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INTerpath-001: mRNA-based individualized neoantigen therapy intismeran autogene plus pembrolizumab (pembro) vs pembro alone for adjuvant treatment of resected stage IIB-IV melanoma

Whilst adjuvant anti-PD-1 therapy has enhanced outcomes for patients with resected high-risk melanoma, many patients still progress.1 Consequently, a clear unmet need has been to broaden antitumor immunity beyond checkpoint blockade in this setting. Intismeran autogene is an individualized mRNA-based neoantigen therapy that encodes up to 34 patient-specific neoantigens to generate tumor-specific T-cell responses.,2

The Phase III INTerpath-001 trial (NCT05933577), presented at the European Society for Medical Oncology (ESMO) 2026 Congress, evaluated intismeran and pembrolizumab in adults with resected stage IIB–IV melanoma. In this study, 1,137 patients were randomized 2:1 to pembrolizumab plus intismeran or placebo plus pembrolizumab. The primary endpoint was recurrence-free survival (RFS), with distant metastasis-free survival (DMFS), overall survival (OS) and safety as secondary endpoints.

At a median follow-up of 24.6 months, the combination significantly improved RFS (24-month rate 82.2% vs 70.0%; HR 0.58; 95% CI: 0.45–0.75) and DMFS (24-month rate 88.5% vs 80.2%; HR 0.62; 95% CI: 0.45–0.85), with consistent benefit across stage subgroups. As it was an interim analysis, OS data were immature and did not cross the prespecified significance boundary (HR 0.77; 95% CI: 0.45–1.31). Grade ≥3 adverse events occurred in 23.6% versus 20.3% of patients, and intismeran did not potentiate pembrolizumab-associated immune-mediated adverse events.3

Georgina Long, PhD, MBBS, FRACP, FAHMS, from University of Sydney, Sydney, Australia, who presented the data at the congress, comments:

“It was beyond our expectations. [It’s] wonderful to have a new, completely different mode of action that works and stimulates the immune system.”

This study is the first Phase III trial to demonstrate that an individualized neoantigen therapy improves outcomes over standard adjuvant pembrolizumab in this setting. The data are practice-changing, setting a new benchmark in this setting, although mature OS data, regulatory review and the logistics of tumor sequencing and personalized manufacturing will shape its integration into routine care.

References:

  1. Eggermont AMM, Kicinski M, Blank CU, et al. Seven-year analysis of adjuvant pembrolizumab versus placebo in stage III melanoma in the EORTC1325/KEYNOTE-054 trial. Eur J Cancer. 2024 Nov;211:114327.
  2. Weber JS, Carlino MS, Khattak A, et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet. 2024 Feb;403(10427):632-644.
  3. Long GV, Khattak MA, Gogas HJ, et al. INTerpath-001: phase 3 study of the mRNA-based individualized neoantigen therapy (INT) intismeran autogene (intismeran) plus pembrolizumab (pembro) vs pembro alone for adjuvant treatment of resected stage IIB-IV melanoma (MEL). Presented at the ESMO 2026 Congress; October 23-27, 2026; Madrid, Spain.