Mechanisms of recurrence following mRNA-4157 (V940) plus pembrolizumab or pembrolizumab alone in resected melanoma from the mRNA-4157-P201 (KEYNOTE-942) trial

BackgroundmRNA-4157 is a novel mRNA-based individualized neoantigen therapy (INT) designed to enhance endogenous antitumor T-cell responses by targeting unique patient-specific tumor mutations. In the phase 2 mRNA-4157-P201 (KEYNOTE-942) trial, patients with completely resected high-risk stage IIIB–IV melanoma receiving mRNA-4157 + pembrolizumab (pembro) showed prolonged recurrence-free survival and distant metastasis–free survival versus those receiving pembro alone (Weber JS, et al. Lancet 2024). A subset of patients, however, had disease recurrence. Here, we examine potential mechanisms of recurrence.MethodsPatients were randomized 2:1 to receive mRNA-4157 + pembro or pembro alone. A subset of paired baseline and recurrence tumor tissue samples were subject to whole exome and transcriptome sequencing to evaluate tumor mutation and gene expression profiles, respectively. Inflammatory signatures containing known tumor infiltrating lymphocyte and MHC I genes were included in the gene expression score (Ayers M, et al. J Clin Invest 2017).ResultsAs of Nov 2023 data cut (median planned follow-up, 34.9 months), 16 patients (combination: 11; pembro alone: 5) had paired baseline and recurrent tumor samples available. Baseline characteristics of these patients showed lower inflammatory signatures and tumor mutational burden compared with the overall population, consistent with prognostic characteristics of these biomarkers observed in the overall study population (Sullivan R, et al. AACR 2023, CT224). Decreased inflammatory signatures at recurrence were identified in 5 of 16 patients; the remaining 11 patients exhibited increased inflammatory signatures at recurrence. Tumors from patients with recurrence underwent evolution, evidenced by changes in tumor mutations and their allelic frequencies. 91% (median [95% CI: 65–100%]) of INT-encoded mutations were present at recurrence.ConclusionsMultiple potential mechanisms of recurrence can be hypothesized from these observations, including primary resistance to therapy, changes in tumor inflammatory status, and tumor evolution. Further data will be available as the trial matures.Clinical trial identificationNCT03897881.Editorial acknowledgementMedical writing and editorial assistance were provided by Caudex, a division of IPG Health Medical Communications, New York, NY, USA in accordance with Good Publication Practice 2022 guidelines, funded by Moderna Inc. and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, under the direction of the authors.Legal entity responsible for the studyModerna in collaboration with Merck Sharp & Dohme LLC.FundingModerna in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.DisclosureR.J. Sullivan: Financial Interests, Personal, Advisory Board, Advisory board/consultancy: MSD; Financial Interests, Personal, Other, Consultant: Marengo; Financial Interests, Personal, Advisory Board, Consultancy/SAB: Novartis; Financial Interests, Personal, Other, Consultancy: Pfizer, Replimune; Financial Interests, Personal, Royalties: Up-to-Date; Financial Interests, Institutional, Coordinating PI, Phase I trial PI: Marengo; Financial Interests, Institutional, Local PI: Novartis, Synthekine, Immunocore, Springworks; Financial Interests, Institutional, Coordinating PI: Mural, Moderna; Financial Interests, Institutional, Steering Committee Member: Merck. M. Lu, S. Koppolu: Financial Interests, Personal, Full or part-time Employment: Moderna; Financial Interests, Personal, Stocks/Shares: Moderna. J.S. Weber: Financial Interests, Personal, Advisory Board, Ad Boards: BMS; Financial Interests, Personal, Advisory Board: Merck, GSK, Incyte, Genentech, Pfizer, Biond, OncoC4, AstraZeneca, Regeneron, ImCheck, Novartis; Financial Interests, Personal, Stocks/Shares: Biond, Evaxion, Instil Bio, OncoC4; Financial Interests, Personal, Royalties: Moffitt Cancer Center; Financial Interests, Institutional, Local PI: BMS, Regeneron; Financial Interests, Institutional, Coordinating PI: Merck, Novartis; Non-Financial Interests, Principal Investigator: Moderna, BMS; Non-Financial Interests, Member: ASCO. M.S. Carlino: Financial Interests, Personal, Advisory Board, Consultant Advisor: MSD, BMS, Novartis, Amgen, Oncosec, Merck, Sanofi, Ideaya, Pierre Fabre, Eisai, Nektar, Regeneron. M.A. Khattak: Financial Interests, Personal, Invited Speaker: MSD, Moderna; Financial Interests, Personal, Advisory Board: Moderna. M.H. Taylor: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Eisai, Merck, Pfizer, Bayer, Sanofi/Genzyme, Regeneron, Blueprint, Immune-onc, Exelixis, Cascade; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb, Eisai, Blueprint, Merck; Financial Interests, Institutional, Research Funding: Bristol Myers Squibb, Eisai, Merck, Agenus, Moderna, Pfizer, ISA Therapeutics, Immune-Onc, and Simcha. M. Mckean: Financial Interests, Institutional, Research Funding: Aadi, Alpine Immune, Arcus, Arvinas, Ascentage, ASCO, Astellas, Aulos, Bayer, Bicycle, BioMed, BioNTech, Boehringer Ingelheim Ingelheim, Bristol Myers Squibb, C4 Therapeutics, Daiichi Sankyo, Dragonfly, EMD Serono, Epizyme, Erasca, Exelixis, Foghorn, G1 Therapeutic; Financial Interests, Institutional, Speaker, Consultant, Advisor: Castle, IQVIA, Merck, Moderna, Pfizer. G.V. Long: Financial Interests, Personal, Other, Consultant Advisor: Agenus Inc, Amgen Inc, Array Biopharma Inc, AstraZeneca UK Limited, Bayer Healthcare Pharmaceuticals, BioNTech SE, Boehringer Ingelheim Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG, Highlight Therapeutics S.L, IOBiotech, Immunocore Ireland Limited, Innovent Bioilogics USA Inc, Merck Sharp & Dohme, Novartis Pharma AG, PHMR Limited, Pierre Fabre, Regeneron Pharmaceuticals Inc, Scancell Limited, SkylineDX B.V; Non-Financial Interests, Principal Investigator, GL is PI on over 30 clinical trials: GL is PI on over 30 clinical trials. M.B. Faries: Financial Interests, Personal, Advisory Board: Merck, Regeneron, Bristol Myers Squibb, Instil; Financial Interests, Personal, Speaker, Consultant, Advisor: Clario. J.J. Luke: Financial Interests, Personal, Other, Data Safety Monitoring Board: AbbVie, Agenus, Evaxion, Immutep, Shionogi; Financial Interests, Personal, Advisory Board: 7 Hills, Affivant, BioCytics, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio, Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Elipscience, Kanaph, NeoTx, Onc.AI, OncoNano, physIQ, Pyxis, Saros, STipe, Tempest; Financial Interests, Personal, Stocks/Shares: Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Elipscience, Kanaph, NeoTx, Onc.AI, OncoNano, physIQ, Pyxis, Saros, STipe, Tempest; Financial Interests, Personal, Speaker, Consultant, Advisor: AbbVie, Agenus, Alnylam, AstraZeneca, Askgene, Atomwise, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Geneos, Gilead, Glenmark, HotSpot, Kadmon, Ko; Financial Interests, Institutional, Research Funding: AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Hot Spot, Ikena, Immatics, Imugene, Incyte, Janux, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Novartis, Numab, Palleon, Pfizer, Replimmune,; Financial Interests, Personal, Royalties, Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof: US Patent US-11638728. V. Sehgal, A. Rao, H. Mao, J. Guo, R. Meehan, I. Feldman, L. Srinivasan: Financial Interests, Personal, Full or part-time Employment: Moderna; Financial Interests, Personal, Stocks/Shares: Moderna. M. Brown: Financial Interests, Personal, Full or part-time Employment: Moderna; Financial Interests, Personal, Stocks/Shares: Moderna, Bristol Myers Squibb. All other authors have declared no conflicts of interest.