Update from the ongoing phase 1/2 registrational trial of repotrectinib: results in TKI-naïve and TKI-pretreated patients with NTRK fusion-positive advanced solid tumors (TRIDENT-1)

Background: Repotrectinib is a selective, highly potent, next-generation ROS1 and TRK inhibitor that is currently under evaluation in the global registrational phase 1/2 TRIDENT-1 trial. Early clinical data from the TRIDENT-1 trial was presented in a plenary session at the 2021 AACR-NCI-EORTC conference. Repotrectinib was generally well tolerated. In NTRK fusion-positive tyrosine kinase inhibitor (TKI)-naïve (expansion cohort [EXP]-5) and TRK TKI-pretreated (EXP-6) patients with advanced solid tumors, confirmed overall response rates (cORR) per investigator assessment were 41% (95% CI: 18–67) and 48% (95% CI: 27–69), respectively. Efficacy was also observed in patients whose cancers developed solvent front mutations following prior TRK TKI treatment, with investigator-assessed cORR of 62% (95% CI: 32–86). Materials and methods: TRIDENT-1 (NCT03093116) is an ongoing trial enrolling patients whose cancers harbor a ROS1 or NTRK gene fusion. Patients enter 1 of 6 defined EXPs based on cancer type and prior therapy. The primary efficacy endpoint is cORR by Blinded Independent Central Review using RECIST v1.1. Safety and tolerability are also assessed. Results: The data cutoff for the present safety analysis was 11 February 2022. All treated patients were evaluable for safety (n = 380). The most common (>35% of patients) treatment-emergent adverse events (TEAE) were dizziness (60%), dysgeusia (48%), and constipation (35%). The majority (76%) of reported dizziness cases were grade 1 and no events of dizziness led to treatment discontinuation. Most treatment-related AEs (TRAE) were grade 1 or 2. Grade ≥3 TRAEs were observed in 21% of patients; no grade 5 TRAEs were observed. Dose reductions and discontinuations due to TEAEs were reported in 32% and 10% of patients, respectively. Safety results in patients with NTRK fusion-positive advanced solid tumors were similar to those in the overall population. Updated safety and efficacy data for NTRK fusion-positive TKI-naïve (EXP-5) and TKI-pretreated (EXP-6) patients will be available for presentation. Conclusions: In the ongoing registrational phase 1/2 TRIDENT-1 trial, repotrectinib generally was well tolerated in 380 patients. The most common TEAE was low-grade dizziness. Updated efficacy and safety data from this ongoing trial will be presented. Conflict of interest: Ownership: Chul Cho Stock or stock options: TheraCanVac Inc, Gencurix Inc, Bridgebio therapeutics, KANAPH Therapeutic Inc, Cyrus therapeutics, Interpark Bio Convergence Corp. Denise Trone Turning Point Therapeutics Employee Sanjay Thamake Turning Point Therapeutics Employee and Stock or Stock Options Alexander Drilon Stock or stock options: Treeline Bio Advisory Board: Byoung Chul Cho KANAPH Therapeutic Inc, Brigebio therapeutics, Cyrus therapeutics Guardant Health, Joseah BIO. Luydmila Bazhenova Personal Fees Turning point therapeutics, Daichi, BMS, Janssen, Merck, Regeneron, Bayer, Takeda, Boehringer Ingleheim, Novartis, Genentech, Sanofi, Atra Zeneca, Blueprint, Mirati Alexander Drilon Melendi 14ner/Elevation Oncology Novartis Pfizer Loxo/Bayer/Lilly Repare RX Janssen Amgen MonteRosa Benjamin Solomon Roche, Novartis, AstraZeneca, Pfizer, Lilly Amgen, BMS, Merch, Takeda, Beigene Board of Directors: Byoung Chul Cho Gencurix Inc, Interpark Bio Convergence Corp. Other Substantive Relationships: Byoung Chul Cho Research Funding: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD Abbvie, Medpacto, GIInnovationEli Lilly, Blueprint medicines, Interpark Bio Convergence Corp. Royalty: Champions Oncology. Consulting fees: Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Janssen, Medpacto, Blueprint medicines. Founder: DAAN Biotherapeutics Luydmila Bazhenova Research Funding: Beyondspring Personal Fees: ORIC Sanjay Popat Personal Fees: Amgen, AstraZeneca, Bayer, Beigene, Blueprint, BMS, Boehringer Ingelheim Daiichi Sankyo, Guardant Health, Incyte, Jansse, Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, Xcovery Payment for honoraria Personal Fees: AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche, Takeda, Pfizer Payment for expert testimony Personal Fees: Roche, Merck Serono Leadership role (Unpaid): British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, ETOP-IBCSG Partners Foundation Board Adrianus de Langen Grants: BMS, MSD, Boehringer, AstraZeneca Non-Financial Support: Merck Serono, Roche Christina Baik Grants: Hanmi Pharmaceutical, Trident Pharmaceuticals, Daiichi Sankyo, AbbVie, Orchard Therapeutics, AstraZeneca Pharmaceuticals, Hoosier Cancer Research Network, Array, Loxo, Janssen, Blueprint Medicines, Rain Therapeutics, TP therapeutics, Lilly Oncology Consulting fees: Silverback Therapeutics, AstraZeneca, Blueprint Medicines, Daiichi, Takeda, TP Pharmaceutics, Guardant Health, Regeneron Koichi Goto All support for present manuscript: Turning Point Therapeutics, Inc. Grants: Amgen Inc. AstraZeneca K.K., Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Inc., Bristol-Myers Squibb K.K., Blueprint Medicines Corporation., Chugai Pharmaceutical Co., Ltd., DAIICHI SANKYO Co., Ltd. Eisai Co., Ltd., Eli Lilly Japan K.K., Haihe Biopharma Co., Ltd., Ignyta, Inc., Janssen Pharmaceutical K.K., KISSEI PHARMACEUTICAL CO., LTD., Kyowa Kirin Co., Ltd., Life Technologies Japan Ltd., Loxo Oncology, Inc., MEDICAL & BIOLOGICAL LABORATORIES CO., LTD., Merck Biopharma Co., Ltd., Merus N.V., MSD K.K., NEC Corporation., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sumitomo Dainippon Pharma Co., Ltd., Spectrum Pharmaceuticals, Inc., Sysmex Corporation., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd. Payment for honoraria Personal Fees: Amgen Inc., AstraZeneca K.K., Bayer HealthCare Pharmaceuticals Inc., Boehringer Ingelheim Japan, Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., DAIICHI SANKYO Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Guardant Health Inc., Janssen Pharmaceutical K.K., Kyowa Kirin Co., Ltd., Life Technologies Japan Ltd., Medpace Japan K.K. Merck Biopharma Co., Ltd., MSD K.K., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd. Meili Sun: No conflicts to report Jian Fang: No conflicts to report Shun Lu: No conflicts to report Alexander Drilon All support for present manuscript: Pfizer Exelixis GlaxoSmithKlein Teva Taiho PharmaMar Royalty: Wolters Kluwer Consulting fees: 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 i3 Health Payment for honoraria Personal Fees: Ignyta/Genentech/Roche Loxo/ Bayer/Lilly Takeda/Ariad/Millenium TP 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 John Hopkins Lung Cancer Research Other financial or non- financial interests: Boehringer Ingelheim Food/Beverage: Merck, Puma, Merus Copyright: Selpercatinib-Osimertinib (filed/pending) Besse Benjamin Grants (to institution): 4D Pharma, Abbvie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Chugai pharmaceutical, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, EISAI, Genzyme Corporation, GSK, Inivata, IPSEN, Janssen, Onxeo, OSE immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals, Turning Therapeutics Benjamin Solomon Payment for honoraria: Roche AstraZeneca, Pfizer, Amgen, Takeda Christoph Springfeld Payment for honoraria: MSD Young Chul Kim Research Grant: AstraZeneca, Boehringer Ingelheim Payment for honoraria: AstraZeneca, Roche, Amgen, Yuhan, Johnson & Johnson, Boehringer Ingelheim, Norvatis, Pfizer Alice Hervieu All support for present manuscript: Provision of study materials, funding, medical writing Denis Moro-Sibilot Consulting fees: BMS, MSD Payment for honoraria: Roche AstraZeneca Support for attending meetings and/or travel: Roche Jürgen Wolf Consulting fees/Payment for honoraria/ Support for attending meetings and/or travel/Participation on a data safety monitoring board or advisory board: Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Loxo, Merck, MSD, Novartis, Nuvalent, Pfizer, Roche, Seattle Genetics, Takeda, Turning Point, BMS, Janssen Pharmaceutica, Novartis, Pfizer Victor Moreno Consulting fees: Roche, Bayer, Pieris, BMS, Janssen, Basilea. Regeneron/Sanofi, BMS, Bayer. Nanobiotix Other financial or non-financial interests: Principal Investigator – Institutional Funding: AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer Beigene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daichii Sankyo, DEBIOPHARM, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, 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.