Merck's Keytruda (pembrolizumab), combined with Padcev (enfortumab vedotin), has received approval from the European Commission (EC) as a first-line therapy for adults with unresectable or metastatic urothelial carcinoma. This approval introduces a new potential standard of care in the European Union (EU) for these patients, following the endorsement by the European Society for Medical Oncology and European Association of Urology, which recommend this combination as the preferred initial treatment, regardless of the patient's eligibility for platinum-based therapy.
The EC's approval comes after the Committee for Medicinal Products for Human Use (CHMP) issued a positive recommendation in July 2024.
This recommendation was based on the first interim analysis from the Phase 3 KEYNOTE-A39 (EV-302) trial, a study conducted in partnership with Pfizer (formerly Seagen) and Astellas. In this trial, the combination of Keytruda and Padcev showed statistically significant and clinically relevant improvements in overall survival (OS) and progression-free survival (PFS) compared to platinum-based chemotherapy (gemcitabine combined with cisplatin or carboplatin).
After a median follow-up of 17.3 months, the combination of Keytruda and Padcev reduced the risk of death by 53% compared to platinum-based chemotherapy. Additionally, it decreased the risk of disease progression or death by 55% in comparison to the same chemotherapy regimen.
Keytruda now holds approval for three different indications in bladder cancer and 28 indications overall within the EU. Previously, Keytruda was approved in the EU as a monotherapy for the treatment of locally advanced or metastatic urothelial carcinoma in adults who had received prior platinum-based chemotherapy, as well as in those ineligible for cisplatin-containing chemotherapy with tumors expressing PD-L1 with a combined positive score (CPS) of 10 or more, based on results from the KEYNOTE-045 and KEYNOTE-052 studies.
In December 2023, Keytruda in combination with Padcev was also approved in the United States for the treatment of adults with locally advanced or metastatic urothelial carcinoma.
Merck, in collaboration with Pfizer and Astellas, is continuing to explore the potential of this combination therapy in various stages of urothelial cancer through an extensive clinical development program, including two ongoing Phase 3 trials in muscle-invasive bladder cancer—KEYNOTE-B15 and KEYNOTE-905.
Overview of the KEYNOTE-A39 Trial
KEYNOTE-A39 is an open-label, multicenter, randomized, active-controlled Phase 3 study that evaluated the efficacy of Keytruda in combination with Padcev compared to platinum-based chemotherapy (gemcitabine plus cisplatin or carboplatin) for patients with unresectable or metastatic urothelial carcinoma. The primary efficacy endpoints were progression-free survival (PFS) as assessed by blinded independent central review (BICR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and overall survival (OS). Secondary endpoints included objective response rate (ORR) and duration of response (DOR), both assessed by BICR according to RECIST version 1.1. A total of 886 patients were enrolled and randomized (1:1) to receive one of the following treatment regimens via intravenous infusion:
Keytruda 200 mg over 30 minutes on Day 1, combined with Padcev 1.25 mg/kg on Days 1 and 8 of each 21-day cycle.
Gemcitabine 1000 mg/m² on Days 1 and 8, with the investigator's choice of cisplatin 70 mg/m² or carboplatin (AUC 4.5 or 5 mg/mL/min, as per local guidelines) on Day 1 of each 21-day cycle.
Treatment with Keytruda and Padcev continued until RECIST v1.1-defined disease progression, unacceptable toxicity, or, for Keytruda, up to a maximum of 35 cycles (approximately two years). Tumor status was assessed every nine weeks for the first 18 months, followed by assessments every 12 weeks thereafter.
Keytruda is a therapy that targets the programmed death receptor-1 (PD-1), working by enhancing the body's immune system's ability to identify and combat tumor cells. It is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes, which can impact both tumor cells and healthy cells.
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