Oncolytic immunotherapy with nivolumab in muscle-invasive bladder cancer: a phase 1b trial
Roger Li1,2, Nancy Y Villa3,4, Xiaoqing Yu5
1Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. Roger.Li@moffitt.org.
Abstract:
There is a critical unmet need for safe and efficacious neoadjuvant treatment for cisplatin-ineligible patients with muscle-invasive bladder cancer. Here we launched a phase 1b study using the combination of intravesical cretostimogene grenadenorepvec (oncolytic serotype 5 adenovirus encoding granulocyte-macrophage colony-stimulating factor) with systemic nivolumab in cisplatin-ineligible patients with cT2-4aN0-1M0 muscle-invasive bladder cancer. The primary objective was to measure safety, and the secondary objective was to assess the anti-tumor efficacy as measured by pathologic complete response along with 1-year recurrence-free survival. No dose-limiting toxicity was encountered in 21 patients enrolled and treated. Combination treatment achieved a pathologic complete response rate of 42.1% and a 1-year recurrence-free survival rate of 70.4%. Pathologic response was associated with baseline free E2F activity and tumor mutational burden but not PD-L1 status. Although T cell infiltration was broadly induced after intravesical oncolytic immunotherapy, the formation, enlargement and maturation of tertiary lymphoid structures was specifically associated with complete response, supporting the importance of coordinated humoral and cellular immune responses. Together, these results highlight the potential of this combination regimen to enhance therapeutic efficacy in cisplatin-ineligible patients with muscle-invasive bladder cancer, warranting additional study as a neoadjuvant therapeutic option. ClinicalTrials.gov identifier: NCT04610671 .
Insights
A novel combination of intravesical cretostimogene grenadenorepvec and systemic nivolumab shows promise as a safe neoadjuvant treatment for muscle-invasive bladder cancer in cisplatin-ineligible patients.
Area of Science:
- Oncology
- Immunotherapy
- Virology
Background:
- Muscle-invasive bladder cancer (MIBC) lacks effective neoadjuvant options for cisplatin-ineligible patients.
- Current treatments have limitations, creating an unmet clinical need.
Purpose of the Study:
- To evaluate the safety and efficacy of intravesical cretostimogene grenadenorepvec combined with systemic nivolumab in cisplatin-ineligible MIBC patients.
- To assess pathologic complete response (pCR) and 1-year recurrence-free survival (RFS).
Main Methods:
- Phase 1b study enrolling 21 cisplatin-ineligible patients with cT2-4aN0-1M0 MIBC.
- Combination therapy involved intravesical oncolytic adenovirus (cretogene grenadenorepvec) and systemic nivolumab.
- Safety was primary endpoint; pCR and 1-year RFS were secondary efficacy endpoints.
Main Results:
- No dose-limiting toxicities were observed, indicating a favorable safety profile.
- The combination achieved a 42.1% pCR rate and a 70.4% 1-year RFS rate.
- Pathologic response correlated with baseline E2F activity and tumor mutational burden, but not PD-L1 status. Tertiary lymphoid structures were associated with complete response.
Conclusions:
- The combination of cretogene grenadenorepvec and nivolumab is a safe and potentially effective neoadjuvant treatment for cisplatin-ineligible MIBC.
- This regimen warrants further investigation as a neoadjuvant therapeutic option for this patient population.
