mRNA Vaccine/Pembrolizumab Shows Sustained 5-Year RFS in High-Risk Melanoma

Five-year follow-up data of intismeran autogene (mRNA-4157) plus pembrolizumab (Keytruda) assessed in the phase 2b KEYNOTE-942 study (NCT03897881) showed a sustained and clinically meaningful improvement in recurrence-free survival (RFS) for patients with stage III/IV melanoma, according to a press release from Merck.¹

There was a reduction in recurrence or death by 49% (HR, 0.510; 95% CI, 0.294-0.887; P = .0075) in the combination arm vs pembrolizumab alone. Additional data on secondary end points and follow-up analyses will be presented at an upcoming medical meeting.

“For many patients with stage III/IV melanoma, there is a significant risk of recurrence following surgery. As such, demonstrating the longer-term potential of intismeran autogene and [pembrolizumab] to reduce the risk of recurrence for certain patients with melanoma is a meaningful milestone,” Marjorie Green, MD, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, said in the press release.¹

At the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, the results of the 3-year update from KEYNOTE-942 were presented.² Patients were randomly assigned 2:1 to either the combination arm (n = 107) or the pembrolizumab monotherapy arm (n = 50). In the combination arm, patients were given up to 1 year of pembrolizumab, 1 mg of mRNA-4157 intramuscularly every 3 weeks for up to 9 doses, and 200 mg of intravenous pembrolizumab every 3 weeks for up to 18 cycles. In the monotherapy arm, the pembrolizumab dosing was matched.

At the time of the analysis, the median RFS was not evaluable (NE) in the combination arm vs 42.51 months (95% CI, 16.59-NE) in the monotherapy arm (HR, 0.510; 95% CI, 0.288-0.906; P = .019). The RFS rates at 18 months were 79.4% vs 62.2%; at 24 months, they were 76.6% vs 60.0%; and at 30 months, they were 74.8% vs 55.6% between each arm, respectively.

The median distant metastasis-free survival (DMFS) was NE in both arms (HR, 0.384; 95% CI, 0.172-0.858; P = .0.015). The 18-month DMFS rates was 90.9% vs 76.8%, the 24-month rates were 89.3% vs 74.2%, and the 30-month rates were 89.3% vs 68.7% in each respective arm.

The median overall survival (OS) was NE in both arms (HR, 0.425; 95% CI, 0.114-1.584). While there were no OS rates, the authors noted that it was shown to be an encouraging trend with the combination therapy.

Irrespective of PD-L1, tumor mutational burden, and ctDNA status, a benefit was continued to be shown among subgroup analyses with mRNA-4157 plus pembrolizumab.

Any adverse effect (AE) was noted in 100% of patients in the combination arm vs 92% in the pembrolizumab arm, with 34.6% vs 36.0% having grade 3 or higher AEs. Any treatment-related AEs occurred in 100% vs 82%, serious AEs in 14.4% vs 10%, and immune-related AEs in 37.5% vs 36.0% of patients in the combination and monotherapy arms, respectively.

The most common AEs in the combination arm included fatigue (60.6%), injection site pain (56.7%), chills (49.0%), pyrexia (48.1%), and headache (31.7%).

At the time of the presentation, Jeffrey S. Weber, MD, PhD, stated “mRNA-4157 plus pembrolizumab demonstrated a durable clinically significant improvement in RFS and DMFS compared with standard-of-care pembrolizumab in high-risk resected melanoma, with a 49% reduction in the risk of recurrence or death and a 62% reduction of distant recurrence or death with 3 years of follow-up.”²

References

1. Moderna & Merck Announce 5-year data for intismeran autogene in combination with KEYTRUDA® (pembrolizumab) demonstrated sustained improvement in the primary endpoint of recurrence-free survival in patients with high-risk stage III/IV melanoma following complete resection. News release. Merck. January 20, 2026. Accessed January 20, 2026. https://tinyurl.com/yp57p4fn
2. Weber JS, Khattak MA, Carlino MS, et al. Individualized neoantigen therapy mRNA-4157 (V940) plus pembrolizumab in resected melanoma: 3-year update from the mRNA-4157-P201 (KEYNOTE-942) trial. J Clin Oncol. 2024;42(suppl 17):LBA9512. doi.10.1200/JCO.2024.42.17_suppl.LBA9512