627P - Long-term efficacy and safety of larotrectinib in non-primary central nervous system (CNS) TRK fusion cancer

Background

Larotrectinib is the first-in-class, highly selective, CNS-active TRK inhibitor approved for tumour-agnostic use in patients (pts) with TRK fusion cancer. We report long-term efficacy and safety data in adult and paediatric pts with non-primary CNS TRK fusion cancer.

Methods

Data were pooled from 3 larotrectinib clinical trials (NCT02637687 [SCOUT], NCT02576431, NCT02122913). Responses were independent review committee (IRC)-assessed per RECIST v1.1. Pts enrolled in SCOUT were permitted to stop larotrectinib in the absence of on-treatment progression (‘wait-and-see’).

Results

As of 20 July 2023, 304 pts were included, with 302 eligible for efficacy analyses by IRC. Twenty-five pts had CNS metastases at baseline. Median age was 45 years (range 0–90). There were 28 different tumour types, including soft tissue sarcoma (24%), infantile fibrosarcoma (16%), lung (11%) and thyroid (10%). Pts received a median of 1 prior line of systemic therapy; 115 (38%) received ≥2. NTRK gene fusions were detected by NGS, FISH, PCR, NanoString, an unknown method, and chromosomal microarray in 267 (88%), 18 (6%), 14 (5%), 2 (1%), 2 (1%) and 1 (<1%) pt, respectively. ORR was 65% (95% CI 59–70): 82 (27%) CR (including 17 pathological CR), 113 (37%) PR, 55 (18%) SD, 32 (11%) PD and 20 (7%) not evaluable. Median time to response was 1.8 months (mo). Median duration of response, progression-free survival and overall survival were 43 mo (95% CI 33–not estimable), 28 mo (95% CI 20–36) and not reached, respectively, at median follow-ups of 37, 36 and 46 mo. The 6-year OS rate was 57% (95% CI 50–65). Treatment duration was up to 87+ mo. At data cut-off, 118 pts had progressed; 59 continued treatment post-progression for ≥4 weeks due to continued clinical benefit. Fifty-one of 100 paediatric pts enrolled in SCOUT had participated in ‘wait-and-see’. Treatment-related adverse events (TRAEs) were mainly Grade 1/2. Grade 3/4 TRAEs occurred in 68 (22%) pts. Five (2%) pts discontinued due to TRAEs.

Conclusions

Larotrectinib continued to demonstrate rapid and durable responses, extended survival and a favourable safety profile. This supports the wider adoption of NGS panels that include NTRK gene fusions to identify pts who may benefit from treatment with TRK inhibitors.

Clinical trial identification

NCT02637687 (SCOUT); NCT02576431; NCT02122913.

Editorial acknowledgement

Medical writing assistance was provided by Anastasija Pesevska, PharmD, and editorial assistance was provided by Melissa Ward, BA, both of Scion (a division of Prime, London, UK).

Legal entity responsible for the study

Bayer Healthcare Pharmaceuticals, Inc.

Funding

Bayer Healthcare Pharmaceuticals, Inc.

Disclosure

A.E. Drilon: Financial Interests, Personal, Advisory Board: 14ner/Elevation Oncology, AbbVie, AiCME, Amgen, Applied Pharmaceutical Science, Inc, ArcherDX, AstraZeneca, AXIS, BeiGene, BerGenBio, Blueprint Medicines, Boundless Bio, Chugai Pharmaceutical, EMD Serono, Entos, EPG Health, Exelixis, Harborside Nexus, Hel; Financial Interests, Personal, Other, Equity: Treeline Bio; Financial Interests, Institutional, Other, Associated research paid to institution: Exelixis, GSK, Pfizer, PharmaMar, Taiho and Teva; Financial Interests, Personal, Other, Copyright: Selpercatinib-Osimertinib (filed/pending); Financial Interests, Personal, Research Funding: Foundation Medicine; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Other: Boehringer Ingelheim; Financial Interests, Personal, Other, Food/beverage: Merck, Merus, and Puma; Financial Interests, Personal, Other, CME Honoraria: Axis, Clinical Care Options, EPG Health, Imedex, JNCC/Harborside, Liberum, Lungevity, Med Learning, Medscape, MJH Life Sciences, OncLive, Paradigm Medical Communications, Peerview Institute, PeerVoice, Physicians Education Resources, Remedica Ltd, Researc. C.M. van Tilburg: Financial Interests, Personal, Advisory Board: Alexion, Bayer, and Novartis. F. Doz: Financial Interests, Institutional, Advisory Board: Bayer, BMS, Roche, Celgene, Loxo Oncology, Servier, and Tesaro; Financial Interests, Institutional, Other, Travel expenses: Bayer, BMS, and Roche; Financial Interests, Institutional, Other, Consultancy: Servier. D.S.W. Tan: Financial Interests, Personal, Other, Consultancy: Novartis, Merck, Loxo, AstraZeneca, Roche, and Pfizer; Financial Interests, Personal, Other, Travel expenses: Pfizer, Boehringer Ingelheim, and Roche; Financial Interests, Personal, Other, Honoraria: BMS, Takeda, Novartis, Roche, and Pfizer; Financial Interests, Personal, Research Funding: Novartis, GSK, and AstraZeneca. J.J. Lin: Financial Interests, Personal, Other, Consultancy: Genentech, C4 Therapeutics, Blueprint Medicines Corporation, Nuvalent, Bayer, Novartis, Mirati Therapeutics, Turning Point Therapeutics, Elevation Oncology, and Regeneron; Financial Interests, Personal, Other, Honoraria and travel support: Pfizer; Financial Interests, Institutional, Research Funding: Roche/Genentech, Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Linnaeus Therapeutics, Nuvalent, and Novartis; Financial Interests, Personal, Other, CME funding: OncLive, MedStar Health, PeerView, and Northwell Health. B. Geoerger: Financial Interests, Personal, Other, Consultancy: Bayer; Financial Interests, Personal, Advisory Board: Bayer. C.M. Zwaan: Financial Interests, Institutional, Funding: Pfizer, Takeda, AbbVie, Jazz, Kura Oncology; Financial Interests, Personal, Other, Travel expenses: Jazz, Syndax; Financial Interests, Personal, Other, Consultancy: Novartis, Takeda, Incyte, Sanofi, Roche. U.N. Lassen: Financial Interests, Personal, Advisory Board: Bayer, Novartis; Financial Interests, Institutional, Research Grant: Roche, BMS, Pfizer, GSK, Lilly, Incyte, Janssen. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Coordinating PI: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. S. Kummar: Financial Interests, Personal, Advisory Board, Consultant/advisory board: Springworks Therapeutics, Bayer, Genome & Company, HarbourBiomed, BPGbio Therapeutics, Oxford Biotherapeutics, Mundibiopharma, Gilead, Mirati, GI Innovation Inc, XYone Therapeutics, Genome Insight; Financial Interests, Personal, Other, Co-founder and equity holder: PathomlQ; Other, Personal, Other, Spouse is scientific advisor: Cadila Pharmaceuticals; Other, Personal, Other, Spouse is co-founder: Arxeon; Financial Interests, Personal, Ownership Interest, Equity: Fortress Biotech, Inc. R.S. McDermott: Financial Interests, Personal, Advisory Board: Pfizer, Amgen, BMS, Bayer, Janssen, Clovis; Financial Interests, Personal, Invited Speaker: MSD, Ipsen, Astellas; Financial Interests, Personal, Invited Speaker, Speaker at Ad board: Merck Serono; Financial Interests, Institutional, Coordinating PI: MSD; Financial Interests, Institutional, Local PI: Clovis, BMS, Regeneron, Bayer, Astellas; Financial Interests, Institutional, Local PI, Clinical Trial: Seagen. D. Burcoveanu, N. Brega: Financial Interests, Personal, Other, Employee: Bayer. N. Neu: Financial Interests, Personal, Other, External employee: Bayer. T. Laetsch: Financial Interests, Personal, Other, Consultancy: Bayer, Cellectis, Deciphera, Jumo Health, Lilly, Loxo Oncology, Novartis and Y-mAbs Therapeutics; Financial Interests, Personal, Research Funding: AbbVie, Amgen, Atara, Biotherapeutics, Bayer, BMS, Epizyme, GSK, Janssen, Jubilant Pharmaceuticals, Lilly, Loxo Oncology, Novartis, Novella Clinical, Pfizer and Servier. 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, Advisory Board: 28Bio, Affini-T, Astellas, Fate Therapeutics, CARSgen, InduPro, Projects in Knowledge, Quanta, Ridgeline, Stanford; 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, Biomea, Immunogenesis, Revolution Medicine, STCube. L. Shen: Financial Interests, Personal, Advisory Board: MSD, BI, Servier, AZ, Transcenta Holding Limited; Financial Interests, Institutional, Funding: BeiGene, Ltd.; Financial Interests, Institutional, Trial Chair: Rongchang Pharmaceutical, Roche, Innovent, BeiGene, Ltd., NovaRock Biotherapeutics Limited. All other authors have declared no conflicts of interest.