First and only systemic regimen to demonstrate durable survival benefit in this patient population
KEYNOTE-905 marks the fifth study of a KEYTRUDA-based regimen in an earlier stage of cancer to demonstrate an overall survival benefit
Results from the Phase 3 KEYNOTE-905 trial were selected for an official Press Briefing and will be presented during a Presidential Symposium session at the European Society for Medical Oncology (ESMO) Congress 2025
RAHWAY, N.J.–(BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced landmark results demonstrating KEYTRUDA® (pembrolizumab) plus Padcev® (enfortumab vedotin-ejfv) reduced the risk of event-free survival (EFS) events by 60% and reduced the risk of death by 50% when given before and after surgery (radical cystectomy) versus surgery alone, the current standard of care, in patients with muscle-invasive bladder cancer (MIBC) who are not eligible for or declined cisplatin-based chemotherapy. These late-breaking data will be presented for the first time today during a Presidential Symposium session at the European Society for Medical Oncology (ESMO) Congress 2025 (Presentation #LBA2) and were selected for an official Press Briefing.
After a median follow-up of 25.6 months, KEYTRUDA plus Padcev, as perioperative treatment, demonstrated a statistically significant and clinically meaningful improvement in EFS, the trial’s primary endpoint, reducing the risk of EFS events by 60% (HR=0.40 [95% CI, 0.28-0.57]; p<0.0001) versus surgery alone in patients with MIBC who are not eligible for or declined cisplatin-based chemotherapy. Median EFS was not reached [NR] (95% CI, 37.3-NR) for the KEYTRUDA plus Padcev regimen versus 15.7 months (95% CI, 10.3-20.5) for surgery alone.
“For decades, patients with muscle-invasive bladder cancer who are ineligible for cisplatin treatment have faced limited treatment options, often relying on surgery alone. The groundbreaking benefits seen in the KEYNOTE-905/EV-303 trial, at this interim analysis, position the pembrolizumab and enfortumab vedotin combination to change the way we approach the treatment of patients with this disease,” said Dr. Christof Vulsteke, head of the Integrated Cancer Center Ghent (IKG) and Clinical Trial Unit Oncology Ghent, and KEYNOTE-905/EV-303 principal investigator.
KEYTRUDA plus Padcev also demonstrated a statistically significant and clinically meaningful improvement in key secondary endpoints of overall survival (OS) and pathologic complete response (pCR) rate. KEYTRUDA plus Padcev reduced the risk of death by 50% (HR=0.50 [95% CI, 0.33-0.74]; p=0.0002) versus surgery. For patients who received the KEYTRUDA plus Padcev regimen, median OS was NR (95% CI, NR-NR) versus 41.7 months (95% CI, 31.8-NR) for patients receiving surgery alone. The pCR rate increased from 8.6% in patients treated with surgery alone (n=15/174) to 57.1% in patients treated with perioperative KEYTRUDA plus Padcev (n=97/170), an estimated increase of 48.3 percentage points (95% CI, 39.5-56.5; p<0.000001).
“KEYTRUDA plus Padcev has once again demonstrated a significant improvement in survival for patients with bladder cancer, this time in an earlier stage of the disease as the KEYNOTE-905 study results show,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “These data – from the first-ever positive Phase 3 trial exclusively in this cisplatin-ineligible patient population – represent a potentially practice-changing advancement to help address a critical unmet need for these patients.”
The trial, evaluating Merck’s KEYTRUDA, an anti-PD-1 therapy, plus Padcev, an antibody-drug conjugate (ADC), was conducted in collaboration with Pfizer (previously Seagen) and Astellas. The companies plan to share these results with regulatory authorities worldwide. KEYTRUDA plus Padcev is currently approved for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC) in the U.S., the European Union (EU), Japan and several other countries around the world based on results from the Phase 3 KEYNOTE-A39 trial, also known as EV-302. KEYTRUDA as a monotherapy is also approved in the U.S., EU, Japan and other countries for the treatment of certain patients with la/mUC or a type of non-muscle-invasive bladder cancer (NMIBC).
Four additional Phase 3 studies are currently evaluating KEYTRUDA across all stages of bladder cancer, including non-muscle-invasive, muscle-invasive and metastatic disease. Three of these studies are in MIBC including KEYNOTE-B15 (NCT04700124), which is also known as EV-304 and is being conducted in collaboration with Pfizer and Astellas, KEYNOTE-866 (NCT03924856) and KEYNOTE-992 (NCT04241185). KEYTRUDA is also being evaluated in combination with Bacillus Calmette-Guerin (BCG) in patients with NMIBC in the Phase 3 KEYNOTE-676 (NCT03711032) trial.
KEYNOTE-905 is one of five Phase 3 studies of a KEYTRUDA-based regimen in an earlier stage of cancer to demonstrate an OS benefit, in addition to KEYNOTE-A18 in combination with concurrent chemoradiotherapy (CRT) for newly diagnosed patients with high-risk (stage IB2-IIB with lymph node-positive disease and stage III-IVA with and without lymph node-positive disease) locally advanced cervical cancer, KEYNOTE-522 in newly diagnosed, high-risk early-stage triple-negative breast cancer, KEYNOTE-671 in resectable stage II, IIIA or IIIB non-small cell lung cancer (in both studies, as treatment with chemotherapy before surgery and then as a single agent after surgery, compared to pre-operative chemotherapy), as well as KEYNOTE-564 in renal cell carcinoma for patients at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions (compared to placebo). It is also the 13th positive pivotal trial for a KEYTRUDA-based regimen in earlier-stage cancers.
Study design and additional data from KEYNOTE-905
KEYNOTE-905, also known as EV-303, is an open-label, randomized, multi-arm, controlled Phase 3 trial (NCT03924895) evaluating perioperative KEYTRUDA, with or without Padcev, versus surgery alone in patients with MIBC who are either not eligible for or declined cisplatin-based chemotherapy. The trial enrolled 595 patients who were randomized to receive either:
- Arm A: Three cycles of neoadjuvant KEYTRUDA, followed by surgery to remove the bladder (radical cystectomy), followed by 14 cycles of adjuvant KEYTRUDA;
- Arm B: Surgery alone;
- Arm C: Three cycles of neoadjuvant KEYTRUDA plus enfortumab vedotin, followed by surgery to remove the bladder (radical cystectomy), followed adjuvantly by six cycles of KEYTRUDA plus enfortumab vedotin and then eight cycles of KEYTRUDA alone.
The primary objective of this trial is to compare EFS between arm C and arm B, defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes radical cystectomy (RC) surgery or failure to undergo RC surgery in participants with residual disease, gross residual disease left behind at the time of surgery, local or distant recurrence as assessed by imaging and/or biopsy or death due to any cause. The key secondary objectives are to compare OS and the difference in pCR rate between arm C and arm B, as well as EFS, OS and the difference in pCR rate between arm A and arm B. The study remains ongoing to test hypotheses between arm A and arm B.
The safety profile of KEYTRUDA plus Padcev in this study was consistent with the known safety profiles of each agent. Treatment-emergent adverse events (TEAEs) occurred in 100% of patients receiving KEYTRUDA plus Padcev (n=167) and 64.8% of patients receiving surgery alone (n=103); Grade ≥3 TEAEs occurred in 71.3% (n=119) versus 45.9% (n=73), respectively. The most frequent grade ≥3 TEAE of special interest (based on distinct prespecified lists for each drug) was severe skin reactions for KEYTRUDA and skin reactions for Padcev.
About bladder cancer
Bladder cancer is the ninth most common cancer worldwide, diagnosed in more than 614,000 patients each year globally. Muscle-invasive bladder cancer represents approximately 30% of all bladder cancer cases. The standard of care for patients with MIBC has been neoadjuvant cisplatin-based chemotherapy followed by surgery, which is shown to prolong survival. However, up to half of patients with MIBC are not eligible to receive cisplatin and face limited treatment options, typically undergoing surgery alone.
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, 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 Cancer
KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma:
- who are not eligible for any platinum-containing chemotherapy, or
- who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.
See additional selected KEYTRUDA indications 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 programmed death receptor-1 (PD-1) or the programmed death ligand 1 (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 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. 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 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.
Hepatotoxicity and Immune-Mediated Hepatitis
KEYTRUDA as a Single Agent
KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.
KEYTRUDA With Axitinib
KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.
Immune-Mediated Endocrinopathies
Adrenal Insufficiency
KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
Hypophysitis
KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
Thyroid Disorders
KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.
Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism. The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment, including Grade 3 (0.2%) hyperthyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism.
Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis
Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
Immune-Mediated Nephritis With Renal Dysfunction
KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.
Immune-Mediated Dermatologic Adverse Reactions
KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.
Other Immune-Mediated
Contacts
Media Contacts:
Julie Cunningham
(617) 519-6264
Marian Cutler
(973) 517-0519
Investor Contacts:
Peter Dannenbaum
(732) 594-1579
Steven Graziano
(732) 594-1583
