ESMO 2021: Dose-Dense Methotrexate, Vinblastine, Doxorubicin and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients with MIBC: GETUG/AFU VESPER V05 Phase III Trial

( In this presentation, Dr. Christian Pfister presented results of the GETUG/AFU VESPER V05 phase III clinical trial, which compared dose-dense Methotrexate, Vinblastine, Doxorubicin and Cisplatin (ddMVAC) versus Gemcitabine and Cisplatin (GC) as perioperative chemotherapy for patients with muscle-invasive bladder cancer (MIBC). The standard of care for MIBC in 2021 is radical cystectomy with perioperative chemotherapy, however, to date, there is no randomized phase 3 clinical trial data to define the optimal perioperative chemotherapy regimen. Level 1 evidence supports the use of neoadjuvant chemotherapy. Lower level evidence exists for adjuvant chemotherapy, but nevertheless, it is frequently used. GC and ddMVAC are the two peri-operative chemotherapy regimens with the strongest data. The GETUG/AFU VESPER V05 trial sought to determine the optimal perioperative chemotherapy regimen.

This trial was designed to randomize 500 men with MIBC to receive GC or ddMVAC in the perioperative setting. Notable inclusion criteria were pure or mixed urothelial bladder cancer (neuroendocrine excluded), ECOG PS < 2, cisplatin eligible. Patients with cT2-4N0M0 were eligible for neoadjuvant chemotherapy; patients with pT2-4 or N+ (node-positive) M0 disease were eligible for adjuvant chemotherapy. Patients were randomized to receive 4 cycles of GC (Gemcitabine 1250 mg/m2 on Day 1 and Day 8 and Cisplatin 70 mg/m2 on Day 1) every 3 weeks or 6 cycles of ddMVAC (Methotrexate 30 mg/m2 on Day 1, Vinblastine 3 mg/m2 on Day 2, Doxorubicin 30 mg/m2 on Day 2, and Cisplatin 70 mg/m2 on Day 2 with GCSF support) every 2 weeks.

From February 2013 to March 2018, 500 patients from 28 French cancer centers were randomized with 493 eligible for the intention-to-treat analysis. The majority of patients (437; 88%) received neoadjuvant therapy with a minority (56; 12%) receiving adjuvant therapy. The primary endpoint of the study was three-year progression-free survival (PFS).

The two study groups were well-balanced for demographic and baseline characteristics including age, sex, receipt of neoadjuvant versus adjuvant chemotherapy. Notably, a similar proportion of patients in the GC (90%) and ddMVAC (91%) arms treated in the neoadjuvant setting went on to undergo radical cystectomy. However, the pathologic response rates suggested greater activity in patients treated with ddMVAC. Pathologic complete response rates (42% versus 36%) and organ-confined disease (78% versus 63%) were higher for patients treated with ddMVAC than GC.


Analysis of the Kaplan-Meier curves also suggests improved outcomes for patients treated with ddMVAC than GC. While three-year PFS did not meet the pre-specified statistical threshold, there was a trend towards improvement in the ddMVAC arm versus GC (HR 0.77, 95% CI 0.57-1.02; Padj = 0.077). Among patients treated with neoadjuvant chemotherapy, there was a significant improvement in three-year PFS for patients treated with ddMVAC (66%) compared to those treated with GC (56%) (HR 0.70, 95% CI 0.51-0.96; P = 0.025). Likewise, there was a significant improvement in overall survival (OS) in the neoadjuvant patients treated with ddMVAC versus GC (HR 0.66, 95% CI 0.47-0.92). The current median follow-up is 40 months. The prespecified overall survival analysis will occur when follow-up reaches five years.


Dr. Pfister concluded that ddMVAC should now be the gold standard regimen for neoadjuvant chemotherapy because of higher local control and a significant improvement in three-year PFS. While the overall survival data is immature, he expects that the final results will confirm the signal demonstrated in this presentation that ddMVAC in the perioperative setting improves overall survival compared to GC for men with MIBC. 

Presented by: Christian Pfister, MD, PhD, Department of Urology, Charles Nicolle University Hospital

Written by: Jacob Berchuck, MD, Genitourinary Medical Oncologist, Dana-Farber Cancer Institute (Twitter: @jberchuck) during the 2021 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021.