Phase 2 trial of CV301 vaccine plus atezolizumab (Atezo) in advanced urothelial carcinoma (aUC).
Authors: Sonpavde Guru P. , Maughan Benjamin L. , McGregor Bradley Alexander , Wei Xiao X. , Kilbridge Kerry L. , Lee Richard J. , Yu Evan Y. , Schweizer Michael Thomas , Montgomery Robert B. , Cheng Heather H. , Hsieh Andrew Caleb , Jain Rohit K. , Grewal Jaspreet Singh , Pico Cesar , Gafoor Zarina , Perschy Teresa Pico , Grivas Petros 
Published: February 2022

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Background: PD(L)1 inhibitors can achieve durable responses in aUC but only in a minority of patients (pts). Combination strategies with agents that “prime and stimulate” the immune system may improve outcomes. CV301 comprises 2 recombinant poxviruses, Modified Vaccinia Ankara (MVA) and Fowlpox (FPV), encoding the human transgenes for CEA, MUC-1, and a Triad of Co-stimulatory Molecules (TRICOM: ICAM-1, LFA-3, and B7-1). MVA-CV301 is used for priming and FPV-CV301 is used for booster doses. Preliminarily, BN-platform vaccine plus PD-(L)1 inhibitors exhibited synergistic preclinical anti-tumor efficacy and the combination of CV301 and anti-PD-(L)1 agent demonstrated an acceptable safety profile. We hypothesized that this combination would be safe and effective in cisplatin-ineligible or platinum-refractory pts with aUC. Methods: A Phase 2, single-arm multicenter trial was designed to study CV301 + atezo as 1st-line treatment in pts with aUC ineligible for cisplatin-based chemotherapy regardless of PD-L1 status (Cohort 1; C1) and in pts progressing on/after platinum-based chemotherapy (Cohort 2; C2). MVA-CV301 was given subcutaneously (SC) on Days 1 and 22 and FPV-CV301 SC from day 43 every 21 days for 4 doses, then every 6 weeks until 6 months, then every 12 weeks until 2 years. Atezo 1200mg IV was given every 21 days. Primary endpoint: objective response rate (ORR). Secondary endpoints: OS, PFS, response duration, AEs and antigen-specific T-cell responses to CEA and MUC-1 by ELISPOT. Using 1-sided α 2.5%/cohort, a 2-stage design with 14/19 and 13/22 stage 1/2 subjects, respectively, will achieve ≥70% power if the true ORR for C1 is 43% and C2 is 33%. 3 C1 and 2 C2 responders were required in stage 1 to move forward. Results: 43 evaluable pts were enrolled and received therapy: 19 in C1; 24 in C 2. Overall, 9 pts experienced ≥ Grade 3 AEs related to the combination of treatment: 5 in C1, and 4 in C2. In C1, 1 pt had partial response (PR), for ORR 5.3% (90%CI: 0.3, 22.6) and 5 (26.3%, 90%CI: 11.0, 47.6) had stable disease (SD) as best response. In C2, 1pt had CR and 1 had PR, for ORR 8.3% (90%CI: 1.5, 24.0) and 3 (12.5%, 90%CI: 3.5, 29.2) had SD as best response. Median PFS and OS in C1 were 2.0 mo and 13.8 mo, and in C2 1.95 and 8.13 mo, respectively. The trial was halted for futility. Responding pts in C2 exhibited T-cell responses to CEA and pts with SD exhibited responses to MUC-1. Conclusions: CV301 + atezo exhibited an acceptable safety profile but did not demonstrate sufficient efficacy in pts with aUC as 1st-line therapy in cisplatin-ineligible pts or in the platinum-refractory setting. The development of effective vaccines to generate robust and durable responses as single agents and/or combined with anti-PD(L)1 remains an unmet need in aUC. Clinical trial information: NCT03628716.