LBA49 - mRNA-4157 (V940) individualized neoantigen therapy + pembrolizumab vs pembrolizumab in high-risk resected melanoma: Clinical efficacy and correlates of response

Background

In patients (pts) with resected high-risk stage IIIB–IV melanoma, mRNA-4157 + pembrolizumab (pembro) extended recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) vs pembro alone (phase 2 KEYNOTE-942; NCT03897881). Minimal residual disease (MRD; by plasma circulating tumor DNA [ctDNA]) at treatment onset was associated with shorter RFS. We examined ctDNA longitudinal dynamics and associated clinical outcomes and report impact of ctDNA status on BRAF subgroup.

Methods

Pts were assigned to mRNA-4157 + pembro or pembro alone. RaDaR® (Inivata) was used to measure plasma ctDNA during treatment and at follow-up. The table defines longitudinal ctDNA molecular responders (MRs) and non-responders (MNRs). BRAF status was derived from whole exome sequencing of baseline tumor tissue. Kaplan–Meier method was used to estimate RFS and DMFS. Cox proportional hazards regression was used to estimate HRs.

Results

142/157 pts were evaluable for longitudinal ctDNA analyses (100/107 mRNA-4157 + pembro; 42/50 pembro alone). Across treatment arms, pts with available ctDNA and recurrence events were limited (n=30). 57% (8/14) of MRs and 94% (15/16) of MNRs had recurrence. Local recurrence was more common in MRs; MNRs had more distant events. This trend was supported by stronger separation in DMFS vs RFS between MRs and MNRs. There was a trend for enhanced efficacy of mRNA-4157 + pembro across BRAF V600E/K WT (n=96) (HR [95% CI]: 0.808 [0.366–1.784]) and MUT (n=61) subpopulations (0.332 [0.130–0.850]); however, considering ctDNA status by focusing on ctDNA-negative subpopulation increased similarity of efficacy across BRAF WT (n=68) and MUT (n=42) subgroups (0.334 [0.121–0.923] vs 0.069 [0.009–0.563]). Table: LBA49

Conclusions

These results suggest a potential relationship between ctDNA dynamics and treatment outcomes in pts with high-risk resectable melanoma and support further exploration in upcoming planned studies.

Clinical trial identification

NCT03897881.

Editorial acknowledgement

Medical 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 under the direction of the authors.

Legal entity responsible for the study

Moderna TX.

Funding

Moderna Tx.

Disclosure

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. A. Khattak: Financial Interests, Personal, Funding: BMS. M. Carlino: Financial Interests, Personal, Advisory Board, Consultant Advisor: MSD, BMS, Novartis, Amgen, Oncosec, Merck, Sanofi, Ideaya, Pierre-Fabre, Eisai, Nektar, Regeneron. R.J. Sullivan: Financial Interests, Personal, Advisory Board: Merck, Novartis, Bristol Myers Squibb, Eisai, Iovance, Oncosec, Pfizer, Replimmune, Marengo; Financial Interests, Personal, Royalties: Up-to-date; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Local PI: GSK, Sanofi, Moderna, BiomedValley DIscoveries, Astex, Compugen, Beigene, Novartis, Rubius, Alkermes, Synthekine; Financial Interests, Institutional, Coordinating PI: Pfizer, Roche-Genentech, Simcha Therapeutics, OnKure, Marengo. J.J. Luke: Financial Interests, Personal, Advisory Board: Amgen, Evaxion, Bayer, Eisai, EMD Serono, Janssen, Castle, BMS, Arch Oncology. M. Taylor: Financial Interests, Personal, Advisory Board: BMS, Eisai, Novartis, Merck, Bayer, Sanofi/Genzyme, Regeneron, Loxo, Blueprint, Exelixis. G. Ansstas: Financial Interests, Personal, Advisory Board: BMS, Merck. K. Kim: Financial Interests, Personal and Institutional, Advisory Board: Genetech, BMS, Merck. M. Mckean: Financial Interests, Institutional, Other, Consulting: Pfizer, Castle Biosciences, Eisai, IQVIA, Merck, Moderna; Financial Interests, Personal, Other, Consulting: iTeos; Financial Interests, Institutional, Research Grant: Acentage Pharma Group, Bicycle Therapeutics, Dragonfly Therapeutics, Epizyme, Exelixis, Genentech, GSK, IDEAYA Biosciences, Ikena Oncology, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Moderna, NBE Therapeutics, Novartis, Oncorus, Plexxicon, Prelude Therapeutics, Regeneron, Sapience Therapeutics, Seattle Genetics, Tizona Therpeutics, TMUNITY Therapeutics, TopAlliance Biosciences, Aadi Biosciences, Alpine Immune Sciences, Arcs Biosciences, Bayer, Arvinas, ASCO, Astellas, BioMed Valley Discoveries, BioNTech, C4 Therapeutics, EMD Serono, Erasca, Foghorn Therapeutics, Kechow Pharma, G1 Therapeutics, Gilead Sciences, ImmVira Pharma, Kezar Life Sciences, Kinnate BioPharma, MedImmune, Mereo BioPharma, Metabomed, Nektar, OncoC4, PACT Pharma, Pfizer, Poseida, Pyramid Biosciences, Scholar Rock, Synthrox, Takeda Pharmaceuticals, Teneobio, Tempest Therapeutics, Xilio. M. Faries: Financial Interests, Institutional, Research Grant: Merck, BMS, Pfizer, Amgen. C..L. Cowey: Financial Interests, Institutional, Research Funding: Merck, BMS, Novartis. A. Pecora: Financial Interests, Institutional, Research Funding: Merck, BMS, bayer, eisai, emd serono. V.G. Atkinson: Financial Interests, Personal, Advisory Board: BMS, MSD, Nektar, Novartis, Pierre fabre, QBiotics; Financial Interests, Personal, Invited Speaker: BMS, MSD, Novartis, Pierre Fabre, Limbic; Financial Interests, Personal, Other, Travel Support: BMS. G. Gibney: Financial Interests, Personal, Advisory Board, Limited Consultant Role: Bristol Myers-Squibb, Merck, Lyell, Eisai, Regeneron, Genentech, Sapience Therapeutics; Financial Interests, Personal, Other, Consultant: Novartis; Financial Interests, Personal, Advisory Board, Consultant for data monitoring committee.: Huyabio; Financial Interests, Personal, Advisory Board, Limited role on data monitor committee.: Exicure; Financial Interests, Institutional, Coordinating PI, Support for investigator initiated trial.: Exelixis, Lucerno Dynamics; Financial Interests, Institutional, Local PI, Support for clinical trial: Jounce. E. Buchbinder: Financial Interests, Personal, Advisory Board: Instilbio, Nektar, Novartis, BMS, Iovance, Merck, Sanofi, Xilio; Financial Interests, Institutional, Coordinating PI: Genentech, Partners therapeutics; Other, Spouse employment: AstraZeneca, Takeda. R. Meehan: Financial Interests, Personal, Full or part-time Employment: Moderna TX. G.V. Long: Financial Interests, Personal and Institutional, Research Grant: BMS; Financial Interests, Personal and Institutional, Research Funding: Merck, Pfizer, Amgen, EMD serono. All other authors have declared no conflicts of interest.