Frontline mRNA Vaccine Plus Pembrolizumab Achieves 83% ORR in Melanoma

The cancer antigen therapy mRNA-4359 yielded a high rate of antitumor responses in combination with pembrolizumab (Keytruda) as first-line treatment for locally advanced or metastatic melanoma, according to results presented at the American Association for Cancer Research Annual Meeting 2026.¹

In a dose expansion cohort of a phase 1/2 trial (NCT05533697), the investigational immune evasion–targeted cancer antigen therapy contributed to an 83% overall response rate (ORR) in 12 participants with a disease control rate (DCR) of 92%, with translational data confirming antigen-specific immune activation consistent with the drug's proposed mechanism of action.^1,2

Key Efficacy Results

Among 12 response-evaluable patients, mRNA-4359 plus pembrolizumab produced an ORR of 83% (95% CI, 52%-98%), with 2 patients achieving a complete response and 8 achieving a partial response. The DCR was 92% (95% CI, 62%-100%). The median time to response was 6.0 weeks (range, 5.6-24.0 weeks). Both median duration of response and median progression-free survival had not been reached at the data cutoff of December 1, 2025, with a median follow-up of 54.2 weeks (range, 22.3-76.0 weeks).¹

Responses were observed across baseline tumor PD-L1 expression categories. Among the 8 patients with PD-L1 tumor proportion score (TPS) of at least 1%, the ORR was 88% (95% CI, 47%–100%), with 2 complete responses and 5 partial responses. Among the 3 patients with PD-L1 TPS less than 1%, the ORR was 67% (95% CI, 9%-99%), with 2 partial responses. One patient lacked PD-L1 expression data. The consistency of responses across PD-L1 expression levels is noteworthy given that PD-L1 negativity has historically been associated with reduced benefit from checkpoint inhibitor monotherapy.

Translational and Immunologic Findings

Translational data provided mechanistic corroboration of the clinical results. Antigen-specific T-cell responses against PD-L1 and IDO1, the 2 antigens encoded by mRNA-4359, were detected in all 7 patients with evaluable blood samples. Treatment was also associated with time-dependent induction of novel expanded T-cell receptor (TCR) clones; median counts of novel expanded clones increased from 8-28 at an earlier cycle (cycle 2, day 1) to 16-43 at later treatment cycles in patients with clinical benefit.

Baseline tumor biopsies from 7 evaluable patients expressed both IDO1 and PD-L1 (CD274) genes and showed gene expression features consistent with a tumor-inflamed phenotype, suggesting these patients had immunologic characteristics potentially favorable for response to this combination.

Patient Population and Safety Profile

The patient population had a median age of 58 years (range, 38–80). Four patients (33%) had received prior neoadjuvant or adjuvant therapy, including 3 who had received prior immunotherapy, making the responses particularly notable in a subset with prior immune checkpoint inhibitor exposure.

mRNA-4359–related treatment-emergent adverse events (TEAEs) occurred in 11 of 12 patients (92%), all of which were grade 1 or 2. The most common mRNA-4359–related TEAE was injection site pain, reported in 67% of patients. Pembrolizumab-related TEAEs occurred in 11 patients (92%), with grade 1/2 events in 58% and grade 3/4 events in 33%. No new immune-related adverse events were identified beyond those expected with pembrolizumab. The mRNA-4359 component contributed no grade 3 or higher toxicity.¹

Mechanism, Context, and Development Path

mRNA-4359 encodes broad epitopes of PD-L1 and IDO1, 2 proteins expressed on both tumor cells and immunosuppressive cells within the tumor microenvironment. The therapy is designed to elicit cytotoxic T-cell responses that simultaneously kill PD-L1– and IDO1-expressing tumor cells and deplete immunosuppressive cells shielding the tumor, hypothetically rebalancing the tumor microenvironment toward an immune-permissive state.²

In this cohort, the patients received 9 cycles of mRNA-4359 as intramuscular injection every 3 weeks with up to 2 years of pembrolizumab every 6 weeks intravenously.

These first-line findings build on earlier data presented at the 2025 European Society for Medical Oncology Congress, in which mRNA-4359 plus pembrolizumab achieved a 24% ORR and 60% DCR in 29 evaluable patients with checkpoint inhibitor–resistant or refractory melanoma, a more heavily pretreated population in whom responses are typically harder to achieve.³

The FDA has granted fast track designation for mRNA-4359 in combination with pembrolizumab for treatment of checkpoint inhibitor–refractory unresectable or metastatic melanoma with PD-L1 TPS greater than 1%. The investigators cautioned that the current cohort is small, and they anticipate further evaluation to establish the combination's role in the treatment landscape.

“This early data supports the potential activity of the mRNA-4359 plus pembrolizumab combination, with promising anti-tumor activity,” Pavlina Spiliopoulou, MD, of School of Cancer Sciences, University of Glasgow, stated in a news release. “The consistent activation of antigen-specific T-cell responses provides important early evidence that mRNA technology could be used to help direct the immune system against melanoma in a multi-targeted manner.”²

REFERENCES

1. Moderna to present phase 1/2 data on its investigational cancer antigen therapy mRNA-4359 as first-line therapy in combination with pembrolizumab in locally advanced or metastatic melanoma at the 2026 AACR Annual Meeting. News release. Moderna. April 20, 2026. Accessed April 21, 2026. https://tinyurl.com/3utmkkvn

2. Spiliopoulou P, Khattak A, Medina T, et al. First-Line mRNA-4359 plus pembrolizumab (pembro) in locally advanced or metastatic melanoma: Results from the phase 1/2 mRNA-4359-P101 study. Cancer Res. 2026;86(suppl 8):CT106. doi:10.1158/1538-7445.AM2026-CT106

3. Pinato DJ, Sullivan RJ, Khattak A, et al. Clinical outcomes and PD-L1 expression analyses from a trial of mRNA-4359 plus pembrolizumab in checkpoint inhibitor-resistant/refractory (CPI-R/R) melanoma. Ann Oncol. 2026;36(suppl 2):S844-S845. doi:10.1016/j.annonc.2025.08.2146