1372P - Repotrectinib in patients (pts) with NTRK fusion-positive (NTRK+) advanced solid tumors, including NSCLC: Update from the phase I/II TRIDENT-1 trial

Background

Repotrectinib, a next-generation ROS1 and TRK tyrosine kinase inhibitor (TKI), has shown clinical activity and manageable safety in pts with ROS1+ NSCLC or NTRK+ locally advanced/metastatic solid tumors in the pivotal phase 1/2 TRIDENT-1 trial (NCT03093116). This is the first report of repotrectinib efficacy by Blinded Independent Central Review (BICR), with 8.7 mo minimum follow-up in pts with TKI-naïve and -pretreated NTRK+ solid tumors, including NSCLC, and safety in all pts treated at the recommended phase 2 dose (RP2D).

Methods

Pts with NTRK+ solid tumors were enrolled in TKI-naïve and -pretreated cohorts. RP2D was 160 mg QD for 14 d, then 160 mg BID. Phase 2 primary endpoint: confirmed objective response rate (cORR) by BICR.

Results

At data cutoff (19 Dec 2022), median follow-up was 17.8 mo (range, 8.7–64.6) in the TKI-naïve cohort (n = 40), and 20.1 mo (8.7–69.4) in the TKI-pretreated cohort (n = 48). The table shows efficacy in pts with NTRK+ solid tumors and subgroups of interest. NSCLC was the most common tumor (TKI-naïve, 52%; TKI-pretreated, 29%). In TKI-naïve NTRK+ NSCLC, cORR was 62% (95% CI, 38–82) and estimated 12-mo duration of response (DOR) and progression-free survival (PFS) was 92% (95% CI, 76–100) and 64% (43–86), respectively. In TKI-pretreated NTRK+ NSCLC, cORR was 42% (18–71) and estimated 12-mo DOR and PFS was 44% (1–88) and 23% (0–49), respectively. In all pts treated at RP2D in TRIDENT-1 (n = 426), dizziness (62%; grade ≥3, 3%) was the most common treatment-emergent adverse event (TEAE). Grade ≥3 TEAEs occurred in 51% of pts (29% treatment-related AEs). Treatment discontinuation rate due to TEAEs was 7% (3% due to treatment-related AEs).

Conclusions

In TRIDENT-1, with 8.7 mo minimum follow-up, repotrectinib showed robust responses and durable clinical activity in both TKI-naïve and -pretreated pts with NTRK+ solid tumors, including NSCLC. Repotrectinib safety at RP2D was manageable, consistent with prior reports. Table: 1372P

Repotrectinib in NTRK+ solid tumors

^aTumors included NSCLC (52% TKI-naïve; 29% TKI-pretreated), salivary gland cancer (8%; 17%), thyroid cancer (12%; 8%), soft tissue sarcoma (8%; 12%); others <10% each. ^bPer RECIST v1.1. ^cMay have received 1-2 prior TKI.

Clinical trial identification

NCT03093116.

Editorial acknowledgement

Medical writing support was provided by Elaine Heatherington, PhD, of Bio Connections, LLC, and was funded by Bristol Myers Squibb Company.

Legal entity responsible for the study

Turning Point Therapeutics Inc, a wholly owned subsidiary of Bristol Myers Squibb Company.

Funding

Turning Point Therapeutics Inc, a wholly owned subsidiary of Bristol Myers Squibb Company.

Disclosure

B.J. Solomon: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Merck, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Roche/Genentech; Financial Interests, Personal, Advisory Board: Amgen, Roche-Genentech, Eli Lilly, Takeda, Janssen; Financial Interests, Personal, Full or part-time Employment, Employed as a consultant Medical Oncologist at Peter MacCallum Cancer Centre: Peter MacCallum Cancer Centre; Financial Interests, Personal, Member of Board of Directors: Cancer Council of Victoria, Thoracic Oncology Group of Australasia; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Steering Committee Member, Principal Investigator and Steering committee Chair: Roche/Genentech, Pfizer; Financial Interests, Institutional, Steering Committee Member: Novartis. A. Drilon: Financial Interests, Personal, Advisory Board: 14ner/Elevation Oncology, AbbVie, Amgen, ArcherDX, AstraZeneca, BeiGene, BerGenBio, Blueprint Medicines, EcoR1, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Liberum, Loxo/Bayer/Lilly, Melendi, Monopteros, Monte Rosa, Novartis, Pfizer, Remedica Ltd., TP Therapeutics, Takeda/Ariad/Millennium, Tyra Biosciences, Verastem Oncology; Financial Interests, Personal, Other, CME: AiCME, Clinical Care Options, MJH Life Sciences, Med Learning, Medscape, Medscape, Onclive, Paradigm Medical Communications, PeerView Institute, PeerVoice, Physicians Education Resources, Targeted Oncology, WebMD; Financial Interests, Personal, Other, Consulting: Applied Pharmaceutical Science, Inc, EPG Health, Entos, Harborside Nexus, Merus, Nuvalent, Ology, Prelude, TouchIME, Treeline Bio, mBrace; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, RV More, Remedica Ltd; 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, PharmaMar, GSK, Teva, Taiho; Financial Interests, Personal, Funding, Research: Foundation Medicine; Non-Financial Interests, Member: ASCO, AACR, IASLC; Other, Food/Beverage: Merck, Puma, Merus; Other: Boehringer Ingelheim. J.J. Lin: Financial Interests, Personal, Other, Consulting: Turning Point Therapeutics, Nuvalent, Elevation Oncology, C4 Therapeutics, Bayer, Novartis, Mirati Therapeutics, Regeneron, CLaiM Therapeutics; Financial Interests, Personal, Advisory Board, Consulting: Blueprint Medicines, Genentech; Financial Interests, Personal, Other, Honorarium, travel: Pfizer; Financial Interests, Institutional, Local PI: Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche/Genentech, Novartis, Hengrui Therapeutics, Pfizer, Nuvalent. K. Goto: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Amgen K.K., Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Amgen Inc., Amoy Diagnostics Co., Ltd., AstraZeneca K.K., Bayer HealthCare Pharmaceuticals Inc., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb K.K., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Guardant Health Inc., Merck Biopharma Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Thermo Fisher Scientific K.K., Taiho Pharmaceutical Co., Ltd., Syneos Health Clinical K.K., Life Technologies Japan Ltd.; Financial Interests, Personal, Advisory Board: Janssen Pharmaceutical K.K., Medpace Japan K.K., Haihe Biopharma Co., Ltd.; Financial Interests, Personal and Institutional, Funding: Amgen Inc., Amgen K.K., AstraZeneca K.K., 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., Haihe Biopharma Co., Ltd., Ignyta,Inc., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Loxo Oncology, Inc., Medical ＆ Biological Laboratories Co., Ltd., Merck Biopharma Co., Ltd., Merus N.V., MSD K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sysmex Corporation., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Turning Point Therapeutics,Inc., Amgen Astellas BioPharma K.K., Bayer Yakuhin, Ltd., Blueprint Medicines Corporation., Life Technologies Japan Ltd., NEC Corporation., Novartis Pharma K.K., Craif Inc., Pfizer R&D Japan G.K., Turning Point Therapeutics,Inc.; Non-Financial Interests, Member: American Society of Clinical Oncology, The Japan Lung Cancer Society, Japanese Society of Medical Oncology, The Japanese Cancer Association. J. De Langen: Financial Interests, Institutional, Advisory Role: AstraZeneca, Bristol Myers Squibb, MSD Oncology, Roche, Boehringer Ingelheim, Pfizer, Lilly, Blueprint Medicines; Financial Interests, Institutional, Research Funding: AstraZeneca, Bristol Myers Squibb, Merck Serono, MSD Oncology, Roche, Merus. D. Kim: Financial Interests, Personal, Invited Speaker: Korean Cancer Association, Korean Society of Medical Oncology, Korean Association for Lung Cancer, Taiwan Lung Cancer Society, Japan Cancer Association; Financial Interests, Personal, Other, Scientific Advisor: Health Insurance Review & Assessment Service, Korea; Financial Interests, Personal, Writing Engagement, Medical writing assistance: Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Chong Keun Dang, Daiichi Sankyo, GSK, Novartis, Pfizer, MSD, Merck, Roche, Takeda, Yuhan; Financial Interests, Institutional, Local PI, Clinical Trial Funding: Hanmi, Alpha Biopharma, Amgen, AstraZeneca/Medimmune, Boehringer Ingelheim, Daiichi Sankyo, Janssen, Merus, MIrati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Bridge BioTherapeutics, GSK; Financial Interests, Institutional, Coordinating PI, Clinical Trial Funding: Chong Keun Dang; Financial Interests, Institutional, Research Grant, Laboratory research funding to my institution: InnoN; Non-Financial Interests, Advisory Role: Amgen, BMS / Ono Pharmaceuticals, Daiichi Sankyo, Janssen, GSK, Pfizer, AstraZeneca, SK Biopharm, Takeda, Yuhan; Non-Financial Interests, Member of Board of Directors: Korean Cancer Association, Korean Society of Medical Oncology, Korean Association for Lung Cancer, Asian Thoracic Oncology Research Group; Other, Travel support for advisory board meeting attendance: Amgen, Daiichi Sankyo; Other, Clinical trial research funding to my institution: Asian Thoracic Oncology Research Group. J. Wolf: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, Ignyta, Janssen, Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda; Financial Interests, Personal, Invited Speaker: Bayer, Chugai; Financial Interests, Institutional, Research Grant: BMS, Janssen, Novartis, Pfizer. S. Popat: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Novartis, Amgen, Janssen, Daiichi Sankyo, AstraZeneca, Bayer, BMS, Blueprint, Merck Serono, Guardant Health, BeiGene, Takeda, Lilly, Roche, Turning Point Therapeutics, GSK, MSD, Pfizer, Sanofi, EQRx; Financial Interests, Personal, Invited Speaker: Medscape, VJ Oncology; Financial Interests, Personal, Other, Journal Deputy Editor, Lung Cancer: Elsevier; Financial Interests, Institutional, Other, Sub-investigator: Amgen; Financial Interests, Institutional, Coordinating PI: Ariad, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Takeda, Turning Point Therapeutics, Roche, Janssen, BMS, Lilly; Financial Interests, Institutional, Local PI: AstraZeneca, Roche, GSK, Trizel; Financial Interests, Institutional, Other, Sub-Investigator: MSD, Blueprint; Financial Interests, Institutional, Research Grant: Guardant Health; Non-Financial Interests, Leadership Role, Chair of Steering Committee, Unpaid: British Thoracic Oncology Group; Non-Financial Interests, Officer, Thoracic Faculty, Unpaid: European Society of Medical Oncology; Non-Financial Interests, Leadership Role, Foundation Council Member, Unpaid: European Thoracic Oncology Platform; Non-Financial Interests, Advisory Role, Mesothelioma Task-force Member, Unpaid: International Association for the Study of Lung Cancer; Non-Financial Interests, Member of Board of Directors, Unpaid: Mesothelioma Applied Research Foundation; Non-Financial Interests, Advisory Role, Honorary Clinical Advisor, Unpaid: ALK Positive UK; Non-Financial Interests, Advisory Role, Research Advisory Group Member, Unpaid: Ruth Strauss Foundation; Non-Financial Interests, Advisory Role, Scientific Advisory Board Member, Unpaid: Lung Cancer Europe. D.W. Lim: Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim; Financial Interests, Institutional, Advisory Board: MSD, Roche, BeiGene; Financial Interests, Institutional, Trial Chair, Grant funding for investigator-sponsored study: Bristol Myers Squibb; Financial Interests, Institutional, Steering Committee Member: Novartis. C.S. Baik: Financial Interests, Institutional, Research Funding: AbbVie, Rain Therapeutics, Nuvalent, Blueprint, TurningPoint, Lilly, AstraZeneca, Janssen, Daiichi, Spectrum, Pfizer, Loxo; Financial Interests, Personal, Speaker, Consultant, Advisor: Daiichi, Boehringer, Janssen, Regeneron, Silverback, Pfizer, AstraZeneca, Guardant, TurningPoint, Takeda. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer, AstraZeneca; Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Institutional, Local PI, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer BeiGene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daiichi 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: Multiple. S. Thamake: Financial Interests, Institutional, Other, Employee: Bristol Myers Squibb. F. Ades: Financial Interests, Institutional, Other, Employee: Bristol Myers Squibb. D. Trone: Financial Interests, Institutional, Other, Employee: Bristol Myers Squibb. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, Eisai, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. All other authors have declared no conflicts of interest.