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Long-term efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion gastrointestinal (GI) cancer: An expanded dataset
Background
Neurotrophic tyrosine receptor kinase ( NTRK ) gene fusions are oncogenic drivers in various tumour types. Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved for use in adult and paediatric patients with TRK fusion cancer, demonstrating an objective response rate (ORR) of 41% across 18 patients with gastrointestinal (GI) cancer (Boni et al, WCGI 2021). We report an updated analysis from an expanded dataset of patients with TRK fusion GI cancer with longer follow-up.
Methods
Patients with TRK fusion GI cancer treated with larotrectinib in the phase II clinical trial NAVIGATE (NCT02576431) were included in this analysis. Responses were investigator-assessed using RECIST v1.1. Data cut-off was 20 July 2021.
Results
As of data cut-off, 34 patients with metastatic TRK fusion GI cancer were enrolled. Median age was 63.5 years (range 32–90). The tumour types included were colorectal (CRC; n=19), pancreatic (n=6), cholangiocarcinoma (n=4), appendiceal (n=1), duodenal (n=1), gastric (n=1), hepatocellular carcinoma (n=1) and oesophageal (n=1). Among the patients with CRC, 10 were microsatellite instability high (MSI-H), seven were MSI-H not detected (including stable) and two were unknown. Overall, 32%, 35% and 18% of patients had received 1, 2, or ≥3 prior lines of systemic therapy, respectively. ORR in the 33 evaluable patients was 33% (95% confidence interval [CI] 18–52): one complete response (CR; 3%), 10 partial responses (PR; three pending confirmation [30%]), 15 stable disease (SD; 45%), four progressive disease (PD; 12%) and three not determined (ND; 9%). Median time to response was 1.9 months (range 1.7–5.0). Median duration of response (DoR) was 7.3 months (95% CI 3.5–27.3); median follow-up was 26.4 months. Median progression-free survival (PFS) was 5.4 months (95% CI 2.7–9.0); median follow-up was 5.4 months. Median overall survival (OS) was 12.5 months (95% CI 6.1–33.4); median follow-up was 7.7 months. In the 19 patients with CRC, ORR was 47% (95% CI 24–71): one CR (5%), eight PR (three pending confirmation [42%]), eight SD (42%), one PD (5%) and one ND (5%). Of the nine responders, six were MSI-H. The median DoR was not reliably estimable, but the 12-month rate was 67% (95% CI 29–100); median follow-up was 17.8 months. Median PFS was 5.5 months (95% CI 2.7–not estimable); median follow-up was 5.6 months. Median OS was 12.5 months (95% CI 6.1–36.5); median follow-up was 7.8 months. Treatment duration for all GI patients ranged from 0.2+ to 32.2+ months. At data cut-off, 14 patients had progressed; four continued treatment post-progression for ≥4 weeks. Treatment-related adverse events (TRAEs) occurred in 65% of patients (27% were Grade [G]1, 21% G2, 12% G3 and 6% G4). No patients discontinued treatment due to TRAEs.
Conclusions
In this expanded dataset with longer follow-up, larotrectinib continues to demonstrate rapid, durable responses, extended survival and a favourable safety profile in patients with TRK fusion GI cancer, particularly in those with CRC. These results highlight the importance of identifying NTRK gene fusions in patients with GI cancer, particularly in those with MSI-H CRC.
Clinical trial identification
NAVIGATE (NCT02576431).
Editorial acknowledgement
Medical writing assistance was provided by Luke Springall, PhD, and editorial and typesetting assistance was provided by George Chappell, MSc, both of Scion (London, UK), supported by Bayer Healthcare Pharmaceuticals, Inc.
Legal entity responsible for the study
Bayer.
Funding
Bayer Oncology.
Disclosures
E. Garralda: Advisory / Consultancy: Roche/Genentech, F.Hoffmann/La Roche, Ellipses Pharma, Neomed Therapeutics 1 Inc, Boehringer Ingelheim, Janssen Global Service, SeaGen, Alkermes, Thermo Fisher, Bristol-Mayers Squibb, MabDiscovery, Anaveon and F-Star Therapeutics; Speaker Bureau / Expert testimony: Merck Sharp & Dohme, Roche, Thermo Fisher, Lilly; Leadership role: Affimed Gmbh, Amgen SA, Anaveon AG, AstraZeneca AB, Biontech Gmbh, Catalym Gmbh, Cytomx, F.Hoffmann La Roche Ltd, F-Star Beta Limited, Genentech Inc, Genmab B.V., Hutchison Medipharma Limited, Icon, Imcheck Therapeutics, Immunocore Ltd, Janssen-Cilag SA, Medimmune Llc, Merck Kgga, Novartis Farmacéutica, S.A, Peptomyc, Ribon Therapeutics, Roche Farma SA, Seattle Genetics Inc, Symphogen A/S, and Taiho Pharma Usa Inc.; Research grant / Funding (institution): Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho, and BeiGene. D. Hong: Advisory / Consultancy: Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, and Trieza Therapeutics, Molecular Match, Presagia Inc; Research grant / Funding (self): 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, ; Travel / Accommodation / Expenses: Loxo Oncology, MiRNA, ASCO, AACR, SITC, and Genmab; Officer / Board of Directors: OncoResponse. J. Deeken: Research grant / Funding (institution): BMS, Merck, and Bayer/Loxo. A. Italiano: Advisory / Consultancy: Bayer, Daiichi Sankyo, Epizyme, Ipsen, Roche, and Springworks; Research grant / Funding (institution): AstraZeneca, Bayer, Merck, MSD, Pharmamar, and Roche. A. Ferrandiz: Advisory / Consultancy: Lilly, Merck, BMS, Amgen, Servier, Boehringer-Ilgenheim, Roche, Pfizer. J. Patel: Advisory / Consultancy: ARIAD, Abbvie, AstraZeneca, and Takeda Science Foundation. D. Lee: Honoraria (self): AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, CJ Healthcare, Eli Lilly, ChongKeunDang, Janssen, Merck, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm, ST Cube, and Abbvie; Non-remunerated activity/iesA: Blueprint Medicine, Takeda, Genexine, Menarini, and BC Pharma. H. Chung: Honoraria (Institution): Merck-Serono and Lilly; Advisory / Consultancy: Taiho, Celltrion, MSD, Lilly, BMS, Merck-Serono, Gloria, Beigene, Amgen, and Zymework; Research grant / Funding (institution): Lilly, GSK, MSD, Merck-Serono, BMS/Ono, Taiho, Amgen, Beigene, Incyte, and Zymework. J. Berlin: Advisory / Consultancy: Bayer; Research grant / Funding (institution): Bayer. T. André: Honoraria (self): Amgen, Astra-Zeneca, Bristol-Myers Squibb, Gritstone Oncology, GlaxoSmithKline, Haliodx, Kaleido Biosciences, Merck & Co., Inc., Pierre Fabre, Sanofi, Servier et, Merck & Co., Inc, Servier; Advisory / Consultancy: Astellas Pharma, BMS, Gritstone Oncology,Transgène,Roche/Ventana, Seagen, Merck & Co., Inc, Sevier; Research grant / Funding (institution): BMS, Seagen, GSK; Travel / Accommodation / Expenses: BMS, Merck & Co., Inc. S. Leyvraz: Advisory / Consultancy: Bayer; Travel / Accommodation / Expenses: Bayer. M. Miguel: Honoraria (Institution): Roche, Janssen, and MSD; Advisory / Consultancy: Syneos; Research grant / Funding (institution): Abbvie, Array,Achilles, Bayer, Basilea, Biontech, Faron, MSD, Novartis, Cytomex, Genentech, Genmab, Janssen, Menarini, Nektar, Catalym, Pharmamar, Regeneron, and Zenith. R. Norenberg: Full / Part-time employment: Chrestos Concept GmbH & Co KG, external employee at Bayer. M. Fellous: Full / Part-time employment: Bayer. C. Mussi: Full / Part-time employment: Bayer. A. Drilon: Honoraria (self): Helsinn, Beigene, Remedica Ltd., TP Therapeutics, Verastem, Ignyta/Genentech/Roche, AstraZeneca, Liberum, Loxo/Bayer/Lilly, Lungevity, Lung Cancer Considered podcasts, NIH, PER, OncLive, Clinical Care, Options, Lung Cancer Canada, AIOT, Chugai Pharm, Sirio Libanes Hospital, Answers in CME, Faculty RTP, RV More, Personalized Therapies in Thoracic Oncology Conference, AiCME, I3 Health; Advisory / Consultancy: Takeda/Ariad/Millenium, Exelixis, Monopteros, Ignyta/Genentech/Roche, AstraZeneca, EMD Serono, Melendi, 14ner/Elevation Oncology, Novartis, Pfizer, Loxo/Bayer/Lilly, Repare RX, Janssen, Amgen, ArcherDX, Abbvie, BergenBio, Hengrui Therapeutics, Blueprint Medicines, Ignyta/Genentech/Roche, AstraZeneca, MORE Health, Tyra Biosciences, Loxo/Bayer/Lilly, Pfizer, Nuvalent, Merus, AXIS, Medscape, Liberum, Med Learning, PeerView, EPG Health, JNCCN/ Harborside, Ology, Clinical Care Options, TouchIME, Entos, Treeline, Prelude, Applied Pharmaceutical Science, Inc, mBrace; Research grant / Funding (institution): Pfizer, Exelixis, GSK, Teva, Taiho, and PharmaMar, Foundation Medicine; Travel / Accommodation / Expenses: Merck, Puma, Merus, Boehringer Ingelheim; Licensing / Royalties: Wolters Kluwer. L. Shen: Advisory / Consultancy: BMS/AstraZeneca/BI/MSD/Daiichi Sankyo/Roche; Research grant / Funding (institution): Yaojie Ankang (Nanjing) Technology Co., Ltd./QiLu Pharmaceutical, Baiji Shenzhou (Beijing) Biotechnology Co., Ltd/Zaiding Pharmaceutical, Beijing Xiantong Biomedical Technology Co., Ltd. All other authors have declared no conflicts of interest.
