FDA Prioritizes Review of KEYTRUDA® and KEYTRUDA QLEX™ Combinations with Padcev® for Cisplatin-Eligible Muscle-Invasive Bladder Cancer Patients
Merck & Co., known as MSD outside the United States and Canada, has announced a significant regulatory milestone as U.S. Food and Drug Administration has granted priority review to two supplemental Biologics License Applications (sBLAs) involving its flagship immunotherapy KEYTRUDA and a novel formulation, KEYTRUDA QLEX. Both applications evaluate these therapies in combination with Padcev for the treatment of patients diagnosed with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin-based chemotherapy. The regulatory agency has assigned a target action date of August 17, 2026, under the Prescription Drug User Fee Act (PDUFA), marking an accelerated review timeline that reflects the potential clinical importance of this treatment approach.
If approved, these supplemental applications could meaningfully broaden the role of KEYTRUDA and KEYTRUDA QLEX in bladder cancer care. Specifically, the combination regimens with Padcev would become the first perioperative treatment options for patients with muscle-invasive bladder cancer, irrespective of whether they can tolerate cisplatin-based chemotherapy. This would represent a major expansion beyond the current indication, which already includes use in patients with MIBC who are not eligible for cisplatin. By extending eligibility, the therapy could address a wider patient population and potentially establish a new standard of care in earlier stages of disease management.
Muscle-invasive bladder cancer remains an aggressive and challenging malignancy, often associated with high rates of recurrence and progression even when treated with surgery and chemotherapy aimed at cure. According to Dr. Marjorie Green, senior vice president and head of oncology, global clinical development at Merck Research Laboratories, the data supporting these applications challenge longstanding assumptions about treatment outcomes in this setting. She emphasized that despite aggressive interventions such as surgery combined with chemotherapy, many patients continue to experience disease progression or limited overall survival. The emerging evidence suggests that incorporating immunotherapy-based combinations earlier in the treatment pathway may offer a transformative benefit.
The regulatory submissions are supported by findings from the Phase 3 KEYNOTE-B15 trial, also known as EV-304, a large, randomized study conducted in collaboration with Pfizer and Astellas Pharma. Results from this study were recently presented at the ASCO Genitourinary Cancers Symposium, a leading forum for advancements in genitourinary oncology. The companies have indicated their intention to submit these findings to regulatory authorities around the world, suggesting that global regulatory filings may soon follow.
The KEYTRUDA plus Padcev combination has already demonstrated substantial clinical value in advanced stages of bladder cancer. It is currently approved in the United States, the European Union, Japan, and several other regions for the treatment of adults with locally advanced or metastatic urothelial cancer (la/mUC). Additionally, in the U.S., the regimen has been approved for patients with muscle-invasive bladder cancer who are not candidates for cisplatin-based chemotherapy. Beyond combination therapy, KEYTRUDA as a single agent also holds multiple approvals globally for treating certain forms of urothelial cancer, including non-muscle-invasive bladder cancer (NMIBC).
Importantly, the combination of KEYTRUDA and Padcev has now shown an overall survival benefit across three separate Phase 3 clinical trials in bladder cancer. Alongside KEYNOTE-B15, these include the KEYNOTE-905 study, which evaluated patients with MIBC who were either ineligible for or declined cisplatin-based chemotherapy, and the KEYNOTE-A39 trial, which focused on patients with locally advanced or metastatic disease. The consistent demonstration of survival benefit across multiple studies underscores the robustness of this therapeutic approach and reinforces its potential to reshape treatment paradigms.
Further expanding its clinical development program, Merck is currently conducting additional Phase 3 trials to evaluate KEYTRUDA-based regimens across the full spectrum of bladder cancer stages. Among these are KEYNOTE-866 and KEYNOTE-992, both targeting muscle-invasive disease, as well as KEYNOTE-676, which is exploring the combination of KEYTRUDA with Bacillus Calmette-Guerin (BCG) in patients with non-muscle-invasive bladder cancer. These studies highlight a comprehensive strategy aimed at integrating immunotherapy across disease stages, from early intervention to advanced treatment.
The KEYNOTE-B15 trial itself holds particular significance within the broader oncology landscape. It represents one of six Phase 3 studies evaluating KEYTRUDA-based regimens in earlier-stage cancers that have demonstrated an overall survival benefit. Moreover, it marks the 15th positive pivotal trial for a KEYTRUDA-based regimen in early-stage disease settings. This growing body of evidence continues to solidify KEYTRUDA’s position as a cornerstone of modern cancer immunotherapy.
Taken together, the priority review designation granted by the FDA signals both the urgency and promise associated with these new applications. Should approval be granted, the expanded use of KEYTRUDA and KEYTRUDA QLEX in combination with Padcev could significantly alter the treatment landscape for muscle-invasive bladder cancer, offering new hope for improved survival outcomes and potentially redefining standards of care for this challenging disease.
About KEYNOTE-B15/EV-304
KEYNOTE-B15, also known as EV-304, is an open-label, randomized Phase 3 trial (ClinicalTrials.gov, NCT04700124) evaluating perioperative KEYTRUDA in combination with Padcev and surgery (radical cystectomy and pelvic lymph node dissection) versus neoadjuvant chemotherapy (gemcitabine plus cisplatin) and surgery in patients with MIBC who are cisplatin-eligible. The trial enrolled 808 patients who were randomized to receive either:
- Four cycles (each cycle length is 21 days) of neoadjuvant KEYTRUDA intravenous (IV) infusion plus enfortumab vedotin IV infusion, followed by surgery, followed by 13 cycles of adjuvant KEYTRUDA IV infusion plus five cycles of enfortumab vedotin IV infusion, or;
- Four cycles (each cycle is 21 days) of standard of care neoadjuvant chemotherapy followed by surgery.
The primary endpoint is event-free survival (EFS), defined as the time from randomization to the first occurrence of the following events: radiographic disease progression precluding radical cystectomy and pelvic lymph node dissection, failure to undergo surgery in participants with residual disease, gross residual disease left behind at time of surgery, local or distant recurrence based on blinded independent central review or death due to any cause. The key secondary endpoints are OS and pathologic complete response rate.
About bladder cancer
In 2022, bladder cancer changed the lives of more than 600,000 people around the world. According to some clinical practice guidelines, about 25% of newly diagnosed bladder cancer cases are MIBC. The standard of care for patients with MIBC has been neoadjuvant cisplatin-based chemotherapy followed by surgery, which is shown to prolong survival. However, nearly half of patients who undergo this standard treatment experience recurrence.
About Merck’s research in genitourinary cancers
Merck is advancing research aimed at helping transform the treatment landscape and broaden options for people with genitourinary (GU) cancers, including bladder, kidney and prostate cancers. Globally, GU cancers account for an estimated 2.6 million new cancer diagnoses each year, equaling over 1 in 8 of all cancer incidences. Through a robust clinical development program with more than 50 ongoing clinical trials evaluating more than 22,000 patients around the world, Merck is investigating the potential of several portfolio medicines and pipeline assets, leveraging multiple novel combination strategies, across various stages of disease, to help address unmet needs in GU cancers.
About Merck’s early-stage cancer clinical program
Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is evaluating our portfolio of medicines and pipeline candidates in earlier disease states, with more than 30 ongoing registrational studies across multiple types of cancer.
About KEYTRUDA® (pembrolizumab) injection for intravenous use, 100 mg
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 tumor 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 tumor cells and healthy cells.
Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 2,800 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.
About KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) injection for subcutaneous use, 165mg + 2,000 units/mL
KEYTRUDA QLEX is a fixed-combination drug product of pembrolizumab and berahyaluronidase alfa. Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody and berahyaluronidase alfa enhances dispersion and permeability to enable subcutaneous administration of pembrolizumab. KEYTRUDA QLEX is administered as a subcutaneous injection into the thigh or abdomen, avoiding the 5 cm area around the navel, over one minute every three weeks (2.4 mL) or over two minutes every six weeks (4.8 mL).
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