15MO - Efficacy and ctDNA analysis in an updated cohort of patients with TRK fusion lung cancer treated with larotrectinib

Background

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various cancers, including lung cancer. Larotrectinib, a highly selective, central nervous system (CNS)-active tropomyosin receptor kinase (TRK) inhibitor, demonstrated a 73% objective response rate (ORR) in 15 patients (pts) with TRK fusion lung cancer (Drilon et al. JCO Precis Oncol 2022). We report efficacy and safety with circulating tumour DNA (ctDNA) analysis in pts with TRK fusion lung cancer treated with larotrectinib.

Methods

Pts treated with larotrectinib in 2 clinical trials were analysed. NTRK gene fusions were determined by local testing before enrolment. Larotrectinib was administered at 100 mg twice daily. Response was assessed by an independent review committee (IRC) per RECIST v1.1. ctDNA was analysed using Guardant360 and GuardantOMNI.

Results

As of 20 July 2021, 26 pts (12 pts with CNS metastases) were enrolled. Among 23 pts (10 pts with CNS metastases) evaluable per IRC, ORR was 83% (95% confidence interval [CI] 61–95; 2 complete response, 17 partial response, 4 stable disease). Median duration of response (DoR) was not reached (95% CI 9.5–not estimable [NE]), with a 12-month DoR rate of 72%. Median progression-free survival was not reached (95% CI 9.9–NE). Median overall survival was 40.7 months (95% CI 19.4–NE). Treatment-related adverse events were mostly Grade 1–2. ctDNA data were available for 14 pts. ctDNA analysis detected NTRK gene fusions in 6 of the 14 pts at treatment start. Assessment of baseline co-occurring mutations revealed the inclusion of 3 patients with mutation-positive NSCLC who had failed prior anti-EGFR therapy. By the data cut-off, 6 pts had progressed, with ctDNA data available for 5 pts. Potential acquired mutations were identified in 3 pts.

Conclusions

Larotrectinib demonstrated durable responses, extended survival benefit, and a favourable safety profile in patients with advanced lung cancer harbouring NTRK gene fusions, including those with treatment-naive NSCLC or with prior EGFR inhibitor therapy. ctDNA next-generation sequencing represents a promising technology to test NTRK gene fusions or resistance mutations.

Clinical trial identification

NCT02122913, NCT02576431.

Editorial acknowledgement

Editorial assistance was provided by Anastasija Pesevska, PharmD, and Joe Alling, BSc, (Scion, London UK) funded by Bayer HealthCare Pharmaceuticals, Inc.

Legal entity responsible for the study

Bayer Healthcare Pharmaceuticals Inc. and Loxo Oncology.

Funding

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

Disclosure

M. Hoejgaard: Financial Interests, Personal, Other, Advisory role for various diagnostic companies/investors: LingoMedical; Financial Interests, Personal, Stocks/Shares, Stocks, <20000USD: Bavarian Nordic, Pacific Biosciences, Illumina Inc.; Financial Interests, Personal, Stocks/Shares, stocks<20000USD: Agilent; Financial Interests, Institutional, Funding: Roche; Non-Financial Interests, Personal, Principal Investigator, TRESR trial and MYTHIC trial: Repare Therapeutics; Non-Financial Interests, Personal, Principal Investigator, AMG160 master protocol and Bemarituzumab trial: Amgen; Non-Financial Interests, Personal, Principal Investigator, INC93318-122: Incyte Cooperation; Non-Financial Interests, Personal, Principal Investigator, KN-4802 trial: Kinnate Biopharma; Other, Personal, Other, Board member, tumor agnostic board. Public service: Danish Medicines Council. A. Drilon: Financial Interests, Personal, Advisory Board: Ignyta/Genentech/Roche, Loxo/Bayer/Eli 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, EcoR1, Monte Rosa; 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, AiCME; Financial Interests, Personal, Other, CME, Consulting: Axis; Financial Interests, Personal, Other, Consulting: Nuvalent, Merus, EPG Health, mBrace, 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, Personal, Other, stocks: mBrace; Financial Interests, Institutional, Funding, Research funding: Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, PharmaMar; Financial Interests, Personal, Funding, Research: Foundation Medicine; Non-Financial Interests, Personal, Member: ASCO, AACR, IASLC; Other, Personal, Other, Food/Beverage: Merck, PUMA, Merus; Other, Personal, Other, Other: Boehringer Ingelheim. J.J. Lin: Financial Interests, Personal, Other, Consulting: Turning Point Therapeutics, Nuvalent, Elevation Oncology, C4 Therapeutics, Bayer, Novartis, Mirati Therapeutics; Financial Interests, Personal, Advisory Board, Consulting: Blueprint Medicines, Genentech; Financial Interests, Personal, Other, Honorarium, travel: Pfizer; Financial Interests, Institutional, Invited Speaker: Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche/Genentech, Novartis, Hengrui Therapeutics, Pfizer, Nuvalent. S. Kummar: Financial Interests, Personal, Advisory Board: Bayer, Gilead, Mundibiopharma, Boehringer Ingelheim, Springworks Theraepeutics, HarbourBiomed, Boehringer Ingelheim, Oxford BioTherapeutics; Financial Interests, Personal, Advisory Board, Spouse: Cadila Pharmaceuticals; Financial Interests, Personal, Other, Chair, DSMC: Mirati; Financial Interests, Personal, Ownership Interest: Pahtomiq; Financial Interests, Personal, Other, co-founder: Pathomiq; Financial Interests, Institutional, Invited Speaker: ADC Therapeutics, Pionyr Therapeutics, Eisai, Bristol Myers Squibb, Syndax, SeaGen, ORIC, EMD Serono, Genome & Company, Moderna, Amgen, ASTX Therapeutics, PMV Pharmaceuticals, Elevation Oncology, VelosBio Inc, Gilead, Day One Biopharmaceuticals, Vincerx Pharma, Inc. D.S.W. Tan: Financial Interests, Personal, Advisory Board: Amgen, Novartis, Boehringer Ingelheim, C4 Therapeutics, AstraZeneca, GSK, Takeda, Eisai, Guardant, Merck, Pfizer, Roche; Financial Interests, Institutional, Research Grant: AstraZeneca, Amgen, Pfizer, ACM Biolabs; Financial Interests, Personal, Invited Speaker: Novartis. J. Patel: Financial Interests, Personal, Advisory Board: AbbVie, AstraZeneca, Takeda; Financial Interests, Personal, Advisory Role: Eli Lilly. S. Leyvraz: Financial Interests, Personal, Advisory Board: Bayer. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer; Financial Interests, Personal, Full or part-time Employment: START; Non-Financial Interests, Personal, Principal Investigator, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BioInvent International AB, BMS, Boehringer Ingelheim, Boston, Celgene, Daiichi Sankyo, Debiopharm, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Eli Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith.: Multiple. L.S. Rosen: Financial Interests, Institutional, Research Grant: Bayer. B. Solomon: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer; Financial Interests, Institutional, Invited Speaker: Daiichi-Sankyo, Iovance, GSK, Mirati, ImmunityBio, AstraZeneca, Amgen; Non-Financial Interests, Personal, Member: ASCO, AACR, ESMO. R. Norenberg: Financial Interests, Personal, Full or part-time Employment: Bayer. D. Burcoveanu: Financial Interests, Personal, Full or part-time Employment: Bayer. L. Yun: Financial Interests, Personal, Full or part-time Employment: Bayer. G. Beckmann: Financial Interests, Personal, Full or part-time Employment: Bayer. C.E. Mussi: Financial Interests, Personal, Full or part-time Employment: Bayer. L. Shen: Financial Interests, Institutional, Research Grant: 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, Advisory Board: MSD, Merck, Boehringer Ingelheim, Harbour; Financial Interests, Personal, Invited Speaker: Hutchison Whampoa, Hengrui,, Zai Lab, CStone Pharmaceuticals. All other authors have declared no conflicts of interest.