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First Phase 3 results for the KEYTRUDA® (pembrolizumab) and Padcev® (enfortumab vedotin-ejfv) combination showed a statistically significant and clinically meaningful improvement in OS, PFS and key secondary endpoint of overall response rate versus chemotherapy in these patients, who may or may not be eligible for cisplatin-based chemotherapy
RAHWAY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced positive topline results from the Phase 3 KEYNOTE-A39 trial (also known as EV-302), which was conducted in collaboration with Seagen and Astellas, evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with Padcev (enfortumab vedotin-ejfv) versus chemotherapy (gemcitabine plus cisplatin or carboplatin) in patients with previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC). The trial enrolled patients who may or may not be eligible for treatment with cisplatin-based chemotherapy, regardless of PD-L1 status.
In the trial, KEYTRUDA in combination with enfortumab vedotin met its dual primary endpoints of overall survival (OS) and progression-free survival (PFS), demonstrating a statistically significant and clinically meaningful improvement versus chemotherapy in patients with previously untreated la/mUC. The combination also showed a statistically significant improvement in overall response rate (ORR), a key secondary endpoint, versus chemotherapy. The safety profile of KEYTRUDA and enfortumab vedotin in this study was consistent with previously reported studies of this combination.
“The results of this pivotal Phase 3 study are highly encouraging and showed a statistically significant survival benefit for the combination of KEYTRUDA with the antibody-drug conjugate enfortumab vedotin in cisplatin-eligible or cisplatin-ineligible patients with previously untreated 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. “This is an important milestone, as many patients with advanced urothelial carcinoma still experience disease progression following chemotherapy. We look forward to sharing these data with the medical community and regulatory authorities.”
The Phase 3 KEYNOTE-A39 trial is intended to serve as the confirmatory trial for the current U.S. accelerated approval of KEYTRUDA in combination with enfortumab vedotin as first-line treatment for patients with la/mUC who are not eligible to receive cisplatin-containing chemotherapy 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).
About the KEYNOTE-A39 (EV-302) trial
The KEYNOTE-A39 trial (ClinicalTrials.gov, NCT04223856) is an open-label, randomized, controlled Phase 3 trial evaluating KEYTRUDA in combination with enfortumab vedotin compared with chemotherapy (gemcitabine plus cisplatin or carboplatin) for the treatment of patients with previously untreated la/mUC who may or may not be able to receive treatment with cisplatin-based chemotherapy. The dual primary endpoints are PFS as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and OS. Key secondary endpoints include 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:
About bladder and urothelial cancer
Urothelial cancer, or bladder cancer, begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis and some other organs. In the U.S., it is estimated that approximately 82,290 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. Urothelial cancer accounts for about 90% of all bladder cancers. 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.
About KEYTRUDA® (pembrolizumab) injection, 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 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.
Selected KEYTRUDA® (pembrolizumab) Indications in the U.S.
Urothelial Carcinoma
KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):
KEYTRUDA, as a single agent, is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.
See additional selected indications for KEYTRUDA in the U.S. after the Selected Important Safety Information
Selected Important Safety Information for KEYTRUDA
Severe and Fatal Immune-Mediated Adverse Reactions
KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.
Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.
Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.
Pneumonitis occurred in 41 (7%) patients, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. In adult patients who received adjuvant therapy for NSCLC, patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (
