The GETUG-AFU V05 VESPER trial, a randomized phase III study involving 500 patients with urothelial carcinoma of the bladder, has identified the BaSq molecular subtype as a significant predictor of poorer outcomes, regardless of the chemotherapy regimen used. The findings, presented by Dr. Yves Allory at the 2024 International Bladder Cancer Network (IBCN) Annual Meeting, highlight the importance of molecular subtyping in bladder cancer treatment strategies.
The VESPER trial randomized patients with cT2-4aN0M0 urothelial carcinoma to either six cycles of dose-dense MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) every two weeks or four cycles of gemcitabine and cisplatin every three weeks, administered either before (neoadjuvant) or after surgery (adjuvant). Initial results, published in 2022, focused on the primary endpoint of three-year progression-free survival (PFS).
Neoadjuvant Chemotherapy Outcomes
The intent-to-treat population comprised 493 patients, with 88.6% receiving neoadjuvant chemotherapy. The three-year PFS was significantly higher in the dose-dense MVAC arm (66%) compared to the gemcitabine and cisplatin arm (56%), with a hazard ratio (HR) of 0.70 (95% CI: 0.51-0.96, p = 0.025). Furthermore, overall survival (OS) also favored the dose-dense MVAC regimen (HR 0.71, 95% CI: 0.52-0.97).
Extended Follow-Up Data
An extended follow-up, published earlier in 2024, revealed that in the neoadjuvant subgroup, the 5-year OS was improved in the dose-dense MVAC group (66%, 95% CI: 60-73) compared to the gemcitabine + cisplatin group (57%, 95% CI: 50-64), with an HR of 0.71 (95% CI: 0.52-0.97). Time to death due to bladder cancer also favored the dose-dense MVAC arm (5-year cumulative incidence: 24%, 95% CI: 18-30 vs 38%, 95% CI: 32-45; HR 0.55, 95% CI: 0.39-0.78).
Impact of BaSq Subtype
The molecular subtyping analysis of the VESPER trial data revealed that the BaSq subtype (either pure or mixed) was associated with decreased PFS and OS compared to other subtypes, irrespective of the chemotherapy arm. A multivariable Cox model further confirmed this association, with the BaSq subgroup exhibiting a hazard ratio of 2.0 (95% CI: 1.36-3.0) for progression-free survival.
Unanswered Questions
Despite these significant findings, Dr. Allory highlighted several remaining questions, including the biological underpinnings of mixed tumors, methods for handling clinical heterogeneity detection, and strategies to improve the prognosis for patients with BaSq (pure or mixed) tumors. These questions underscore the need for continued research to refine treatment approaches based on molecular subtyping in bladder cancer.
