Phase 3 Trial Establishes ADC and Immunotherapy Combination as Preferred Strategy in Cisplatin-Ineligible Cystectomy Cohorts

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Summary of  New England Journal of Medicine https://doi.org/10.1056/NEJMoa2608323
Dr. Thomas Powles et al.

Points

UCLA Health Jonsson Comprehensive Cancer Center researchers co-led the international phase three VOLGA trial evaluating six hundred ninety five patients with muscle invasive bladder cancer across twenty five countries.
Cisplatin ineligible or refusing patients were assigned to receive neoadjuvant durvalumab plus enfortumab vedotin, a triplet regimen adding tremelimumab, or radical cystectomy alone without systemic therapy.
At twenty four months event free survival reached sixty three point five percent in the durvalumab enfortumab vedotin group compared to forty five point one percent in surgical control arms.
Pathological evaluation established that neoadjuvant durvalumab and enfortumab vedotin eliminated detectable cancer in forty five point one percent of surgical specimens compared to nine point six percent in controls.
Authors concluded that perioperative durvalumab combined with neoadjuvant enfortumab vedotin provides a highly effective survival extending therapeutic strategy for patients unable to receive standard cisplatin chemotherapy.

Summary

This phase 3 international trial evaluated perioperative immunotherapy and antibody-drug conjugate (ADC) therapy in cisplatin-ineligible or -refusing patients with muscle-invasive bladder cancer. Published in The New England Journal of Medicine by UCLA Health Jonsson Comprehensive Cancer Center researchers including senior author Dr. Alexandra Drakaki, the VOLGA trial evaluated 695 patients across 229 centers in 25 countries. Given that nearly half of muscle-invasive bladder cancer patients cannot receive standard neoadjuvant cisplatin-based chemotherapy due to renal impairment, neuropathy, or hearing loss, the investigation sought to determine whether combining the PD-L1 inhibitor durvalumab with the nectin-4-targeted ADC enfortumab vedotin (EV)—with or without the CTLA-4 inhibitor tremelimumab—improves event-free survival (EFS) and overall survival (OS) compared to radical cystectomy alone.

Patients were randomized to receive neoadjuvant durvalumab plus EV (n=233), neoadjuvant durvalumab, tremelimumab, plus EV (n=233), or radical cystectomy alone (n=229). At 24 months, EFS was 63.5% (95% CI, 56.5 to 69.7) in the durvalumab-EV group versus 45.1% (95% CI, 38.2 to 51.8) in controls (HR for event or death, 0.51; 95% CI, 0.38 to 0.67; P<0.001). Twenty-four-month OS was 78.4% versus 69.4%, respectively (HR for death, 0.58; 95% CI, 0.40 to 0.83; P=0.003). Pathological complete response reached 45.1% with durvalumab-EV versus 9.6% in controls. The triplet regimen demonstrated a 24-month EFS of 60.1% (95% CI, 53.2 to 66.2; HR vs. control, 0.61; 95% CI, 0.47 to 0.80; P<0.001). Grade 3 or higher adverse events occurred in 71.1% of the durvalumab-EV cohort (treatment-related, 30.7%), 79.5% of the triplet cohort (treatment-related, 44.5%), and 50.2% of controls.

The authors conclude that perioperative durvalumab plus neoadjuvant enfortumab vedotin significantly improves event-free survival and overall survival compared to surgery alone in cisplatin-ineligible muscle-invasive bladder cancer. Administering enfortumab vedotin exclusively prior to surgery while continuing adjuvant durvalumab monotherapy mitigates post-operative treatment burden while delivering meaningful long-term clinical benefit.

Link to the article: https://www.nejm.org/doi/10.1056/NEJMoa2608323?referrer=https%3A%2F%2Fmedicalxpress.com%2F

References

Powles, T., Grande, E., Simone, G., Gómez De Liaño, A., Maruzzo, M., Velho, P. I., Kikuchi, E., Vu, T. Q., Popovic, L., Çil, T., Gravis, G., Radkowski, R., Hernández, L. R. N., Cutuli, H. J., Bamias, A., Bauernhofer, T., Pavic, M., Choi, Y. J., Chang, C.-H., … Drakaki, A. (2026). Durvalumab, tremelimumab, and enfortumab vedotin in muscle-invasive bladder cancer. New England Journal of Medicine, NEJMoa2608323. https://doi.org/10.1056/NEJMoa2608323