- 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
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 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.
Source: Merck. (2025). KEYTRUDA® (pembrolizumab) Plus Padcev® (enfortumab vedotin-ejfv) Reduced Risk of Event-Free Survival Events by 60% and Risk of Death by 50% for Certain Patients with Muscle-Invasive Bladder Cancer When Given Before and after Surgery [Press release]. https://www.merck.com/news/keytruda-pembrolizumab-plus-padcev-enfortumab-vedotin-ejfv-reduced-risk-of-event-free-survival-events-by-60-and-risk-of-death-by-50-for-certain-patients-with-muscle-invasive-bladder-ca/.
Related Content: ESMO 2025: Perioperative Enfortumab Vedotin (EV) plus Pembrolizumab (Pembro) in Participants with Muscle-Invasive Bladder Cancer (MIBC) Who Are Cisplatin-Ineligible: The Phase 3 KEYNOTE-905 Study