Five-Year KEYNOTE-942 Results Show Durable Benefit With Intismeran Plus Pembrolizumab in Resected Melanoma

Clinical Summary:

• Design/Population: KEYNOTE-942 was a phase 2b randomized trial evaluating intismeran plus pembrolizumab vs pembrolizumab alone in adult patients with resected stage IIIB to IV cutaneous melanoma.
• Key Outcomes: At a median planned follow-up of 60.3 months, intismeran plus pembrolizumab reduced the risk of recurrence or death by 49% and the risk of distant metastasis or death by 59% compared with pembrolizumab alone. Five-year recurrence-free survival rates were 68.8% vs 49.1%, respectively, with a trend toward improved overall survival.
• Clinical Relevance: The sustained separation in recurrence-free and distant metastasis-free survival at 5 years supports the durability of benefit with individualized neoantigen therapy plus PD-1 blockade in high-risk resected melanoma and strengthens the rationale for ongoing phase 3 evaluation.

Five-year follow-up results from the phase 2b KEYNOTE-942 trial showed that intismeran, an mRNA-based individualized neoantigen therapy, plus pembrolizumab continued to provide durable recurrence-free survival (RFS) and distant metastasis-free survival benefits compared with pembrolizumab alone in patients with high-risk resected melanoma.

In this study, 157 patients with resected stage IIIB to IV cutaneous melanoma were randomized 2:1 to receive either 1 mg of intramuscular intismeran every 3 weeks for 9 doses plus 200 mg of intravenous pembrolizumab every 3 weeks for 18 doses (n = 107) or pembrolizumab alone (n = 50). The primary end point was RFS. Key secondary end points included distant metastasis-free survival and safety. Overall survival (OS) was assessed as an exploratory end point.

At a median follow-up of 60.3 months, few new events had occurred during the additional 2 years of follow-up beyond the previously reported 3-year analysis. Intismeran plus pembrolizumab maintained a 49% reduction in the risk of recurrence or death compared with pembrolizumab alone. The landmark 5-year RFS rate was 68.8% in the intismeran plus pembrolizumab arm and 49.1% in the pembrolizumab arm. 

The combination also continued to demonstrate a durable distant metastasis-free survival advantage, with a 59% reduction in the risk of distant metastasis or death. The hazard ratio for OS was 0.47, with 5-year OS rates of 92.2% and 71.3%, respectively.

The safety profile of intismeran remained consistent with prior analyses, with no new tolerability concerns identified during extended follow-up. Seven deaths occurred in each treatment arm, primarily due to disease progression (57.1% vs 85.7%).

"These long-term findings show that intismeran [plus] pembro treatment benefits were sustained and durable over time, despite all pts having completed study treatment before primary analysis," concluded study authors. "Intismeran [plus] pembro is being evaluated in a phase 3 study of high-risk resected stage II–IV melanoma (INTerpath-001; NCT05933577) and in studies of pts with other malignancies." 

Source: 

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. Published online: June 1, 2026. doi: 10.1200/JCO.2026.44.16_suppl.9500