Pembrolizumab plus chemoradiation shows feasibility in muscle-invasive bladder cancer

The addition of pembrolizumab (Keytruda) to trimodality therapy (TMT) was feasible and demonstrated encouraging activity in patients with muscle-invasive bladder cancer (MIBC), according to results from a multicenter phase 2 trial (NCT02621151) published in European Urology.¹

The regimen achieved a 2-year bladder-intact disease-free survival (BIDFS) rate of 60%, alongside favorable metastasis-free survival (MFS) and overall survival (OS), supporting the feasibility of integrating immunotherapy into bladder-preserving regimens.

“This phase 2 trial provides important proof-of-concept that integrating PD-1 blockade with gemcitabine-based chemoradiation is feasible and yields encouraging signals of antitumor activity, particularly for systemic control, with 2-year metastasis-free survival of 81% and overall survival of 83%,” said lead author Minas P. Economides, MD, of NYU Langone Health, in correspondence with Urology Times^®.

How was this trial designed?

The open-label, single-arm, multicenter phase 2 study evaluated pembrolizumab in combination with gemcitabine-based chemoradiation following maximal transurethral resection of bladder tumor (TURBT) in patients with localized MIBC (clinical stage T2–T4a, N0, M0). To be eligible for enrollment, patients needed to have an ECOG Performance Status of 1 or lower and no prior exposure to PD-1/PD-L1 inhibitors. Patients were either ineligible for or declined radical cystectomy.

The treatment protocol included a single dose of pembrolizumab (200 mg IV) prior to maximal TURBT. After a 3- to 5-week healing interval, patients received concurrent hypofractionated radiation (52 Gy over 4 weeks), low-dose gemcitabine (27 mg/m² IV) administered twice weekly, and pembrolizumab every 3 weeks for 3 doses. The primary end point was 2-year BIDFS, with secondary end points including MFS, OS, complete response (CR) rate, and safety.

What was the efficacy and safety of pembrolizumab plus chemoradiation?

Among 54 enrolled patients (48 evaluable for efficacy), 67% had clinical stage T2 disease.

At 2 years, BIDFS was 60% (95% CI, 45 to 73). The observed BIDFS did not meet the study’s predefined target of a 20% improvement over historical controls. However, the investigators observed relatively high MFS and OS rates. MFS and OS were 81% (95% CI, 66 to 92) and 83% (95% CI, 69 to 91), respectively. The 12-week CR rate was 56% per protocol, which increased to 77% in the intention-to-treat population.

“While the 2-year bladder-intact disease-free survival of 60% did not meet the ambitious 80% target, the high rates of metastasis-free and overall survival highlight the potential of addition of immunotherapy to improve distant disease control in muscle-invasive bladder cancer,” Economides shared with Urology Times.

Treatment-related adverse events (AEs) of any grade occurred in 92% of patients, with grade 3 or higher treatment-related AEs reported in 25% of patients. The most common AEs included diarrhea, cytopenias, and cystitis.

Immune-related AEs included colitis, neutropenia, and 1 treatment-related death due to colonic perforation. Notably, 19% of patients discontinued at least 1 component of therapy due to toxicity, and 6 patients ultimately underwent cystectomy, including 5 for treatment-related toxicity despite achieving pathologic CR. The median time to cystectomy was 19 months.

The authors also noted concerns about the increased incidence of late cystitis, possibly reflecting enhanced radiation-related inflammation in the presence of immune checkpoint blockade.

Economides added, “The high rate of salvage cystectomies due to persistent toxicity (despite pathologic complete response in most cases) raises concerns of augmented local inflammation with the combination treatment.”

The authors acknowledged several limitations of the study, including its single-arm design, modest sample size, and potential overestimation of MFS due to imaging constraints.

These considered, they suggest that the findings support the feasibility of integrating immune checkpoint inhibition with gemcitabine-based chemoradiation. They also pointed to ongoing randomized phase 3 trials that are expected to clarify whether immunotherapy can meaningfully improve outcomes when integrated into bladder-preserving regimens.

“Results of KEYNOTE-992 [NCT04241185] and S1806 [NCT03775265] will be key to understand the role of [immunotherapy] in this setting,” Economides concluded.

REFERENCE

1. Economides MP, O’Donnell PH, Alva AS, et al. Pembrolizumab in combination with gemcitabine and concurrent hypofractionated radiation therapy as bladder-sparing treatment for muscle-invasive urothelial cancer of the bladder: A multicenter phase 2 trial. Eur Urol. 2026 Apr 6:S0302-2838(26)02034-8. doi:10.1016/j.eururo.2026.02.016