Long-term data show no survival benefit with perioperative dose-dense MVAC in MIBC

Five-year data from the phase 3 VESPER trial (NCT01812369) showed that perioperative dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) did not extend survival (OS) compared with gemcitabine and cisplatin in patients with muscle-invasive bladder cancer.

“Now the oncological challenge is to establish the best therapeutic option in the perioperative setting: chemotherapy combined with immunotherapy, immunotherapy for all, or personalized treatment with chemotherapy or immunotherapy according to tumor molecular profiling,” the study’s investigators wrote.

Among the final intent-to-treat (ITT) population, investigators noted that there was no evidence of OS benefit at the 5-year mark in the perioperative MVAC arm vs the comparator arm, with a 5-year OS rate of 64% (95% CI, 58%-70%) compared with 56% (95% CI, 50%-63%), respectively (HR, 0.79; 95% CI, 0.59-1.05). Additionally, the 5-year cumulative incidence of death was 27% (95% CI, 21%-32%) vs 40% (95% CI, 34%-46%) in each respective arm (HR, 0.61; 95% CI, 0.45-0.84).

Conversely, investigators noted that there was an OS benefit when dose-dense MVAC was used in the neoadjuvant setting, with a 5-year OS rate of 66% (95% CI, 60%-73%) in the experimental arm compared with 57% (95% CI, 50%-64%; HR, 0.71; 95% CI, 0.52-0.97). Moreover, the 5-year cumulative incidence of bladder cancer–related death was 24% (95% CI, 18%-30%) in the MVAC arm compared with 38% (95% CI, 32%-45%) in the gemcitabine/cisplatin arm (HR, 0.55; 95% CI, 0.39-0.78).

An adjuvant subgroup was also included in the study, although the findings were considered to be inconclusive because of the small sample size.

“Now the oncological challenge is to establish the best therapeutic option in the perioperative setting: chemotherapy combined with immunotherapy, immunotherapy for all, or personalized treatment with chemotherapy or immunotherapy according to tumor molecular profiling,” the study’s investigators wrote.

The open-label phase 3 VESPER study included adult patients between the ages of 18 and 80 years who had been diagnosed with a primary bladder tumor with histologically confirmed muscle-invasive urothelial carcinoma. Those receiving neoadjuvant chemotherapy were required to have (c)T2, cT3, or cT4a; N0, and M0 disease. Additionally, those who were receiving adjuvant chemotherapy needed to have (p)T3 or pT4 or pN1 to 2 disease irrespective of pT and M0.

Those who had been diagnosed with pure adenocarcinoma or pure squamous cell carcinoma, or mixed or pure small cell neuroendocrine carcinoma; a left ventricular ejection fraction of less than 50%; or a history of cancer within the last 5 years besides basal cell carcinoma or a carcinoma in-situ of the uterine cervix were ineligible for the study.

The study used 1:1 randomization. Those in the dose-dense MVAC cohort were treated with 30 mg/m2 of methotrexate on day 1, 3 mg/m2 of vinblastine on day 2, 30 mg/m2 of doxorubicin on day 2, and 70 mg/m2 of cisplatin on day 2. This was paired with an associated granulocyte-colony stimulating factor from day 3 to day 9 by neutrophil count every 2 weeks for 6 cycles. In the standard chemotherapy group, patients received 1250 mg/m2 of gemcitabine on day 1 and 8 and 70 mg/m2 of cisplatin every 3 weeks for a total of 4 cycles.

The primary end point was progression-free survival (PFS), and the secondary end points included response rate, OS, and time to death from bladder cancer.

A total of 500 patients were randomly assigned from February 25, 2013 to March 1, 2018. Additionally, 493 patients were included in the ITT population, including 245 patients in the gemcitabine and cisplatin arm and 248 in the MVAC arm.

Most patients were male (83%) and in the neoadjuvant group (89%). The median patient age was 63 years (IQR, 58-68). The study had a median follow-up of 5.3 years (IQR, 5.1-5.4).

For those in the perioperative cohort, the 5-year PFS rate was 59% (95% CI, 53%-66%) in the MVAC group vs 51% (95% CI, 45%-58%) in the gemcitabine/cisplatin cohort (HR, 0.78; 95% CI, 0.59-1.02). In the neoadjuvant population, the 5-year PFS was 61% (95% CI, 54%-68%) vs 52% (95% CI, 46%-60%) in each respective cohort (HR, 0.74; 95% CI, 0.55-0.99).

A total of 190 deaths were reported in the overall patient population at the 5-year cutoff, including 104 in the gemcitabine/cisplatin group and 86 in the MVAC group. The most common reasons for death were bladder cancer progression (83%), intercurrent disease (5%), cardiovascular events (4%), chemotherapy-related toxicity (2%), and secondary cancers (2%).

Reference

1. Pfister C, Gravis G, Flechon A, et al. Perioperative dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin in muscle-invasive bladder cancer (VESPER): survival endpoints at 5 years in an open-label, randomised, phase 3 study. Lancet Oncol. Published online December 21, 2023. doi:10.1016/S1470-2045(23)00587-9