A phase II open label randomized trial of neoadjuvant chemoimmunotherapy with either dose dense Cisplatin, Methotrexate, Vinblastine (ddCMV) OR Gemcitabine and Cisplatin (GC) for muscle invasive bladder cancer (MIBC)

Surgery remains a key component in the treatment of localized muscle-invasive bladder cancer (MIBC). However, the high rate of recurrence following surgery alone has driven interest in exploring adjuvant and neoadjuvant strategies to improve outcomes. Neoadjuvant chemotherapy (NAC) has demonstrated a survival benefit, with the ABC meta-analysis reporting a 5 percent absolute improvement in overall survival at five years for patients with MIBC receiving platinum-based NAC. Several chemotherapy regimens have been studied, but the optimal combination remains under discussion. Commonly used regimens include dose-dense methotrexate, vinblastine, doxorubicin (adriamycin), and cisplatin (ddMVAC), as well as gemcitabine plus cisplatin (GC). While comparative studies have produced varied results, GC has a more favorable toxicity profile which has contributed to its frequent use in clinical practice.

Recent advancements have underscored the potential role of immunotherapy in the neoadjuvant setting. The NIAGARA trial demonstrated the clinical benefit of neoadjuvant immunotherapy, supporting its regulatory approval in this context.

This phase 2 randomized controlled trial aims to evaluate the efficacy and safety of two neoadjuvant regimens: dose-dense cisplatin, methotrexate, and vinblastine (ddCMV) in combination with immunotherapy and GC with immunotherapy. ddCMV represents a dose-intensified regimen, distinct from the ddMVAC backbone due to the omission of doxorubicin, which may influence toxicity profiles. The impact of gemcitabine-induced lymphopenia on immunotherapy efficacy is also of interest, given immunotherapy’s reliance on T cell activity. There is still ongoing debates on whether ddMVAC is better than GC. The ddCMV is a novel regimen which may be more tolerable than the ddMVAC regimen.

This randomized phase 2 trial, focuses on assessing the safety and efficacy of two regimens which are ddCMV with GC with the addition of immunotherapy, providing insights into their use in the neoadjuvant setting. The primary and secondary endpoints include pathologic complete response (pCR), event-free survival (EFS), overall survival (OS), overall clinical response rates, and the incidence and severity of adverse events (AEs). This study aims to contribute valuable data to inform future strategies for optimizing neoadjuvant treatment in MIBC