A Phase III trial of intismeran autogene, the mRNA-based individualized neoantigen therapy co-developed by Merck (NYSE: MRK) and Moderna (Nasdaq: MRNA), has met both its primary and a key secondary endpoint in patients with completely resected stage IIB-IV melanoma, the companies announced. The result marks the first Phase III success for any individualized neoantigen therapy and the first Phase III trial to demonstrate improvement over pembrolizumab monotherapy in the adjuvant melanoma setting.
The INTerpath-001 trial enrolled 1,137 patients with high-risk resected cutaneous melanoma and no prior systemic therapy, randomized 2:1 to receive intismeran in combination with Merck's Keytruda (pembrolizumab) or pembrolizumab alone for approximately one year. At a pre-specified interim analysis, the combination produced statistically significant and clinically meaningful improvements in both recurrence-free survival (RFS), the primary endpoint, and distant metastasis-free survival (DMFS), a key secondary endpoint. No specific hazard ratios or p-values were disclosed in the topline announcement; full data are expected at an upcoming international medical meeting. The safety profile was consistent with prior studies, with no new signals observed. Overall survival evaluation continues per protocol.
The result converts a durable Phase II signal into Phase III confirmation. Five-year follow-up data from the Phase IIb KEYNOTE-942 trial, presented at the 2026 ASCO Annual Meeting, showed intismeran plus pembrolizumab reduced the risk of recurrence or death by 49% (HR=0.51; 95% CI, 0.294–0.887) and the risk of distant metastasis or death by 59% (HR=0.411; 95% CI, 0.200–0.843) compared to pembrolizumab alone, with an exploratory overall survival trend also favoring the combination. INTerpath-001, with more than seven times the patient population of KEYNOTE-942, was designed to provide the registrational evidence regulators require.
Intismeran is manufactured individually for each patient: a tumor sample is sequenced to identify up to 34 patient-specific neoantigens, which are encoded in a synthetic mRNA and administered to train T cells to recognize and attack residual cancer cells bearing that mutational signature. The approach is designed to augment the checkpoint blockade provided by pembrolizumab, which blocks PD-1 to restore T-cell activity against tumors that exploit the pathway to evade immune surveillance.