scientific advisor: Cadila Pharmaceuticals Ltd., Arxeon Inc. U.N. Lassen: Financial Interests, Personal, Advisory Board: Bayer, Pfizer, Novartis; Financial Interests, Personal, Research Funding: BMS, GSK, Pfizer, Roche. R.S. McDermott: Financial Interests, Personal, Advisory Board: Amgen, Bayer, BMS, Clovis, Janssen, Pfizer; Financial Interests, Personal, Invited Speaker: MSD, Ipsen, Astellas; Financial Interests, Institutional, Local PI: Astellas, Bayer, BMS, Clovis, Regeneron; Financial Interests, Institutional, Coordinating PI: MSD. T. Patil: Financial Interests, Personal, Other, Honorarium: Roche, Genentech, AstraZeneca, PRIME Oncology, Aptitude Health, LLC; Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy: Guidepoint, Axiom. D. Burcoveanu, N. Brega: Financial Interests, Personal, Full or part-time Employment: Bayer. R. Norenberg: Financial Interests, Personal, Full or part-time Employment, External employee: Bayer. T.W. Laetsch: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy: Novartis, Cellectis, Bayer, Loxo Oncology, Lilly, Deciphera, Jumo Health, Y-mAbs Therapeutics; Financial Interests, Personal, Research Funding: Pfizer, Novartis, Bayer, Loxo Oncology, AbbVie, Amgen, Atara, Biotherapeutics, BMS, Lilly, Epizyme, GSK, Janssen, Jubilant Pharmaceuticals, Novella Clinical, Servier. D.S. Hong: Financial Interests, Personal, Research 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, Pfizer, Seagen, Takeda; Financial Interests, Personal, Other, Travel/accommodation/expenses: Loxo Oncology, MiRNA, ASCO, AACR, SITC, Genmab; Financial Interests, Personal, Speaker, Consultant, Advisor, Consulting/advisory roles: Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seagen, Takeda, Trieza Therapeutics; Financial Interests, Personal, Ownership Interest, Advisor: Molecular Match, Presagia Inc.; Financial Interests, Personal, Ownership Interest, Founder: OncoResponse. All other authors have declared no conflicts of interest.
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