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Recently, the antibody-drug conjugate (ADC) Padcev (enfortumab vedotin), developed by Astellas and Seagen, a subsidiary of Pfizer, in combination with MSD's PD-1 inhibitor Keytruda (pembrolizumab)Phase 3 Clinical Trial Results for First-Line Treatment of Locally Advanced or Metastatic Urothelial Carcinoma (la/mUC) in Adult PatientsInThe New England Journal of Medicine（NEJM) Published on。The results showed that,Padcev CombinationKeytrudaFirst-line treatmentThe survival outcomes of la/mUC patients are significantly better than chemotherapy, and the safety is consistent with previous reports.

This is an open-label, randomized trial conducted in 886 patients with la/mUC who had not previously received systemic therapy.Phase 3 ClinicalTrialEV-302/KN-A39，Patients were randomly assigned in a 1:1 ratio to receiveGemcitabine combined with cisplatin or carboplatin (n=444) orTreatment with Padcev in combination with Keytruda (n=442). The primary efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) as analyzed by blinded independent central review.

As of the data on August 8, 2023,The confirmed overall response rate (ORR) for patients receiving Padcev combination therapy was 67.7% (95% CI: 63.1-72.1), higher than the 44.4% (95% CI: 39.7-49.2) in the platinum-containing chemotherapy group, p<0.001.In the Padcev combination therapy group, 29.1% of patients achieved complete remission, compared to 12.5% in the platinum-based chemotherapy group. The median duration of response (DOR) has not yet been reached in the Padcev combination therapy group, while the DOR in the chemotherapy group was 7.0 months. In the Padcev combination therapy group, the proportion of patients still in remission at 12 and 18 months was 67.3% and 59.6%, respectively, while in the chemotherapy group, the proportions were 35.2% and 19.3%, respectively.

The median follow-up time for survival was 17.2 months.AndCompared with platinum-based chemotherapy regimens,Patients receiving the combination therapy of Padcev and Keytruda showed statistically significant improvements in both OS and PFS.Median PFS for Patients Receiving Padcev Combination Therapy is 12.5 Months（95% CI：10.4-16.6）, the median PFS for patients receiving platinum-based chemotherapy was 6.3 months.（95% CI：6.2-6.5），Compared with chemotherapy, the PFS of patients in the combination therapy group was significantly prolonged, and the risk of disease progression or death was reduced by 55% (HR:0.45，95% CI：0.38-0.54，p<0.001）。

▲PFS Data from the EV-302/KN-A39 Study (Image Source: Reference [1])

The median OS for patients receiving Padcev combination therapy was 31.5 months (95% CI: 25.4–not estimable), and the median OS for patients receiving platinum-based chemotherapy was 16.1 months (95% CI: 13.9–18.3)., that is, compared with the chemotherapy group,The risk of death was reduced by 53% in the combination therapy group (HR: 0.47, 95% CI: 0.38-0.58, p<0.001).

▲OS Data from the EV-302/KN-A39 Study (Image Source: Reference [1])

Padcev is an antibody-drug conjugate that targets Nectin-4, a protein located on the cell surface and highly expressed in bladder cancer.Preclinical data suggest that the anticancer activity of this drug is due to its binding to cells expressing Nectin-4, followed by the internalization and release of the antitumor agent MMAE into the cells, leading to cell cycle arrest and programmed cell death (apoptosis).

Keytruda is a PD-1 monoclonal antibody that blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2.Thereby activating T lymphocytes to exert anti-tumor effects. In April 2023, the U.S. FDA granted accelerated approval for Padcev in combination with Keytruda for the treatment of adult patients with la/mUC who are not eligible for cisplatin-containing chemotherapy, based on the results of the EV-103 trial.

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References:

[1] Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. doi: 10.1056/NEJMoa2312117. 

[2] Niegisch, G. (2024). Enfortumab Vedotin and Pembrolizumab — A New Perspective on Urothelial Cancer. New England Journal of Medicine, 390, 944-946. https://doi.org/10.1056/NEJMe2400311

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