Pembrolizumab/Vaccine Combo Improves RFS in High-Risk Resected Melanoma

Meaningful improvements in recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were observed with a mRNA-based cancer vaccine, intismeran autogene, plus pembrolizumab (Keytruda) among patients with high-risk resected melanoma, according to a presentation at the 2026 American Society of Clinical Oncology Annual Meeting (ASCO) on 5-year follow-up data from the phase 2 KEYNOTE-942 trial (NCT03897881).¹

With a median planned follow-up of 60.3 months (range, 50.5-76.4 months), the intismeran plus pembrolizumab arm demonstrated a 49% reduction in the risk of recurrence (HR, 0.51; 95% CI, 0.29-0.89) and a 59% reduction in the risk of distant metastasis or death (HR, 0.41; 95% CI, 0.20-0.84). These findings, which also included a trend toward improved overall survival (OS), build on earlier analyses and represent the longest follow-up reported to date for this novel individualized neoantigen therapy in the adjuvant melanoma setting.

“This study confirms that intismeran plus pembrolizumab demonstrates a durable benefit over pembrolizumab alone in resected high-risk melanoma,” said presenting author Matteo S. Carlino, MD, PhD, FRACP, during the presentation.¹ Carlino is a medical oncologist at Westmead and Blacktown Hospitals, faculty member at Melanoma Institute Australia, and a clinical senior lecturer at The University of Sydney in Australia.

Intismeran is an mRNA-based individualized neoantigen therapy that encodes up to 34 personalized tumor-derived neoantigens. Following intramuscular injection, the construct promotes antigen presentation on both MHC class I and class II molecules, leading to expansion of CD8+ cytotoxic T cells and CD4+ helper T cells in the tumor microenvironment. The addition of a checkpoint inhibitor is designed to potentiate T-cell and tumor-cell engagement.

KEYNOTE-942: Trial Design

The randomized KEYNOTE-942 trial enrolled 157 patients aged 18 years or older with resected stage IIIB to IV cutaneous melanoma between July 2019 and September 2021.² Patients were randomized 2:1 to receive 9 doses of intismeran 1 mg intramuscularly every 3 weeks plus 18 doses of pembrolizumab 200 mg intravenously every 3 weeks (n = 107), or 18 doses of pembrolizumab 200 mg alone (n = 50). All patients were required to have tumor tissue available for next-generation sequencing to facilitate neoantigen design, and pembrolizumab initiation was required within 13 weeks of surgery.

The primary end point was RFS; secondary end points included DMFS and safety. OS was an exploratory end point as the study was not sufficiently powered for an OS evaluation, and no alpha was assigned to this analysis.

Safety and Tolerability

No new safety signals emerged with extended follow-up. The overall rate of treatment-related adverse events (AEs) was numerically higher in the combination arm; however, rates of immune-related AEs were similar between arms, with grade 3 immune-related AEs occurring in 10.6% of patients receiving intismeran plus pembrolizumab and 12% of those receiving pembrolizumab alone. AEs attributed to intismeran were predominantly grade 1 or 2 and included fatigue, injection-site pain, fever, and chills. No grade 4 or 5 events were attributable to intismeran.

Translational Findings: T-Cell Receptor Dynamics

The 5-year update included exploratory analyses of T-cell receptor dynamics. Patients treated with intismeran plus pembrolizumab demonstrated an increase in T-cell clonality following addition of intismeran, an increase that was maintained at long-term follow-up approximately 6 months after the last dose of intismeran. By contrast, patients in the pembrolizumab-alone arm showed no significant increase in clonality.

Generation of novel T-cell clones was observed in both arms but was greater with the combination. Among patients who received intismeran plus pembrolizumab, a higher number of novel clones was observed in those who did not experience recurrence compared with those who did. This association between novel clone generation and lack of recurrence was not observed in the pembrolizumab-alone arm.

Next Steps in Clinical Development

The investigators acknowledged several limitations of KEYNOTE-942, including the small sample size inherent to a phase 2 study, the immaturity of the OS data, and the need for further validation of the translational findings.

The phase 3 INTerpath-001 study (NCT05933577), which is evaluating intismeran plus pembrolizumab vs pembrolizumab alone in a broader population of patients with resected stage II to IV melanoma, has completed enrollment, and results are anticipated. Additional studies of intismeran plus pembrolizumab are ongoing across multiple tumor types, according to Carlino.

DISCLOSURES: Carlino reported honoraria from Bristol-Myers Squibb and Novartis; and a consulting or advisory role with Amgen, Bristol-Myers Squibb, Eisai, IDEAYA Biosciences, Innovent Biologics, Medison, Merck Serono, Moderna Therapeutics, MSD, Nektar, Novartis, OncoSec, Pierre Fabre, QBiotics, Regeneron, Sanofi, and Strand Therapeutics.

References

1. Carlino MS, Khattak A, Meniawy T, et al. Individualized neoantigen therapy intismeran autogene (intismeran) plus pembrolizumab (pembro) in resected melanoma: 5-year update of the KEYNOTE-942 study. J Clin Oncol. 2026;44(suppl 16):9500. doi:10.1200/JCO.2026.44.16_suppl.9500
2. An efficacy study of adjuvant treatment with the personalized cancer vaccine mRNA-4157 and pembrolizumab in participants with high-risk melanoma (KEYNOTE-942). ClinicalTrials.gov. Updated December 3, 2025. Accessed June 1, 2026. https://clinicaltrials.gov/study/NCT03897881