Pembrolizumab Plus Chemo Misses EFS End Point in Cisplatin-Eligible MIBC

Perioperative pembrolizumab (Keytruda) added to neoadjuvant cisplatin and gemcitabine did not significantly improve event-free survival (EFS) vs placebo plus chemotherapy in patients with cisplatin-eligible muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy with pelvic lymph node dissection, according to findings from the phase 3 KEYNOTE-866 trial (NCT03924856) presented at the 2026 ESMO Congress.¹

Overall survival (OS) outcomes were similar between the arms, and the pathologic complete response (pCR) rate was numerically higher with pembrolizumab, although neither end point was formally tested per the trial’s statistical design. The adverse effects (AEs) observed were consistent with prior reports with pembrolizumab and cisplatin-based chemotherapy.

In the second prespecified interim analysis, which served as the final EFS analysis, the median time from randomization to the January 26, 2026, data cutoff was 60.9 months (range, 40.7-78.7). In the intention-to-treat population (pembrolizumab arm, n = 453; placebo arm, n = 454), EFS events per investigator assessment occurred in 157 patients (34.7%) in the pembrolizumab arm and 168 patients (37.0%) in the placebo arm. The median EFS was 74.1 months (95% CI, 72.4–not reached [NR]) with pembrolizumab vs NR (95% CI, 67.7 months-NR) with placebo (HR, 0.88; 95% CI, 0.71-1.10; 1-sided P = .1366); the P value did not cross the 1-sided significance boundary of 0.0225. The 60-month EFS rates were 63.5% vs 61.9% in these respective arms.

“Efficacy outcomes in the placebo group surpassed the conventional benchmarks [for] cisplatin [plus] gemcitabine [undergoing] radical cystectomy and pelvic lymph node dissection in patients with MIBC,” Jens Bedke, MD, of Klinikum Stuttgart’s Eva Mayr-Stihl Cancer Center in Germany, stated in a presentation of the data.

How was the KEYNOTE-866 trial designed?

The double-blind, placebo-controlled trial randomly assigned 907 patients between July 19, 2019, and September 5, 2022. The trial enrolled adult patients with MIBC staged as clinical T2-T4aN0M0 or T1-T4aN1M0 on central assessment, with urothelial histology in at least 50% of the tumor, who were candidates for radical cystectomy with pelvic lymph node dissection and had an ECOG performance status of 0 or 1. Patients meeting any Galsky criterion for cisplatin ineligibility were excluded, including a glomerular filtration rate of at least 60 mL/min. Randomization was stratified by PD-L1 combined positive score (CPS; ≥ 10 vs < 10), clinical stage, and geographic region.

Patients received 4 cycles of neoadjuvant pembrolizumab at 200 mg or placebo every 3 weeks plus cisplatin at 70 mg/m² on day 1 and gemcitabine at 1000 mg/m² on days 1 and 8, followed by radical cystectomy with pelvic lymph node dissection and 13 cycles of adjuvant pembrolizumab or placebo. EFS, assessed by investigators, was the primary end point, and OS and pCR (assessed by central pathology review) were key secondary end points.

The median age was 65.0 years in both arms, and 80.6% and 82.6% of patients in the pembrolizumab and placebo arms, respectively, were male. The neoadjuvant phase was started by 450 and 449 patients, respectively, 393 patients in each arm completed all 4 cycles of therapy, and 415 vs 399 of respective patients underwent cystectomy. The adjuvant phase was started by 318 vs 315 patients, respectively, of whom 209 vs 244, respectively, completed all 13 cycles.

What did the KEYNOTE-866 secondary end points and subgroup analyses show?

OS events occurred in 135 patients in each respective arm (29.8% vs 29.7%); the median OS was NR (95% CI, NR-NR) in both arms (HR, 1.00; 95% CI, 0.79-1.27), and the 60-month OS rates were 70.8% vs 70.9%, respectively. The pCR rate at the time of surgery was 44.4% (95% CI, 39.8-49.2) with pembrolizumab vs 35.8% (95% CI, 31.3-40.4) with placebo, translating to an estimated difference of 8.9% (95% CI, 2.5%-15.1%). Patients who did not undergo radical cystectomy with pelvic lymph node dissection were counted as nonresponders.

The effects of treatment on EFS were broadly similar across several patient subgroups, including those with a PD-L1 CPS of at least 10 (HR, 0.87; 95% CI, 0.65-1.19) and below 10 (HR, 0.94; 95% CI, 0.68-1.28). Any subsequent therapy was received by 85 patients (18.8%) in the pembrolizumab arm and 108 patients (23.8%) in the placebo arm.

What did the KEYNOTE-866 safety analysis show?

In the safety population (pembrolizumab arm, n = 450; placebo arm, n = 449), the median duration of therapy was 13.0 months (range, 0.03-47.6) vs 13.4 months (range, 0.03-25.8), respectively. Any-grade treatment-emergent AEs (TEAEs) occurred in 99.8% vs 98.7% of respective patients, and grade 3 to 5 TEAEs occurred in 80.2% vs 75.1% of patients, respectively. Serious TEAEs occurred in 61.8% vs 55.2% of respective patients, and TEAEs led to discontinuation of any study drug in 36.7% vs 26.7% of respective patients. TEAEs led to death in 3.8% vs 4.5% of patients, respectively, including 1 treatment-related AE leading to death in each arm (0.2%) due to multiple organ dysfunction syndrome with pembrolizumab and hemophagocytic lymphohistiocytosis with placebo. The most common any-grade TEAEs in these respective arms were nausea (54.9% vs 52.3%), anemia (54.4% vs 55.2%), and neutropenia (53.1% vs 50.6%).

Any-grade immune-mediated AEs and infusion reactions occurred in 28.9% vs 9.4% of patients, respectively, with grade 3 to 5 AEs of this category reported in 8.9% vs 1.8% of patients, respectively; hypothyroidism was the most common (10.4% vs 1.3%). None of these AEs were fatal in the pembrolizumab arm, and 1 (0.2%) was fatal in the placebo arm. During the surgery phase (pembrolizumab arm, n = 412; placebo arm, n = 396), any-grade TEAEs occurred in 80.3% vs 79.3% of patients, respectively, including grade 3 to 5 AEs of this category in 42.7% vs 46.5% of respective patients.

What do the KEYNOTE-866 data mean for perioperative MIBC management?

KEYNOTE-866 is the first placebo-controlled study to evaluate PD-1/PD-L1 immunotherapy given before and after surgery alongside neoadjuvant cisplatin plus gemcitabine and radical cystectomy with pelvic lymph node dissection in patients with MIBC. This treatment setting currently includes perioperative durvalumab (Imfinzi) plus neoadjuvant cisplatin-based chemotherapy, which was FDA approved in 2025, perioperative enfortumab vedotin-ejfv (Padcev) plus pembrolizumab, which was FDA approved in 2026.^2,3

The KEYNOTE-866 investigators concluded that the data do not support adding perioperative pembrolizumab to neoadjuvant cisplatin-based chemotherapy for these patients, whereas perioperative enfortumab vedotin plus pembrolizumab is now an established standard of care in this setting.¹

Disclosures: Bedke reported receiving institutional research funding from Astellas Pharma, Daiichi Sankyo Europe GmbH, Johnson & Johnson, Merck Sharp & Dohme LLC (a subsidiary of Merck & Co., Inc.), Pfizer, Roche, and Seagen; performing consulting or advisory roles for Apogepha, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo Europe GmbH, Eisai, Ipsen, Janssen, Merck Sharp & Dohme, Pfizer, and Roche; serving on speakers’ bureaus for Apogepha, Astellas Pharma, Bayer, Bristol-Myers Squibb, Ipsen, Merck Sharp & Dohme, and Pfizer; receiving travel, accommodations, or expenses to his institution from Ipsen and Johnson & Johnson; and receiving study funding, medical writing, and editorial support from Merck Sharp & Dohme.

References

1. Bedke J, Arkosy P, Nishiyama H, et al. Perioperative pembrolizumab or placebo plus neoadjuvant cisplatin and gemcitabine in participants with muscle-invasive bladder cancer: the double-blind, phase 3 KEYNOTE-866 study. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract 4735O.
2. FDA approves durvalumab for muscle invasive bladder cancer. FDA. March 28, 2025. Accessed October 23, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-muscle-invasive-bladder-cancer
3. FDA approves pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph each with enfortumab vedotin-ejfv for muscle invasive bladder cancer. FDA. July 10, 2026. Accessed October 23, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-or-pembrolizumab-and-berahyaluronidase-alfa-pmph-each-enfortumab-vedotin