Pembrolizumab Plus Enfortumab Vedotin Earns CHMP Recommendation in Frontline Metastatic Urothelial Carcinoma

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion recommending the approval of pembrolizumab (Keytruda) in combination with enfortumab vedotin-ejfv (Padcev) for the first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma. The European Commission will review the recommendation for marketing authorization in the European Union (EU), and a verdict is anticipated in the third quarter of 2024.¹

The recommendation is supported by findings from the phase 3 KEYNOTE-A39/EV-302 study (NCT04223856), which compared the safety and efficacy of pembrolizumab plus enfortumab vedotin vs platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. At a median follow-up of 17.2 months, patients who received the combination (n = 442) experienced a median overall survival (OS) of 31.5 months (95% CI, 25.4–not reached [NR]) vs 16.1 months (95% CI, 13.9-18.3) for those given chemotherapy (n = 444; HR, 0.47; 95% CI, 0.38-0.58; P < .0001). The median progression-free survival (PFS) was 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5), respectively (HR, 0.45; 95% CI, 0.38-0.54; P < .0001).²

“The CHMP’s positive opinion reinforces the landmark results from KEYNOTE-A39 and follows the recent adoption of the ESMO and European Association of Urology clinical guidelines recommending pembrolizumab plus enfortumab vedotin as the preferred first-line treatment for patients with advanced or metastatic urothelial carcinoma, regardless of platinum eligibility,” Eliav Barr, MD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said in a news release.¹ “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.”

KEYNOTE-A39/EV-302 was a global, open-label study that enrolled patients with previously untreated locally advanced or metastatic urothelial carcinoma. In order to be eligible for the study, patients needed to be at least 18 years of age; have a life expectancy of at least 12 weeks; have an ECOG performance status of 2 or less; and have adequate hematologic, hepatic, and renal function. Patients who received prior treatment with a PD-1/L1 inhibitor or other systemic therapy beyond neoadjuvant or adjuvant chemotherapy following surgery, with recurrence more than 12 months after treatment completion, were excluded.²

Patients were randomly assigned 1:1 to receive intravenous (IV) enfortumab vedotin at 1.25 mg/kg on days 1 and 8 of each 3-week cycle plus IV pembrolizumab at 200 mg once every 3 weeks; or gemcitabine plus either cisplatin or carboplatin. The choice of chemotherapy was based on the patient’s eligibility to receive cisplatin.

The coprimary end points were OS and PFS per blinded independent central review (BICR). Secondary end points included overall response rate (ORR) by RECIST 1.1 per BICR assessment, duration of response (DOR), time to pain progression, and safety.

Additional findings from KEYNOTE-A39/EV-302 demonstrated that the ORRs in the investigational and control arms were 67.7% (95% CI, 63.1%-72.1%) vs. 44.4% (95% CI, 39.7%-49.2%), respectively, (P < .001), with respective complete response rates of 29.1% and 12.5%. The median DOR was NR vs 7.0 months, respectively. The 12- and 18-month DOR rates were 67.3% vs 35.2%, respectively, for pembrolizumab plus enfortumab vedotin and 59.6% vs 19.3%, respectively, for chemotherapy.

In terms of safety, treatment-related adverse effects (TRAEs) were reported at rates of 97.0% vs 95.6% in the pembrolizumab/enfortumab vedotin and chemotherapy arms, respectively. The most common any-grade TRAEs in the investigational arm included peripheral sensory neuropathy (50.0%), pruritus (39.8%), and alopecia (33.2%). The most common any-grade TRAEs in the chemotherapy arm included anemia (56.6%), neutropenia (41.6%), and nausea (38.8%). Four patients in both the combination and chemotherapy arms experienced TRAEs leading to death.

If pembrolizumab plus enfortumab vedotin is approved in the EU, it will be the third indication in bladder cancer for pembrolizumab in the region. Pembrolizumab previously received approval in adult patients with locally advanced or metastatic urothelial carcinoma who previously received platinum-based chemotherapy, as well for the treatment of these patients who are ineligible for cisplatin-containing chemotherapy, based on findings from the phase 3 KEYNOTE-045 (NCT02256436) and phase 2 KEYNOTE-052 studies (NCT02335424), respectively. Additionally, pembrolizumab plus enfortumab vedotin received FDA approval in December 2023 for the treatment of adult patients with locally advanced or metastatic urothelial cancer, based on findings from KEYNOTE-A39.^1,3

The combination of pembrolizumab and enfortumab vedotin is also being examined in other clinical trials in multiple stages of urothelial cancer. The phase 3 KEYNOTE-B15 (NCT04700124) and KEYNOTE-905 studies (NCT03924895) are evaluating the combination in muscle-invasive bladder cancer.¹

References

1. 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. July 26, 2024. 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/
2. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117
3. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed July 26, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer