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EV-302/KEYNOTE-A39: combination enfortumab vedotin and pembrolizumab improves outcomes versus chemotherapy in patients with advanced urothelial carcinoma

The Phase III EV-302/KEYNOTE-A39 (NCT04223856) trial demonstrated that the combination of enfortumab vedotin and pembrolizumab significantly improved overall survival (OS) and progression-free survival (PFS) compared to chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC). This finding represents a new standard of care in the first-line setting.1

For decades prior to this, platinum-based chemotherapy has been the standard first-line therapy in la/mUC for all patients fit to receive cisplatin or carboplatin. 2 However, these therapies have limited activity and considerable toxicity, and a large proportion of patients are considered ineligible for cisplatin, presenting an unmet need for safe and efficacious regimens in the first-line setting. 3

Pembrolizumab is a monoclonal antibody (mAb) that targets the programmed cell death receptor 1 (PD-1), thereby preventing T-cell inhibition.4 In 2017, pembrolizumab was granted approval by the US Food and Drug Administration (FDA) in the second-line setting for patients with la/mUC who had progressed on platinum-based chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-based chemotherapy. Simultaneously, the FDA granted approval for pembrolizumab in the first-line setting for cisplatin-ineligible la/mUC patients.5 Enfortumab vedotin is an antibody-drug conjugate (ADC) developed to target nectin-4, a transmembrane protein which is aberrantly expressed in several types of cancer, including UC.6

The EV-302/KEYNOTE-A39 trial is a global, open-label, randomized, Phase III trial that evaluated the combination of enfortumab vedotin and pembrolizumab (EV+P) versus gemcitabine with cisplatin or carboplatin in patients with previously untreated la/mUC who were eligible for platinum-based chemotherapy. 1

886 patients were randomized 1:1 to receive either EV+P or chemotherapy. The primary endpoints were PFS and OS and key secondary endpoints included overall response rate (ORR) and safety. At the data cutoff, the median follow-up time was 17.2 months. PFS was significantly prolonged with EV+P compared to chemotherapy, with a median PFS of 12.5 months and 6.3 months for the respective arms (HR 0.45; 95% CI 0.38-0.54). OS was significantly prolonged with EV+P versus chemotherapy, with a median OS of 31.5 months versus 16.1 months, respectively (HR 0.47; 95% CI 0.38-0.58).

The confirmed ORR was 67.7% for EV+P versus 44.4% for patients receiving chemotherapy. Treatment-related adverse events (TRAEs) that were Grade 3 or higher occurred in 55.9% of patients in the EV+P arm and 69.5% in the chemotherapy arm. The most common TRAEs for EV+P were maculopapular rash (7.7%), hyperglycemia (5.0%), and neutropenia (4.8%); and for chemotherapy, anemia (31.4%), neutropenia (30%), and thrombocytopenia (19.4%).

In summary, the combination of EV+P significantly improved patient outcomes in terms of PFS and OS compared to chemotherapy, and the safety profile was manageable. These exciting results support EV+P as a new standard of care for the first-line treatment of patients with la/mUc.

Written by Josie Scott

Edited by Ellie Jackson

References

  1. Powles TB, Perez Valderrama B, Gupta S, et al. LBA6 EV-302/keynote-A39: Open-label, Randomized Phase III study of enfortumab vedotin in combination with Pembrolizumab (EV+P) vs Chemotherapy (chemo) in previously untreated locally advanced metastatic urothelial carcinoma (LA/MUC). Annals of Oncology. 2023;34. doi:10.1016/j.annonc.2023.10.106
  2. Cathomas R, Lorch A, Bruins HM, et al. The 2021 updated European Association of Urology guidelines on metastatic urothelial carcinoma. European Urology. 2022 Jan 1;81(1):95-103.
  3. Hoimes CJ, Flaig TW, Milowsky MI, et al. Enfortumab vedotin plus pembrolizumab in previously untreated advanced urothelial cancer. Journal of Clinical Oncology. 2023 Jan 1;41(1):22-31.
  4. McDermott J, Jimeno A. Pembrolizumab: PD-1 inhibition as a therapeutic strategy in cancer. Drugs of Today (Barcelona, Spain: 1998). 2015 Jan 1;51(1):7-20.
  5. FDA. Pembrolizumab (Keytruda): Advanced or Metastatic Urothelial Carcinoma. Available here.
    • Heath EI, Rosenberg JE. The biology and rationale of targeting nectin-4 in urothelial carcinoma. Nature Reviews Urology. 2021 Feb;18(2):93-103.