FDA Approves Keytruda/Padcev Combo in Advanced Urothelial Cancer 

Pictured: FDA sign in front of building/Courtesy Sarah Silbiger/Getty Images

Pictured: FDA sign in front of building/Courtesy Sarah Silbiger/Getty Images

The FDA has approved the combination regimen of Merck’s Keytruda (pembrolizumab) and Seagen and Astellas’ Padcev (enfortumab vedotin-ejfv) for the first-line treatment of locally advanced or metastatic urothelial carcinoma, the companies announced Monday.

This marks the first approved therapeutic regimen that combines a PD-1 blocker and an antibody-drug conjugate (ADC) in the U.S. in this indication, according to the press release.

Data from three cohorts of the Phase Ib/II KEYNOTE-869 (also called EV-103) trial supported the approval of the combination regimen. In the study, Keytruda plus Padcev led to a 68% objective response rate, with a complete and partial response rate of 12% and 55%, respectively.

The median duration of response was 22.1 months in two cohorts and had not been reached in the other.

Monday's approval is a meaningful one. Approximately half of advanced cancer patients in the U.S. are ineligible for standard treatments and need new therapeutic options, Eliav Barr, chief medical officer, senior vice president and head, Global Clinical Development, Merck Research Laboratories, previously said in a statement.

KEYNOTE-869 is a multi-cohort and open-label global study that enrolled 348 patients with locally advanced or metastatic urothelial carcinoma who had not received prior systemic therapies or were otherwise ineligible for cisplatin-containing chemotherapy. Taken together, 121 patients in total received the combination treatment. 

Aside from efficacy, KEYNOTE-869 also looked at the combination regimen’s safety profile and found that 50% of treated patients developed serious adverse reactions. The most common of these episodes included acute kidney injury, urinary tract infection, urosepsis, hematuria and pneumonia.

Moreover, 5% of patients treated with Keytruda plus Padcev developed fatal toxicities, including sepsis, bullous dermatitis, myasthenia gravis and pneumonitis.

These safety results for the combination regimen mirror the known adverse event profiles of its individual components. Keytruda’s label, for instance, carries precautions for immune-mediated reactions which may be fatal or severe and can occur across different organ systems. These toxicities include pneumonitis, renal dysfunction and hepatitis.

Padcev, meanwhile, has a boxed warning for serious skin reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome, which can also be severe or lead to death.

Based on a surrogate endpoint and due to the unmet medical need it fills, the Keytruda-Padcev combo was greenlit under the FDA’s accelerated approval pathway. To keep it on the market, the pharma partners are running the confirmatory Phase III KEYNOTE-A39/EV-302 study to validate the regimen’s clinical benefit.

Merck, Seagen and Astellas are also assessing the drug combo in the Phase III KEYNOTE-B15/EV-304 and KEYNOTE-905/EV-303 studies in different forms of muscle-invasive bladder cancer.

Back to news