Key takeaways:

• The addition of intismeran autogene to adjuvant pembrolizumab improved RFS and distant metastases-free survival among patients with resected high-risk melanoma.
• OS data remain immature.

The addition of a personalized vaccine to standard adjuvant therapy reduced risk for recurrence or death by 42% among patients with completely resected high-risk melanoma, according to results of the randomized phase 3 INTerpath-001 trial.

The combination also reduced risk for distant metastasis or death by 38%, findings scheduled for presentation during ESMO Congress showed.

Data derived from Long G, et al. LBA 1. Presented at: European Society for Medical Oncology Congress; Oct. 23-27, 2026; Madrid.

“The transformative INTerpath-001 results have the potential to make a foundational shift in how we treat patients with earlier-stage melanoma in the adjuvant setting,” Georgina Long AO, BSc (Hons1, UM) PhD, MBBS (Hons), FRACP, FAHMS, FAA, FASCO, medical director of Melanoma Institute Australia, chair of melanoma medical oncology and translational research at University of Sydney and the trial’s principal investigator, said in a press release issued by Merck and Moderna, the companies developing the vaccine.

“For decades, cancer treatment has largely been defined by where a tumor originates in the body,” she said. “The INTerpath-001 findings support a fundamentally new and individualized approach to treating resected melanoma in the adjuvant setting, one that tailors treatment to the unique mutational signature of a patient’s tumor to enhance an anti-tumor immune response.”

Data released early

Patients with resected high-risk melanoma often develop recurrence despite receipt of adjuvant therapy.

Whether enhancing immune activation could enhance efficacy of adjuvant therapy had not been established, according to study background.

Intismeran autogene (V940/mRNA-4157; Merck/Moderna) is a personalized messenger RNA cancer vaccine designed to target patient-specific, tumor-derived antigens.

As Healio previously reported, results of the randomized phase 2 KEYNOTE-942 trial — presented at ASCO Annual Meeting in 2024 — showed the addition of the vaccine to the anti-PD-therapy pembrolizumab (Keytruda, Merck) significantly improved RFS and distant metastasis-free survival among patients with resected high-risk melanoma.

Researchers aimed to build on those findings in INTerpath-001, which included 1,137 patients with completely resected stage IIB to stage IV melanoma.

Investigators randomly assigned 757 of them to receive 400 mg pembrolizumab via IV every 6 weeks for nine cycles plus 1 mg intismeran administered intramuscularly every 3 weeks for up to nine doses. The other 380 patients received pembrolizumab plus placebo.

Treatment continued until receipt of all doses — approximately 56 weeks — or until disease progression or unacceptable toxicity.

RFS served as the primary endpoint. Secondary endpoints included distant metastases-free survival, OS and safety.

The data had been scheduled for public release during an ESMO presidential symposium on Oct. 24. However, following a data leak on Oct. 22, Merck and Moderna opted to release the findings early.

‘A defining moment’

At the primary prespecified analysis — performed after median follow-up of 24.6 months — results showed statistically significant improvements in RFS (HR = 0.58; 95% CI, 0.45-0.75) and distant metastases-free survival (HR = 0.62; 95% CI, 0.45-0.85) in the combination group.

Median RFS and distant metastases-free survival had not been reached in either group. However, 2-year rates of both endpoints favored the combination (RFS, 82.2% vs. 70%; distant metastases-free survival, 88.5% vs. 80.2%).

Results of a prespecified sensitivity analysis at 6 months showed more pronounced benefits with regard to RFS (HR = 0.42; 95% CI, 0.3-0.58) and distant metastases-free survival (HR = 0.5; 95% CI, 0.34-0.73) with the combination.

OS data remain immature, though investigators observed what they characterized as a favorable trend for the combination.

The study will continue to allow for evaluation of survival data, as well as other endpoints.

Nearly all patients experienced treatment-related adverse events (95.8% for combination vs. 90% for pembrolizumab alone).

Grade 3 or higher adverse events occurred at similar rates in the combination and placebo groups (14.2% vs. 13.4%).

The most common adverse events in the combination group included pyrexia (52.2%), injection site pain (51%) and fatigue (38.5%).

“From the beginning, we believed mRNA technology could make it possible to develop cancer treatments uniquely matched to each patient’s tumor. The INTerpath-001 results mark a defining moment for that vision,” Stéphane Bancel, CEO of Moderna, said in the release. “These results reinforce our conviction that mRNA has the potential to fundamentally change how we treat cancer.”

Other research efforts are underway to evaluate the efficacy and safety of intismeran — both as monotherapy and in combination with pembrolizumab — for multiple cancer types, including lung cancer, pancreatic cancer and gastric cancer.

“While these results are in patients with completely resected stage IIB-IV melanoma, they provide valuable insights and will help inform our understanding of intismeran as clinical research continues into other tumor types and across settings,” Long said.