INTerpath-001: Pembrolizumab with V940 (mRNA-4157) versus pembrolizumab with placebo for adjuvant treatment of high-risk stage II-IV melanoma.

TPS9616 Background: The anti−PD-1 antibody pembrolizumab is approved as adjuvant therapy for stage IIB-C and stage III melanoma by AJCC 8th ed, following complete resection. Adjuvant pembrolizumab has improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with high-risk melanoma, but many patients experience disease recurrence. In the randomized phase 2b KEYNOTE-942 study, the individualized neoantigen therapy V940 showed improved RFS and DMFS when used in combination with pembrolizumab versus pembrolizumab monotherapy in patients with stage III or IV melanoma. INTerpath-001 (NCT05933577) is a double-blind phase 3 randomized controlled trial designed to evaluate the efficacy and safety of adjuvant pembrolizumab plus V940 versus pembrolizumab plus placebo in patients with resected high-risk stage II-IV melanoma. Methods: Eligible patients are aged ≥18 years with surgically resected stage IIB or IIC (pathologic or clinical), III, or IV cutaneous melanoma per AJCC 8th ed and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients are ineligible if they have received any prior systemic therapy and if more than 13 weeks has elapsed between last surgical resection and first dose of pembrolizumab. Patients with ocular or mucosal melanoma and past or current in-transit metastases or satellitosis are excluded. All patients must provide a blood sample and a formalin-fixed, paraffin-embedded tumor sample for sequencing. Patients will be stratified by risk (IIB, IIC, IIIA, and IIIB vs IIIC/D and IV) and age (<65 years vs ≥65 years). Approximately 1089 patients will be randomly assigned 2:1 to receive pembrolizumab 400 mg plus V940 1 mg or pembrolizumab 400 mg with placebo. Pembrolizumab will be administered intravenously every 6 weeks and v940 or placebo will be administered intramuscularly every 3 weeks. Treatment will continue for up to 9 doses or until disease recurrence, unacceptable toxicity, or patient withdrawal. The primary end point is RFS by investigator review. Secondary end points are DMFS by investigator review, overall survival, safety and tolerability, and quality of life. Hazard ratios and 95% CIs will be estimated using a stratified Cox regression model with the Efron method of handling ties. Between-treatment differences will be evaluated using a stratified log-rank test. Enrollment is ongoing. Clinical trial information: NCT05933577 .