Perioperative Enfortumab Vedotin Plus Pembrolizumab in Muscle-Invasive Bladder Cancer
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Reviewed & Translated by Dat Tien Nguyen, B.A, ScM.
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Posted on April 27th, 2026
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Current treatment guidelines for muscle-invasive bladder cancer recommend radical cystectomy combined with neoadjuvant cisplatin-based chemotherapy. However, nearly half of patients are not eligible for cisplatin due to comorbidities or poor overall health. The combination of enfortumab vedotin and pembrolizumab has already been approved for metastatic urothelial carcinoma, prompting investigation into its role in earlier-stage disease.
Funding Source(s): Merck
This phase 3 trial enrolled 344 patients with a median age of approximately 73 years who had clinically nonmetastatic muscle-invasive bladder cancer. About 80% were ineligible for cisplatin-based therapy. Most participants had good functional status, with 60% having an ECOG performance score of 0, 30% a score of 1. 10% of the patients have a score of 2, meaning the patients are ambulatory but cannot perform physical activities for normal daily activities.
Participants were randomly assigned to receive either perioperative enfortumab vedotin plus pembrolizumab or surgery alone. Enfortumab vedotin is an antibody-drug conjugate that delivers a microtubule inhibitor to tumor cells expressing nectin-4, thereby inhibiting cell proliferation. Pembrolizumab is a PD-1 inhibitor that enhances immune-mediated tumor destruction. Treatment was administered in 3-week cycles, with patients receiving nine cycles of enfortumab vedotin and seventeen cycles of pembrolizumab. Radical cystectomy was performed after the first three cycles.
After two years of follow-up, the enfortumab vedotin plus pembrolizumab combination therapy reduced the risk of death or disease progression by 60% compared with surgery alone. This benefit was consistent across subgroups, including those stratified by PD-L1 expression and renal function. Notably, 57.1% of patients receiving combination therapy achieved a pathologic complete response, compared with only 8.6% in the surgery-only group. Although the combination regimen was associated with a higher incidence of adverse events, the study did not provide detailed characterization of these effects. Overall, these findings suggest that perioperative enfortumab vedotin plus pembrolizumab may represent a promising treatment option for patients with muscle-invasive bladder cancer who are not candidates for cisplatin-based chemotherapy.
Funding Source(s): Merck
This phase 3 trial enrolled 344 patients with a median age of approximately 73 years who had clinically nonmetastatic muscle-invasive bladder cancer. About 80% were ineligible for cisplatin-based therapy. Most participants had good functional status, with 60% having an ECOG performance score of 0, 30% a score of 1. 10% of the patients have a score of 2, meaning the patients are ambulatory but cannot perform physical activities for normal daily activities.
Participants were randomly assigned to receive either perioperative enfortumab vedotin plus pembrolizumab or surgery alone. Enfortumab vedotin is an antibody-drug conjugate that delivers a microtubule inhibitor to tumor cells expressing nectin-4, thereby inhibiting cell proliferation. Pembrolizumab is a PD-1 inhibitor that enhances immune-mediated tumor destruction. Treatment was administered in 3-week cycles, with patients receiving nine cycles of enfortumab vedotin and seventeen cycles of pembrolizumab. Radical cystectomy was performed after the first three cycles.
After two years of follow-up, the enfortumab vedotin plus pembrolizumab combination therapy reduced the risk of death or disease progression by 60% compared with surgery alone. This benefit was consistent across subgroups, including those stratified by PD-L1 expression and renal function. Notably, 57.1% of patients receiving combination therapy achieved a pathologic complete response, compared with only 8.6% in the surgery-only group. Although the combination regimen was associated with a higher incidence of adverse events, the study did not provide detailed characterization of these effects. Overall, these findings suggest that perioperative enfortumab vedotin plus pembrolizumab may represent a promising treatment option for patients with muscle-invasive bladder cancer who are not candidates for cisplatin-based chemotherapy.