45 INTerpath-004: A phase 2, randomized, double-blind study of pembrolizumab with V940 (mRNA-4157) or placebo in the adjuvant treatment of renal cell carcinoma

Abstract Background The PD-1 inhibitor pembrolizumab is approved as monotherapy for the adjuvant treatment of patients with renal cell carcinoma (RCC) who are at increased risk of recurrence following nephrectomy or nephrectomy and resection of metastatic lesions based on results from the phase 3 KEYNOTE-564 trial. Novel combination strategies could provide further clinical benefit in the adjuvant setting. V940 (mRNA-4157) is an individualized neoantigen therapy that is hypothesized to increase the antitumor activity of T cells and enhance the activity of pembrolizumab. V940 plus pembrolizumab showed improved clinical outcomes for stage III/IV melanoma compared with pembrolizumab alone in the phase 2b KEYNOTE-942 study. INTerpath-004 is a global, multicenter, randomized, double-blind, phase 2 trial (NCT06307431) designed to evaluate the efficacy and safety of adjuvant pembrolizumab with V940 or placebo in patients with RCC who have undergone nephrectomy. Methods Eligible patients are adults with histologically or cytologically confirmed RCC with clear cell or papillary histology (intermediate-high risk pT2 Gr4, N0, M0 or pT3 Gr3/4, N0, M0, high-risk pT4, N0, M0 or pT any stage, N1, M0, or M1 NED solid, isolated, soft tissue metastases that can be completely resected at the time of nephrectomy or ≤2 years from nephrectomy) with or without sarcomatoid features. Patients must have undergone nephrectomy and/or metastasectomy ≤12 weeks prior to randomization and be tumor-free as assessed by investigator. Patients must not have received prior systemic therapy ≤4 weeks or radiotherapy ≤2 weeks prior to randomization. Approximately 272 patients will be randomly assigned 1:1 to receive pembrolizumab 400 mg intravenously every 6 weeks for up to 9 cycles in combination with either V940 1 mg or placebo intramuscularly every 3 weeks for up to 9 doses or treatment discontinuation due to unacceptable toxicity, disease recurrence, patient withdrawal, or investigator decision. Randomization will be stratified by histology (clear cell vs papillary) and disease risk (intermediate-high vs high vs M1 NED). Imaging assessments (computed tomography or magnetic resonance imagery) will be performed every 12 weeks through year 2, every 16 weeks in years 3-5, and every 24 weeks in year 6 and beyond. The primary endpoint is disease-free survival by investigator assessment. Secondary endpoints include distant metastasis-free survival, overall survival, and safety parameters including adverse events (AEs), laboratory test results, and vital signs. AEs will be monitored throughout the study and for 30 days after the last dose of treatment (90 for serious AEs) and graded per National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Efficacy will be assessed in all randomly assigned patients, and safety will be assessed in all patients who received ≥1 dose of study intervention. Recruitment is ongoing.