Abstract 85P
Background
MET, a receptor tyrosine kinase expressed on cancer cells and neutrophils, plays a role in tumour microenvironment modulation. MET activated tumours respond poorly to checkpoint inhibitors and MET inhibition may overcome immune checkpoint resistance via downregulation of immune checkpoints and immune-suppressive neutrophils. NSCLCs are rich in tumour infiltrating neutrophils which are implicated in immunotherapy resistance.
Methods
The Phase I/II POTENT trial (NCT05782361) investigates whether the MET inhibitor tepotinib can overcome resistance to pembrolizumab in patients (pts) with advanced NSCLC. The primary endpoint of the Phase I was to determine the recommended phase II dose for the combination.
Results
Eight pts were recruited to phase I and dosed at dose level 1, 500 mg (450 mg active moiety) tepotinib once daily (QD) and 200 mg pembrolizumab intravenously three-weekly (Q3W). Patients had advanced NSCLC. All had received prior platinum-based chemotherapy and PD-1/PD-L1 inhibitor (median of 5 lines of therapy). Six pts were evaluable for dose confirmation, all eight pts were evaluable for safety. One grade (G) 3 treatment related adverse event (TRAE), lymphopaenia, was observed. The most common G1/2 TRAEs were nausea (6 pts, 75%), anorexia, oedema, vomiting and fatigue (all 3 pts, 38%). No pts discontinued dosing due to TRAEs. Pneumonitis, a potential overlapping toxicity, was not observed. No events were dose limiting toxicities and the recommended phase II combination dose was confirmed as 450 mg tepotinib OD and 200 mg pembrolizumab Q3W. The plasma concentrations of tepotinib did not exceed levels previously reported. Six pts were evaluable for response: three pts had progressive disease as their best response, three had stable disease as best response with a median duration of 6 months.
Conclusions
The combination of tepotinib with pembrolizumab is feasible and well tolerated. In this small patient cohort of heavily pretreated, non-biomarker selected NSCLC, there was no clear efficacy signal (not primary objective). The phase II is currently recruiting pts with advanced NSCLC with MET exon 14 skipping mutations assessing efficacy and pharmacodynamic endpoints.
Clinical trial identification
EudraCT: 2021-005134-42.
Legal entity responsible for the study
Investigator Initiated Trials Team at Institute of Cancer Research.
Funding
This study is financially supported by Merck (CrossRef Funder ID: 10.13039/100009945). This study is supported in part by a research grant from Investigator-Initiated Studies Program of MSD (UK) Limited, London, UK. The opinions expressed in this paper are those of the authors and do not necessarily represent those of MSD (UK) Limited, London, UK.
Disclosure
K. Koster: Financial Interests, Institutional, Other, Support for attending meetings and/or travel: Takeda, Janssen-Cilag. X. Hu: Financial Interests, Personal, Full or part-time Employment: The Institute of Cancer Research. C. Yap: Financial Interests, Personal, Advisory Board, Statistical Consultant: Faron Pharmaceutical; Financial Interests, Personal, Invited Speaker, Speaker at a TrainingWorkshop: Bayer; Financial Interests, Institutional, Research Grant: AstraZeneca, Celgene, Novartis; Financial Interests, Personal and Institutional, Research Grant: Faron Pharmaceuticals. M.D. Forster: Financial Interests, Personal, Advisory Board: Bayer, Merck, MSD, Roche, Takeda, ultrahuman, Transgene, Immunotep, Amgen, BMS, EQRx, GSK, Janssen, Oxford VacMedix, PharmaMar, Regeneron, Syncorp; Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim, MSD, Merck; Financial Interests, Institutional, Invited Speaker: Roche, Oxford VaxMedix, Apollomics, Takeda, Ellipsis, Moderna, Exsciencia, ALXOncology, GenMab, Janssen; Financial Interests, Personal and Institutional, Invited Speaker, Presented data at ESMO-IO 2022: Achilles; Financial Interests, Institutional, Invited Speaker, Presented Data at SITC 2023: Immutep; Non-Financial Interests, Personal, Advisory Role, Chair of Scientific Advisory Group: Ruth Strauss Foundation. S. Popat: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Novartis, Amgen, Janssen, Daiichi Sankyo, AstraZeneca, Bayer, BMS, Blueprint, Guardant Health, Takeda, Lilly, Turning Point Therapeutics, GSK, MSD, Pfizer, Sanofi, EQRx, AnHeart, Arcus Biosciences, Ellipses, Gilead, IO Biotech, Mirati; Financial Interests, Personal, Expert Testimony: Merck Serono, Roche; Financial Interests, Personal, Invited Speaker: Medscape, VJ Oncology, Novocure, PharmaMar; Financial Interests, Institutional, Other, Subinvestigator: Amgen; Financial Interests, Institutional, Invited Speaker: Ariad, AstraZeneca, Roche, Boehringer Ingelheim, Celgene, Daiichi Sankyo, GSK, Takeda, Trizel, Turning Point Therapeutics, Roche, Janssen, BMS, Lilly; Financial Interests, Institutional, Other, Sub-Investigator: MSD, Blueprint; Financial Interests, Institutional, Research Grant: Guardant Health; Non-Financial Interests, Personal, Leadership Role, Chair of Steering Committee, Unpaid: British Thoracic Oncology Group; Non-Financial Interests, Personal, Officer, Thoracic Faculty, Unpaid: European Society of Medical Oncology; Non-Financial Interests, Personal, Leadership Role, Foundation Council Member, Unpaid: European Thoracic Oncology Platform; Non-Financial Interests, Personal, Advisory Role, Mesothelioma Committee, Unpaid: International Association for the Study of Lung Cancer; Non-Financial Interests, Personal, Member of Board of Directors, Unpaid: Mesothelioma Applied Research Foundation; Non-Financial Interests, Personal, Advisory Role, Honorary Clinical Advisor, Unpaid: ALK Positive UK; Non-Financial Interests, Personal, Advisory Role, Research Advisory Group Member, Unpaid: Ruth Strauss Foundation; Non-Financial Interests, Personal, Advisory Role, Scientific Adivsory Board Member, Unpaid: Lung Cancer Europe. J.S. Lopez: Financial Interests, Personal, Advisory Board: Roche Genentech, Basilea, Ellipses Pharma, Cureteq, Pierre Faber, GSK; Financial Interests, Institutional, Research Grant: Roche Genentech, Basilea, Astex. J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals, Menarini Silicon Biosystems, ImCheck Therapeutics, Crescendo, MetaCurUm, Myricx, Nurix Therapeutics, Oncternal Therapeutics; Financial Interests, Institutional, Advisory Board: Harpoon, Dark Blue Therapeutics, Novartis, Takeda, Tango Therapeutics; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GSK, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics, Menarini Silicon Biosystems, Immunic Therapeutics, MetaCurUm, Myricx, Nurix Therapeutics, Oncternal Therapeutics; Financial Interests, Institutional, Invited Speaker: Amgen; Non-Financial Interests, Personal, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GSK, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals, Crescendo, ImCheck Therapeutics, Immunic Therapeutics; Non-Financial Interests, Institutional, Product Samples: Daiichi, Bayer, Merck Serono, AstraZeneca, Harpoon, Pfizer, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GSK. A. Sharp: Non-Financial Interests, Personal, Principal Investigator, Clinical trial in progress: AstraZeneca, Nurix, Celcuity; Non-Financial Interests, Personal, Principal Investigator, Clinical trial completed: Amgen, Exelixis; Non-Financial Interests, Personal, Principal Investigator, Clinical trial in progress: Roche; Non-Financial Interests, Institutional, Product Samples, Access to IMP as a gift for research: AstraZeneca, Cyclacel; Other, Personal, Other, Paid consultancy (to research): D.E Research, CHARM Therapeutics, Ellipses, Doira; Other, Personal, Other, Paid for teaching session: MSD. U. Banerji: Financial Interests, Personal, Advisory Board, Advisory Board Member: Pegasy, Carrick Therapeutics; Financial Interests, Personal, Advisory Board: Pharmenable, Ellipses Pharma; Financial Interests, Personal, Full or part-time Employment, Employed by the Institute of Cancer Research: The Institute of Cancer Research; Financial Interests, Institutional, Research Grant, Pre clinical grant: Verastem Oncology; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Avacta; Non-Financial Interests, Personal, Principal Investigator: Various pharma companies. C. Lindsay: Financial Interests, Personal, Invited Speaker, Advisory role: Amgen; Financial Interests, Personal, Invited Speaker, Educational Presentation/Workshop: Amgen; Financial Interests, Personal, Advisory Board: Qiagen; Financial Interests, Institutional, Invited Speaker, CI for a phase III clinical trial: Mirati Therapeutics, Amgen; Financial Interests, Institutional, Invited Speaker, CI for a phase I-II clinical trial: BI, Revolution Medicines; Financial Interests, Institutional, Invited Speaker, CI for a phase II clinical trial: Roche; Financial Interests, Institutional, Invited Speaker, PI for a phase II clinical trial: Apollomics; Financial Interests, Institutional, Research Grant, Research funding which includes use of their medical products: Revolution Medicines; Non-Financial Interests, Personal, Other, Travel funding for poster presentation: Boehringer Ingelheim; Other, Personal, Other, Review paper co-oordinated by Amgen. Initially drafted by other writers, with contributions from co-authors.: Amgen. A.R. Minchom: Financial Interests, Personal, Advisory Board: Faron pharmaceuticals, Janssen Pharmaceuticals, Merck pharmaceuticals, Takeda, Pfizer, AstraZeneca, Immutep, MSD, Faron; Financial Interests, Personal, Invited Speaker: GSK, Janssen Pharmaceuticals, Merck pharmaceuticals, Takeda, Seagen; Financial Interests, Institutional, Research Grant: MSD, Merck, Astex/Taiho. All other authors have declared no conflicts of interest.