Pembrolizumab Plus Enfortumab Vedotin Under Review for First-Line Tx of Urothelial Cancer

The Food and Drug Administration (FDA) has accepted for Priority Review the supplemental Biologics License Application (sBLA) for pembrolizumab in combination with enfortumab vedotin-ejfv for the first-line treatment of patients with locally advanced or metastatic urothelial cancer.

The sBLA is supported by data from the phase 3 KEYNOTE-A39 trial (ClinicalTrials.gov Identifier: NCT04223856), which compared the efficacy and safety of pembrolizumab plus enfortumab vedotin-ejfv to standard of care chemotherapy in 886 adults with previously untreated locally advanced or metastatic urothelial cancer. Study participants were randomly assigned to receive either pembrolizumab plus enfortumab vedotin or chemotherapy (gemcitabine plus cisplatin or carboplatin). The coprimary endpoints were progression free survival (PFS) and overall survival (OS).

Results showed that treatment with pembrolizumab plus enfortumab vedotin reduced the risk of disease progression or death by 55% vs chemotherapy (hazard ratio [HR], 0.45 [95% CI, 0.38-0.54]; P <.00001); median PFS was 12.5 months and 6.3 months, respectively. Moreover, pembrolizumab plus enfortumab vedotin reduced the risk of death by 53% vs chemotherapy (HR, 0.47 [95% CI, 0.38-0.58]; P <.00001); median OS was 31.5 months and 16.1 months, respectively. These results were consistent across all predefined subgroups.

Additionally, the trial met key secondary endpoints. The objective response rate was 67.7% in the pembrolizumab plus enfortumab vedotin arm compared with 44.4% in the chemotherapy arm (P <.00001). Median duration of response was not reached in the pembrolizumab plus enfortumab vedotin arm and was 7 months in the chemotherapy arm.

“The FDA’s acceptance of this application for priority review, as well as under the RTOR program, underscores the urgency to bring this treatment option that has demonstrated an OS benefit over chemotherapy to more patients with locally advanced or metastatic urothelial carcinoma,” said Dr Eliav Barr, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “We look forward to working closely with the FDA to provide this important option to patients as quickly as possible.”

A Prescription Drug User Fee Act target date of May 9, 2024 has been set for this application.

Pembrolizumab, an anti-programmed death receptor-1 (PD-1) therapy, is marketed under the brand name Keytruda and is currently approved for 3 urothelial cancer indications:

• in combination with enfortumab vedotin, for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy (accelerated approval; the KEYNOTE-A39 trial will serve as the confirmatory trial).
• As a single agent to treat locally advanced or metastatic urothelial carcinoma: in patients who are ineligible for any platinum-containing chemotherapy; or in those who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
• As a single agent for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Enfortumab vedotin-ejfv, a Nectin-4-directed antibody and microtubule inhibitor conjugate, is marketed under the brand name Padcev and is currently approved for 2 urothelial cancer indications:

• As a single agent to treat locally advanced or metastatic urothelial cancer in adults who have previously received a PD-1 or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or are ineligible for cisplatin-containing chemotherapy and have previously received ≥1 prior lines of therapy. 
• In combination with pembrolizumab to treat locally advanced or metastatic urothelial cancer in adults who are not eligible for cisplatin-containing chemotherapy.

References

• FDA grants Priority Review to Merck’s application for Keytruda® (pembrolizumab) plus Padcev® (enfortumab vedotin-ejfv) for the first-line treatment of patients with locally advanced or metastatic urothelial cancer. News release. Merck. November 30, 2023. https://www.businesswire.com/news/home/20231130062501/en/FDA-Grants-Priority-Review-to-Merck%E2%80%99s-Application-for-KEYTRUDA%C2%AE-pembrolizumab-Plus-Padcev%C2%AE-enfortumab-vedotin-ejfv-for-the-First-Line-Treatment-of-Patients-With-Locally-Advanced-or-Metastatic-Urothelial-Cancer.
• Keytruda® (pembrolizumab) plus Padcev® (enfortumab vedotin-ejfv) reduced risk of death by more than half versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer. News release. Merck. October 22, 2023. https://www.merck.com/news/keytruda-pembrolizumab-plus-padcev-enfortumab-vedotin-ejfv-reduced-risk-of-death-by-more-than-half-versus-chemotherapy-in-patients-with-previously-untreated-locally-advanced-or-metasta/.

This article originally appeared on MPR