Phase 1/2 INTerpath-005 study: V940 (mRNA-4157) plus pembrolizumab with or without enfortumab vedotin (EV) for resected high-risk muscle-invasive urothelial carcinoma (MIUC).

TPS893 Background: It is hypothesized that V940 (mRNA-4157), an individualized neoantigen therapy consisting of an mRNA encoding up to 34 tumor neoantigens, will work in synergy with immune checkpoint inhibitors by generating de novo tumor-specific T-cell activity. In a phase 2 trial of patients with high-risk melanoma, adjuvant V940 + pembrolizumab had a manageable safety profile and improved recurrence-free and distant metastasis–free survival versus pembrolizumab monotherapy. The phase 1/2 INTerpath-005 study (NCT06305767) has 2 cohorts. The phase 1 open-label, single-arm perioperative cohort will evaluate perioperative (neoadjuvant and adjuvant) V940 + pembrolizumab + EV for muscle-invasive bladder cancer (MIBC). The phase 2 double-blind, randomized adjuvant cohort will evaluate adjuvant V940 + pembrolizumab versus placebo + pembrolizumab for high-risk MIUC. Methods: Eligibility criteria for the perioperative cohort include age ≥18 years, diagnosis of MIBC (T2-T4aN0M0 or T1-T4aN1M0) with urothelial carcinoma histology, eligibility and willingness to undergo radical cystectomy (RC) + pelvic lymph node dissection (PLND), and cisplatin ineligibility. Eligibility criteria for the adjuvant cohort include age ≥18 years, diagnosis of MIUC with predominant UC histology, radical resection ≤7 weeks before providing informed consent and ≤14 weeks before randomization, high-risk pathologic disease (ypT2-4a and/or ypN+ after neoadjuvant chemotherapy [NAC]; pT3-4a and/or pN+ without NAC), and cisplatin ineligibility. In the perioperative cohort, approximately 30 patients will receive neoadjuvant pembrolizumab 200 mg IV on day 1 Q3W × 4 cycles + EV 1.25 mg/kg IV on days 1 and 8 Q3W × 4 cycles + V940 1 mg IM on day 1 Q3W × 1-4 doses. Patients will undergo RC + PLND followed by adjuvant pembrolizumab 200 mg IV on day 1 Q3W × 13 cycles + EV 1.25 mg/kg IV on days 1 and 8 Q3W × 5 cycles + V940 1 mg IM on day 1 Q3W × 5-8 doses, depending on number of doses administered in neoadjuvant period, for a total of 9 doses. In the adjuvant cohort, approximately 200 patients will be randomly assigned 1:1 to receive pembrolizumab 400 mg IV Q6W × 9 cycles + V940 1 mg IM Q3W × 9 doses or pembrolizumab 400 mg IV Q6W x 9 cycles + placebo IM Q3W x 9 doses. Randomization in the adjuvant cohort will be stratified by circulating tumor DNA status at screening (positive vs negative vs not evaluable) and prior NAC (yes vs no). The primary end points are safety (perioperative cohort) and DFS per investigator assessment (adjuvant cohort). Secondary end points are pathologic complete response and pathologic downstaging (perioperative cohort); overall survival, distant metastasis–free survival per investigator, safety, and tolerability (adjuvant cohort). Clinical trial information: NCT06305767 .