EV plus pembrolizumab nears EU approval for urothelial carcinoma

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending approval of enfortumab vedotin-ejfv (Padcev, EV) in combination with. pembrolizumab (Keytruda) for the first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma, Astellas and Merck announced in separate news releases.^1,2

The combination of EV plus pembrolizumab was approved in the US in December 2023.

"Treatment options available to patients with unresectable or metastatic urothelial cancer are currently limited mainly to platinum-containing chemotherapy," says Ahsan Arozullah, MD, MPH, Senior Vice President and Head of Oncology Development at Astellas, in the news release.¹ "The data underpinning the CHMP's approval recommendation show that this combination could change how clinicians manage first-line treatment of this disease. We are delighted that the CHMP recognized the potential for enfortumab vedotin in combination with pembrolizumab as first-line treatment for patients with unresectable or metastatic urothelial cancer."

The CHMP’s positive recommendation is based on findings from the first interim analysis of the phase 3 EV-302 trial (KEYNOTE-A39 trial; NCT04223856), in which the combination of EV plus pembrolizumab significantly extended overall survival (OS) and progression-free survival (PFS) vs platinum-based chemotherapy (gemcitabine plus cisplatin or carboplatin) in patients with previously untreated locally advanced or metastatic urothelial carcinoma.³

Specifically, at a median follow-up of 17.2 months, treatment with EV plus pembrolizumab reduced the rate of death by 53% vs chemotherapy. Patients in the combination arm demonstrated a median OS of 31.5 months compared with 16.1 months among patients treated with chemotherapy (HR, 0.47; 95% CI, 0.38 to 0.58; P < .001). Additionally, the median PFS was 12.5 months with EV/pembrolizumab vs 6.3 months with chemotherapy, translating to a 55% reduction in the rate of disease progression or death (HR, 0.45; 95% CI, 0.38 to 0.54; P < .001).

The combination of EV plus pembrolizumab also demonstrated significant improvements on the trial’s secondary end points of objective response rate (ORR) and duration of response (DOR). In the combination arm, the confirmed ORR by blinded independent central review was 67.7% (95% CI, 63.1%-72.1%), vs 44.4% (95% CI, 39.7%-49.2%) in the chemotherapy arm (P < .00001). At the time of data analysis, the median DOR had not yet been reached in the combination arm; in the chemotherapy arm, the median DOR was 7 months.

The safety profile for the combination was consistent with previously reported safety findings from the phase 1/2 EV-103 trial (NCT03288545). In EV-302, treatment-related adverse events of grade 3 or higher were experienced by 55.9% of patients in the combination arm and 69.5% of those in the chemotherapy arm.

In total, the open-label EV-302 trial enrolled 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were eligible for enrollment in the trial regardless of eligibility for cisplatin-based chemotherapy or PD-L1 status. Those included in the trial were randomly assigned 1:1 to receive EV plus pembrolizumab (n = 442) or to chemotherapy (n = 444). Patients in the EV plus pembrolizumab cohort received a median of 12 cycles (range, 1-46) of treatment vs 6 (range, 1-6) cycles in the chemotherapy cohort.

The dual primary end points for the trial were PFS, per blinded independent central review, and OS. Secondary outcome measures included ORR, DOR, time to pain progression, and the incidence of adverse events.

“The CHMP’s positive opinion reinforces the landmark results from KEYNOTE-A39 and follows the recent adoption of the European Society for Medical Oncology and European Association of Urology clinical guidelines recommending KEYTRUDA plus enfortumab vedotin as the preferred first-line treatment for patients with advanced or metastatic urothelial carcinoma, regardless of platinum eligibility,” said Dr. Eliav Barr, senior vice president and head of global clinical development and chief medical officer of Merck Research Laboratories, in the news release.² “We look forward to the European Commission’s decision and are excited to be taking the first steps to provide a potential new first-line standard of care for the treatment of this disease in patients in the EU.”

The combination of EV plus pembrolizumab was approved in the US in December 2023 for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma based on findings from the EV-302 trial.

An approval for the combination in the EU would mark the third approved bladder cancer indication for pembrolizumab in this jurisdiction. Currently, the anti-PD-1 therapy is approved in the EU as a monotherapy for adult patients with locally advanced or metastatic urothelial carcinoma who have received prior platinum-containing chemotherapy, and for the treatment of cisplatin-ineligible patients.

References

1. Astellas receives positive CHMP opinion for PADCEV (enfortumab vedotin) in combination with KEYTRUDA (pembrolizumab) for first-line treatment of advanced bladder cancer. News release. Astellas Pharma Inc. Published online and accessed July 26, 2024. https://www.prnewswire.com/news-releases/astellas-receives-positive-chmp-opinion-for-padcev-enfortumab-vedotin-in-combination-with-keytruda-pembrolizumab-for-first-line-treatment-of-advanced-bladder-cancer-302207704.html

2. Merck receives positive EU CHMP opinion for KEYTRUDA (pembrolizumab) plus Padcev (enfortumab vedotin-ejfv) as first-line treatment for patients with unresectable or metastatic urothelial carcinoma. News release. Merck. Published online and accessed July 26, 2024. https://www.merck.com/news/merck-receives-positive-eu-chmp-opinion-for-keytruda-pembrolizumab-plus-padcev-enfortumab-vedotin-ejfv-as-first-line-treatment-for-patients-with-unresectable-or-metastatic-urothelial-c/

3. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial carcinoma. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117