Frontline Enfortumab Vedotin Plus Pembrolizumab Receives Approval in Japan for Unresectable Urothelial Carcinoma

Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved the combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) for the first-line treatment of adult patients with radically unresectable urothelial carcinoma.¹

The regulatory decision was based on data from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), which showed that patients treated with the combination (n = 442) achieved a median overall survival (OS) of 31.5 months (95% CI, 25.4–not reached) compared with 16.1 months (95% CI, 13.9-18.3) for those given platinum-based chemotherapy (n = 444; HR, 0.47; 95% CI, 0.38-0.58; P < .001).^1,2 The estimated 12-month OS rates were 78.2% (95% CI, 73.9%-81.9%) in the enfortumab vedotin/pembrolizumab arm vs 61.4% (95% CI, 56.6%-65.9%) in the chemotherapy arm.²

Additionally, enfortumab vedotin plus pembrolizumab elicited a median progression-free survival (PFS) of 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5) for chemotherapy (HR, 0.45; 95% CI, 0.38-0.54; P < .001).¹

“Today’s approval by Japan’s MHLW expands the benefits of treatment with enfortumab vedotin in combination with pembrolizumab to patients living with radically unresectable urothelial carcinoma in Japan,” Ahsan Arozullah, MD, MPH, senior vice president, head of Oncology Development at Astellas, stated in a news release. “These patients will now have an alternative to platinum-containing chemotherapy to treat this devastating disease, helping to improve patient outcomes, extend lives and give further hope to the patients and families that we serve.”

In December 2023, the FDA approved enfortumab vedotin plus pembrolizumab for patients with locally advanced or metastatic urothelial cancer.³ The European Commission also approved the combination for adult patients with unresectable or metastatic urothelial cancer who are eligible for platinum-containing chemotherapy in August 2024.⁴

Those regulatory decisions were also supported by findings from EV-302/KEYNOTE-A39, which was a global, open-label trial that enrolled patients with radiologically documented, histologically confirmed, unresectable locally advanced or metastatic urothelial carcinoma, including differentiation in squamous cells or in multiple cell types.² Investigators excluded patients who previously received a PD-1 or PD-L1 inhibitor or other systemic therapy; however, neoadjuvant or adjuvant chemotherapy was allowed if recurrence occurred more than 12 months after the completion of treatment. Other key exclusion criteria consisted of uncontrolled diabetes; ongoing grade 2 or higher sensory or motor neuropathy; and previous autoimmune disease that required systemic treatment within 2 years of enrollment.

Patients were randomly assigned 1:1 to receive enfortumab vedotin at 1.25 mg/kg (up to a maximum dose of 125 mg) on days 1 and 8 plus pembrolizumab at 200 mg on day 1 of each 3-week cycle; or chemotherapy comprised of gemcitabine at 1000 mg/m² on days 1 and 8 plus either cisplatin at 70 mg/m² or carboplatin at area under the curve 4.5 to 5 mg/mL per minute on day 1 of each 3-week cycle.

Stratification factors included cisplatin eligibility (eligible vs ineligible), PD-L1 expression status (high vs low), and liver metastases (yes vs no).

PFS and OS served as the trial’s dual primary end points. Secondary end points included overall response rate (ORR), duration of response, time to pain progression, and safety.

Notably, approximately 30% of patients in the chemotherapy arm received maintenance avelumab (Bavencio) after completing study treatment.¹

Additional data showed the confirmed ORR was 67.7% (95% CI, 63.1%-72.1%) in the experimental arm vs 44.4% (95% CI, 39.7%-49.2%) in the chemotherapy arm (P < .001). The complete response rates were 29.1% and 12.5%, respectively.²

Regarding safety, the most common grade 3 or higher treatment-related adverse effects reported in at least 3% of patients in the enfortumab vedotin/pembrolizumab arm included maculopapular rash, hyperglycemia, neutropenia, peripheral sensory neuropathy, diarrhea, and anemia.1 No new safety issues were reported, and the safety profile of the combination was consistent with prior data.

References

1. Japan’s Ministry of Health, Labour and Welfare approves Padcev (enfortumab vedotin) with Keytruda (pembrolizumab) for first-line treatment of radically unresectable urothelial carcinoma. News release. Astellas. September 24, 2024. Accessed September 24, 2024. https://www.astellas.com/en/news/29451
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 September 24, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
4. European Commission approves Astellas’ Padcev (enfortumab vedotin) in combination with Keytruda (pembrolizumab) for first-line treatment of advanced urothelial cancer. News release. Astellas. August 28, 2024. Accessed September 24, 2024. https://www.astellas.com/en/news/29371