EU CHMP Backs Perioperative KEYTRUDA Plus Padcev for Resectable Muscle-Invasive Bladder Cancer
核心洞察
The EMA's CHMP adopted a positive opinion recommending KEYTRUDA plus Padcev as neoadjuvant and adjuvant treatment for adults with resectable muscle-invasive bladder cancer (搜索).
The recommendation is based on the Phase 3 KEYNOTE-B15 trial, which reduced event-free survival events by 47% versus neoadjuvant chemotherapy and surgery.
KEYNOTE-B15 also showed a 35% reduction in risk of death and a pathologic complete response rate of 55.8% versus 32.5% with chemotherapy.
Merck (搜索) announced that the European Medicines Agency (搜索)'s Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending approval of KEYTRUDA (pembrolizumab) in combination with Padcev (enfortumab vedotin-ejfv) as neoadjuvant treatment and then continued after radical cystectomy as adjuvant treatment for adults with resectable muscle-invasive bladder cancer (搜索) (MIBC). The recommendation also covers KEYTRUDA SC, known as KEYTRUDA QLEX (搜索) (pembrolizumab and berahyaluronidase alfa-pmph) in the United States.
The opinion will now be reviewed by the European Commission for marketing authorization in the European Union, Iceland, Liechtenstein and Norway. A final decision is expected by the fourth quarter of 2026.
If approved, the combination would become the first and only PD-1 (搜索) inhibitor plus antibody-drug conjugate regimen in the European Union for people with MIBC regardless of cisplatin eligibility, expanding on a previously approved indication.
KEYNOTE-B15 Efficacy Results
The recommendation rests on results from the Phase 3 KEYNOTE-B15 trial, also known as EV-304, conducted in collaboration with Pfizer and Astellas. In cisplatin-eligible patients with MIBC, perioperative KEYTRUDA plus Padcev demonstrated a statistically significant improvement in event-free survival (EFS), reducing the risk of EFS events, defined as disease progression, recurrence or death, by 47% compared with neoadjuvant chemotherapy (gemcitabine and cisplatin) and surgery. The hazard ratio was 0.53 (95% CI, 0.41-0.70; p<0.0001), with events reported in 87 of 405 patients (21%) versus 146 of 403 patients (36%).
The combination also demonstrated a statistically significant improvement in overall survival, reducing the risk of death by 35% (HR=0.65 [95% CI, 0.48-0.89]; p=0.0029; 69/405 [17%] versus 99/403 [25%]) compared with neoadjuvant chemotherapy and surgery.
Pathologic complete response (pCR) rate was 55.8% (95% CI: 50.8, 60.7) with KEYTRUDA plus Padcev versus 32.5% (95% CI: 28.0, 37.3) with neoadjuvant chemotherapy, a statistically significant difference (p<0.0001).
"Despite advances in the treatment of muscle-invasive bladder cancer (搜索), recurrence remains a significant concern for many patients regardless of cisplatin eligibility, and up to half may be unable to receive cisplatin-based chemotherapy," said Dr. Marjorie Green, senior vice president, oncology, global clinical development, Merck (搜索) Research Laboratories. "If approved, KEYTRUDA plus Padcev would become the first and only PD-1 (搜索) inhibitor plus antibody-drug conjugate regimen in the European Union for people with muscle-invasive bladder cancer regardless of cisplatin eligibility, expanding on the previously approved indication."
Regulatory Timeline
The CHMP opinion follows two earlier approvals. In June 2026, the European Commission approved KEYTRUDA, including KEYTRUDA SC, in combination with Padcev as neoadjuvant treatment and then continued after radical cystectomy as adjuvant treatment for adults with resectable MIBC who are ineligible for cisplatin-containing chemotherapy, based on the Phase 3 KEYNOTE-905 trial.
In July 2026, the U.S. Food and Drug Administration approved KEYTRUDA in combination with Padcev as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment for adult patients with MIBC, based on KEYNOTE-B15. That approval represented the first and only PD-1 (搜索) inhibitor plus ADC regimen approved in the U.S. for adults with MIBC regardless of cisplatin eligibility.
Safety Profile in KEYNOTE-B15
In KEYNOTE-B15, the most common adverse reactions (at least 20%) in cisplatin-eligible patients with MIBC treated with KEYTRUDA plus enfortumab vedotin-ejfv (n=403) were rash (63%), fatigue (48%), pruritus (46%), peripheral neuropathy (43%), diarrhea (36%), alopecia (32%), decreased appetite (29%), nausea and dysgeusia (28% each), constipation (27%), urinary tract infection and dry eye (25% each), weight loss (22%) and hyperglycemia (20%).
During the neoadjuvant phase, serious adverse reactions occurred in 27% of patients, most frequently rash (3.2%), pneumonitis/interstitial lung disease (2.2%) and diarrhea (1.7%). Fatal adverse reactions occurred in 1.7% of patients. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 17% of patients, most often for rash (2.2%), increased alanine aminotransferase and pneumonitis/ILD (1.7% each) and hepatitis (1.2%). Thirteen patients (3.2%) did not undergo surgery because of adverse reactions, and among 351 patients who had radical cystectomy after neoadjuvant treatment, 26 (7%) experienced a delay of surgery exceeding 8 weeks due to adverse reactions.
In the adjuvant phase, serious adverse reactions occurred in 35% of 249 patients, most frequently urinary tract infection (8%), sepsis (2.8%) and diarrhea, hyperglycemia and pneumonitis/ILD (1.6% each). Fatal adverse reactions occurred in 3.2% of patients. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 23% of patients.
Among the 570 patients with MIBC treated with KEYTRUDA plus enfortumab vedotin-ejfv, 45% (n=259) were 65 to 74 years and 22% (n=125) were 75 years or older. No overall differences in effectiveness were observed between patients 65 years of age or older and younger patients, but patients 75 years or older had a higher incidence of fatal adverse reactions: 11% versus 3.6% in patients younger than 75.
Disease Burden and Unmet Need
Bladder cancer is the eighth most common cancer worldwide, diagnosed in more than 635,000 patients each year globally. In Europe, approximately 224,700 patients were diagnosed with bladder cancer and more than 70,300 died from the disease in 2022. According to some clinical practice guidelines, about 25% of newly diagnosed bladder cancer cases are MIBC.
The standard of care for MIBC is neoadjuvant cisplatin-based chemotherapy followed by surgery, which is shown to prolong survival. Nearly half of patients who undergo this standard treatment experience recurrence, and up to half of patients with MIBC are not eligible for cisplatin and face limited treatment options, typically undergoing surgery alone.
KEYTRUDA is an anti-programmed death receptor-1 (PD-1 (搜索)) therapy that works by increasing the ability of the body's immune system to help detect and fight tumor cells. It is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, activating T lymphocytes. Merck (搜索) states it has more than 2,800 trials studying KEYTRUDA across a variety of cancers and treatment settings.
Merck (搜索) is running more than 50 ongoing clinical trials in genitourinary cancers evaluating more than 22,000 patients, and more than 30 ongoing registrational studies in earlier disease states across multiple cancer types.