Pooled Clinical Trial Meta-Analysis Shows Superior Response Rates with Padcev Plus Keytruda Treating Metastatic Urothelial Carcinoma

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A meta-analysis of 11 randomized and nonrandomized clinical trials shows significant benefits with Padcev (enfortumab vedotin-ejfv) both as a monotherapy and in combination with Keytruda (pembrolizumab) in the treatment of metastatic urothelial carcinoma (mUC). The authors of the analysis, published by JAMA Network Open, said the superior response rates with Padcev alone and in combination compared to conventional chemotherapy highlights the importance of personalized treatment approaches.¹

“(mUC) presents a global health challenge, with a poor 5-year survival rate typically less than 10% despite treatment advancements,” the study authors wrote. “The therapeutic landscape has evolved considerably, with platinum-based chemotherapy regimens traditionally forming the first-line treatment. However, their effectiveness is limited. The introduction of immune checkpoint inhibitors (ICIs) has shifted mUC management, demonstrating durable responses in some patients. Yet, overall response rates to ICIs remain suboptimal, with objective response rates (ORRs) of approximately 20%, highlighting the need for more effective treatments.”¹

Padcev is a first-in-class antibody-drug conjugate directed against Nectin-4 with a microtubule disrupter, monomethyl auristatin. Keytruda is an anti-programed death receptor-1 (PD-1) therapy that improves the immune system's ability to detect and fight tumor cells. The humanized monoclonal antibody blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, which leads to the activation of T lymphocytes that could affect tumor and healthy cells.

The FDA approved Padcev on December 18, 2019, for patients with previously treated locally advanced or mUC (la/mUC). In April 2023, the FDA granted accelerated approval to the Padcev plus Keytruda combination for the treatment of patients with la/mUC who are ineligible for cisplatin-containing chemotherapy.²

The FDA granted the accelerated approval based on tumor response rate and durability of response, with continued approval contingent upon verification and description of clinical benefit in confirmatory trials. The approval was the first for an anti-PD-1 therapy plus an ADC in the United States for this indication. In December 2023, the FDA approved the combination for patients with previously untreated la/mUC.³

“Initially approved as monotherapy in the third-line setting based on the EV-201 (A Study of Enfortumab Vedotin for Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer) trial, enfortumab vedotin has rapidly emerged as a cornerstone therapy,” the study authors wrote. “Its novel mechanism of action potentially overcomes resistance to conventional therapies. The combination of enfortumab vedotin and pembrolizumab has shown promising results in clinical trials. Given the evolving mUC treatment landscape, a comprehensive evaluation of enfortumab vedotin’s effectiveness and safety is imperative.”¹

For the analysis, investigators included three randomized clinical trials and eight nonrandomized prospective studies that enrolled 2128 patients with mUC. A pooled total of 563 patients were administered the Padcev and Keytruda combination, 814 were administered Padcev without Keytruda, and 751 were administered chemotherapy. The primary outcomes of the analysis were pooled disease control rate (DCR), ORR, and one-year survival rate.

Results of the pooled analysis show Padcev plus Keytruda with a DCR of 86% (95% CI, 83%-89%), ORR of 68% (95% CI, 64%-71%), and a one-year survival rate of 79% (95% CI, 75%-82%). Pooled data for Padcev monotherapy show a DCR of 73% (95% CI, 70%-76%), ORR of 43% (95% CI, 40%-47%), and one-year survival rate of 52% (95% CI, 48%-56%).

A network meta-analysis found that Padcev plus Keytruda produced a significant benefit over chemotherapy in ORR (odds ratio [OR], 3.47; 95% CI, 1.49-8.09; P = .004) and one-year survival (OR, 2.32; 95% CI, 1.75-3.06; P < .001).

“In this meta-analysis of 11 studies, enfortumab vedotin–based therapy was associated with favorable outcomes in mUC treatment settings,” the study authors concluded. “Enfortumab vedotin plus pembrolizumab was associated with higher response rates in the first-line setting, while enfortumab vedotin monotherapy was associated with clinical benefit in later lines. The distinct profiles of these regimens underscore the importance of personalized treatment approaches. Ongoing research is crucial to further refine enfortumab vedotin–based therapies and improve outcomes for mUC patients.”¹

References

1. Yajima S, Hirose K, Masuda H. Enfortumab Vedotin With or Without Pembrolizumab in Metastatic Urothelial Carcinoma: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2025;8(3):e250250. doi:10.1001/jamanetworkopen.2025.0250

2. FDA Approves Merck’s KEYTRUDA® (pembrolizumab) in Combination With Padcev® (enfortumab vedotin-ejfv) for First-Line Treatment of Certain Patients With Locally Advanced or Metastatic Urothelial Cancer. Merck. News release. April 3, 2023. Accessed March 12, 2025. https://www.merck.com/news/fda-approves-mercks-keytruda-pembrolizumab-in-combination-with-padcev-enfortumab-vedotin-ejfv-for-first-line-treatment-of-certain-patients-with-locally-advanced-or-metastatic/

3. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. News release. December 15, 2023. Accessed March 12, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer