Merck bags USFDA nod for Keytruda, Padcev combo for urothelial cancer

The approval is based on data from the Phase 3 KEYNOTE-A39 trial (also known as EV-302) in 886 patients with locally advanced or metastatic urothelial cancer, which was conducted in a research collaboration with Pfizer (previously Seagen) and Astellas. In the trial, KEYTRUDA plus enfortumab vedotin demonstrated a statistically significant improvement in the trial’s major efficacy endpoints of overall survival (OS) and progression-free survival (PFS) versus platinum-based chemotherapy (gemcitabine plus cisplatin or carboplatin). KEYTRUDA plus enfortumab vedotin reduced the risk of death by 53% (HR=0.47 [95% CI, 0.38-0.58]; p<0.0001) versus platinum-based chemotherapy. Median OS was 31.5 months (95% CI, 25.4-not reached) for KEYTRUDA plus enfortumab vedotin versus 16.1 months (95% CI, 13.9-18.3) for platinum-based chemotherapy. KEYTRUDA plus enfortumab vedotin reduced the risk of disease progression or death by 55% (HR=0.45 [95% CI, 0.38-0.54]; p<0.0001) versus platinum-based chemotherapy. Median PFS was 12.5 months (95% CI, 10.4-16.6) for KEYTRUDA plus enfortumab vedotin versus 6.3 months (95% CI, 6.2-6.5) for platinum-based chemotherapy.

The trial also demonstrated a statistically significant improvement in objective response rate (ORR) in patients randomized to receive KEYTRUDA plus enfortumab vedotin compared with patients randomized to receive platinum-based chemotherapy. The ORR was 68% (95% CI, 63-72) for KEYTRUDA plus enfortumab vedotin versus 44% (95% CI, 40-49) for platinum-based chemotherapy (p<0.0001). For KEYTRUDA plus enfortumab vedotin, the complete response (CR) rate was 29% and the partial response (PR) rate was 39%, and for platinum-based chemotherapy, the CR rate was 12% and the PR rate was 32%. Efficacy results (OS, PFS and ORR) were consistent across all stratified patient subgroups.

“Advanced bladder cancer is a common cause of cancer-related death,” said Dr. Thomas Powles, primary investigator of KEYNOTE-A39, professor of Genitourinary Oncology and director, Barts Cancer Center. “The overall survival benefit seen in the KEYNOTE-A39 trial demonstrates the potential for KEYTRUDA in combination with enfortumab vedotin to impact the first-line treatment of patients with locally advanced or metastatic urothelial cancer. In my opinion, this is a meaningful advancement over platinum-based chemotherapy in the systemic treatment of these patients.”

“The landmark findings from the KEYNOTE-A39 trial are the first positive Phase 3 results combining a PD-1 inhibitor and an antibody-drug conjugate as first-line treatment for patients with locally advanced or metastatic urothelial cancer. This combination has the potential to change the treatment paradigm in advanced urothelial cancer and to help these patients live longer,” said Dr. Eliav Barr, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “The approval reinforces the value of advancing novel combinations with KEYTRUDA to provide these patients with a treatment option.”

Results from KEYNOTE-A39 were presented at the European Society for Medical Oncology Congress 2023 as late-breaking data during a Presidential Symposium session. KEYTRUDA plus enfortumab vedotin was previously approved under the FDA’s accelerated approval program for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who are not eligible to receive cisplatin-containing chemotherapy based on data from the KEYNOTE-869 trial (also known as EV-103) dose escalation cohort, Cohort A and Cohort K, which was conducted in collaboration with Pfizer and Astellas. In accordance with accelerated approval regulations, continued approval was contingent upon verification and description of clinical benefit; these accelerated approval requirements have been fulfilled with the data from KEYNOTE-A39.

This approval was reviewed under the FDA’s Real-Time Oncology Review program, which aims to improve the efficiency of the review process of applications to ensure that treatments are available to patients as early as possible.