Abstract CT106: First-Line mRNA-4359 plus pembrolizumab (pembro) in locally advanced or metastatic melanoma: Results from the phase 1/2 mRNA-4359-P101 study

Abstract Background: mRNA-4359, an immune evasion-targeted cancer antigen therapy, encodes epitopes of PD-L1 and IDO1 antigens and is designed to elicit T-cell responses against tumor and immunosuppressive cells, resulting in tumor killing and rebalancing of the tumor microenvironment. We report safety, efficacy, and translational data from arm 2a of the phase 2 dose-expansion part of the phase 1/2 mRNA-4359-P101 study (NCT05533697), which evaluated first-line mRNA-4359 + pembro in locally advanced/metastatic melanoma. Methods: Eligible participants (pts; ≥18 y) had previously untreated histologically confirmed locally advanced/metastatic melanoma. Pts received 9 cycles of mRNA-4359 1000 µg IM Q3W + up to 2 years of pembro 400 mg IV Q6W. Primary endpoint was safety; secondary endpoints included ORR, DCR, DOR, and PFS per RECIST v1. 1 by investigator assessment. Antigen-specific T-cell responses and peripheral T-cell receptor (TCR) clonality were assessed in blood samples. Baseline tumor biopsies were analyzed by RNA sequencing, with PD-L1 tumor proportion score (TPS) centrally assessed. Results: By data cutoff (December 1, 2025), 12 pts had received study treatment. Median age was 58 y (range, 38-80), 8 pts (67%) had baseline PD-L1 TPS ≥1%, 3 (25%) had PD-L1 TPS 1%, and 1 (8%) did not have PD-L1 expression data. Four pts (33%) received prior (neo) adjuvant therapy, including 3 pts with prior immunotherapy. Median follow-up was 54. 2 wk (range, 22. 3-76. 0). mRNA-4359-related TEAEs occurred in 11 pts (92%; all grade 1/2) ; the most common TEAE was injection site pain (67%). Pembro-related TEAEs occurred in 11 pts (92%; grade 1/2, 58%; grade 3/4, 33%). Two pts had a CR and 8 had a PR. ORR (95% CI) was 83% (52%-98%) and DCR was 92% (62%-100%) ; median DOR was not reached (NR) ; median TTR was 6. 0 wk (range, 5. 6-24. 0). ORR (95% CI) was 88% (47%-100%) in 8 pts with PD-L1 TPS ≥1% (CR, n=2; PR, n=5) and 67% (9%-99%) in 3 pts with PD-L1 TPS 1% (PR, n=2). Median PFS was NR. Treatment induced peripheral PD-L1- or IDO1-specific T-cell responses in all pts with evaluable samples (n=7). Treatment was associated with time-dependent induction of novel expanded TCR clones; median counts increased from 8-28 at an earlier cycle (C2D1) to 16-43 at later cycles in pts with clinical benefit. Baseline tumor biopsies from 7 evaluable pts expressed both IDO1 and PD-L1 genes and demonstrated gene expression features consistent with tumor-inflamed phenotype. Conclusion: mRNA-4359 + pembro demonstrated a manageable safety profile in pts with previously untreated locally advanced or metastatic melanoma. Responses/disease control occurred in most pts irrespective of baseline tumor PD-L1 expression. Consistent with mRNA-4359 mechanism of action, antigen-specific T-cell responses and novel expanded TCR clonality was observed in all pts with evaluable samples and in pts with clinical benefit, respectively. Citation Format: Pavlina Spiliopoulou, Adnan Khattak, Theresa Medina, Ioannis Karydis, Debashis Sarker, David J. Pinato, Gary W. Middleton, Ryan J. Sullivan, Mark R. Middleton, Hikmat N. Daghestani, Michael Abadier, Xuezhou Mao, Ferdous Barlaskar, Georgina V. Long. First-Line mRNA-4359 plus pembrolizumab (pembro) in locally advanced or metastatic melanoma: Results from the phase 1/2 mRNA-4359-P101 study abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT106.