• 04 Dec 2023
• Admin
• News Article

US-FDA grants priority review status to Merck sBLA for Keytruda plus Padcev to treat locally advanced or metastatic urothelial cancer

Merck, known as MSD outside of the United States and Canada, announced that the US Food and Drug Administration (FDA) has accepted for priority review a new supplemental Biologics License Application (sBLA) seeking approval for Keytruda, Merck’s anti-PD-1 therapy, in combination with Padcev (enfortumab vedotin-ejfv), an antibody-drug conjugate, for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (la/mUC). This application is being reviewed under the FDA’s Real-Time Oncology Review (RTOR) program, which aims to improve the efficiency of the review process of applications to ensure that treatments are available to patients as early as possible. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of May 9, 2024.

The sBLA is based on data from the phase 3 KEYNOTE-A39 trial (also known as EV-302), which was conducted in a research collaboration with Seagen and Astellas, in which Keytruda plus enfortumab vedotin demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) and progression-free survival (PFS) compared to chemotherapy (gemcitabine plus cisplatin or carboplatin). These results were presented at the European Society for Medical Oncology Congress 2023 as late-breaking data during a Presidential Symposium session and showed Keytruda plus enfortumab vedotin significantly improved OS, reducing the risk of death by 53% compared to chemotherapy (median OS, 31.5 months vs. 16.1 months, respectively), an improvement in median OS of more than 15 months; (HR=0.47 [95% CI, 0.38-0.58]; p<0.00001).

Keytruda plus enfortumab vedotin also achieved a significant improvement in progression-free survival (PFS), reducing the risk of disease progression or death by 55% (median PFS, 12.5 months vs. 6.3 months, respectively); (HR=0.45 [95% CI, 0.38-0.54]; p<0.00001). Results were consistent across all pre-defined subgroups, including patients who may or may not be eligible for treatment with cisplatin-based chemotherapy as well as patients whose tumours expressed both high (Combined Positive Score [CPS] =10) or low (CPS <10) levels of PD-L1, and patients with or without liver metastases.

“The FDA’s acceptance of this application for priority review, as well as under the RTOR programme, 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.”

The KEYNOTE-A39 trial is intended to serve as the basis for global regulatory submissions for the treatment of adult patients with la/mUC and as the confirmatory trial for the current US accelerated approval of Keytruda plus enfortumab vedotin for adult patients with la/mUC who are not eligible to receive cisplatin-containing chemotherapy. The accelerated approval is based on data from the KEYNOTE-869 trial (also known as EV-103) dose escalation cohort, Cohort A and Cohort K.

Merck, in collaboration with Seagen and Astellas, are evaluating this combination as part of an extensive clinical development program in multiple stages of urothelial cancer, including two phase 3 clinical trials in muscle-invasive bladder cancer in KEYNOTE-B15 (NCT04700124, also known as EV-304) and KEYNOTE-905 (NCT03924895, also known as EV-303).

The KEYNOTE-A39 trial (ClinicalTrials.gov, NCT04223856) is an open-label, randomized, controlled phase 3 trial evaluating Keytruda plus enfortumab vedotin compared to chemotherapy (gemcitabine plus cisplatin or carboplatin) for the treatment of patients with previously untreated la/mUC. The trial enrolled patients who may or may not be eligible for treatment with cisplatin-based chemotherapy, regardless of PD-L1 status. The dual primary endpoints are PFS as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 and OS. Secondary endpoints include objective response rate (ORR) per RECIST v1.1 by BICR, time to pain progression and duration of response per RECIST v1.1 by BICR. The study enrolled 886 patients who were randomized to receive either:

Keytruda (200 mg intravenously [IV] on Day 1 of each three-week cycle for a maximum of 35 cycles or until a protocol-defined reason for study discontinuation occurs, whichever is first) plus enfortumab vedotin (125 mg/m2 by IV on Days 1 and 8 of each three-week cycle for an unlimited number of cycles until a protocol-defined reason for study discontinuation occurs); or Gemcitabine (administered as IV infusion on Days 1 and 8 of each three-week cycle) plus platinum-containing chemotherapy (either carboplatin [administered by IV on Day 1 of each three-week cycle] or cisplatin [administered by IV on Day 1 of each three-week cycle] for a maximum of six cycles or until a protocol-defined reason for study discontinuation occurs, whichever is first).

Urothelial cancer, or bladder cancer, begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis and some other organs. In the US, it is estimated that approximately 82,300 people will be diagnosed with bladder cancer in 2023. Globally, it is estimated that approximately 573,000 new cases of bladder cancer are reported annually. Approximately 12% of cases are la/mUC at diagnosis. Many patients with advanced urothelial carcinoma face a poor prognosis and experience disease progression following initial treatment with chemotherapy.

Keytruda is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumour cells. Keytruda 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 may affect both tumour cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying Keytruda across a wide variety of cancers and treatment settings. The Keytruda clinical program seeks to understand the role of Keytruda across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with Keytruda, including exploring several different biomarkers.

Astellas and Seagen entered a clinical collaboration agreement with Merck to evaluate the combination of Astellas’ and Seagen’s Padcev (enfortumab vedotin-ejfv) and Merck’s Keytruda (pembrolizumab) in patients with previously untreated metastatic urothelial cancer. Padcev and the Padcev device are trademarks jointly owned by Agensys, Inc., and Seagen Inc.

Merck’s goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumour types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers.