Bladder-sparing, trimodal pembrolizumab-based regimen shows promise in MIBC


An early analysis of pembrolizumab (Keytruda) in combination with gemcitabine and concurrent hypofractionated radiotherapy (RT) for muscle-invasive bladder cancer (MIBC) found that the protocol demonstrated safety and efficacy.1

Findings from the phase 2 trial (NCT02621151) were reported at the 2021 ASCO Annual Meeting1 by lead author Arjun V. Balar, MD, an associate professor of medicine at the NYU Grossman School of Medicine and genitourinary medical oncology program director at NYU Langone’s Perlmutter Cancer Center, New York.

The trial included patients with cT2 to T4aN0M0 MIBC who declined or who were ineligible for cystectomy. Patients had an ECOG performance status of 0 or 1, estimated glomerular filtration rate of more than 30 cc/min, and no contraindications to pelvic radiotherapy or pembrolizumab. No perioperative chemotherapy was allowed.

Patients received a single dose of pembrolizumab at 200 mg followed in 2 to 3 weeks by maximal transurethral resection of the bladder tumor and then whole-bladder RT with twice weekly gemcitabine at 27 mg/m2 and pembrolizumab every 3 weeks for 3 doses. Six patients were enrolled in a safety cohort, and 48 patients were enrolled in an efficacy cohort.

The median age of the entire population was 74 years (range, 51-97). Thirty-nine patients (72%) were male, and the majority of patients (n = 38; 70%) had T2N0 disease at baseline, with T3N0 and T4N0 disease present in 14 (26%) and 2 (4%) men, respectively. Regarding histology, 34 patients (63%) had conventional urothelial carcinoma, 20 (37%) had divergent differentiation, and 14 (26%) had carcinoma in situ. Hydronephrosis was present in 6 patients (11%). Fifteen patients (28%) were not candidates for surgery, whereas 39 patients (72%) declined radical cystectomy.

The primary end point of the study was 2-year bladder-intact disease-free survival (BIDFS), which was defined as muscle-invasive recurrence, regional or distant metastases, need for cystectomy, or death. The key secondary end points were safety, 12 weeks’ complete response rate, metastases-free survival, and overall survival.

A total of 42 patients (85%) completed all protocol therapy in the study. Twelve patients (25%) had dose reductions of gemcitabine. One patient (2%) discontinued RT/gemcitabine, 3 (6%) discontinued gemcitabine only, and 4 (8%) discontinued pembrolizumab.

Twelve-week complete response was 100% in the safety cohort and 77% in the efficacy cohort. The investigators reported a 1-year BIDFS rate in the efficacy cohort of 88%, “which is quite encouraging, but obviously this is at a median follow-up of 14.6 months for the population here,” Balar said. The rate increased slightly to 89% when the safety cohort was added. Metastases-free survival was 85% at 1-year follow-up for the entire cohort.

In the efficacy cohort, the majority of treatment-related toxicities were grade 1 and 2, with fatigue, nausea, diarrhea, urinary urgency, maculopapular rash, decreased platelets, and anorexia observed in 20% or more of the efficacy cohort. Grade 3 and 4 treatment-related toxicities included diarrhea, decreased lymphocyte count, colitis, fatigue, anemia, urinary tract pain, hypokalemia, hyponatremia, urinary tract infection, neutropenia, febrile neutropenia, protein-losing enteropathy, immune-related polyneuropathy, and colonic perforation. Balar noted that 1 patient died of fungemia that was not related to study treatment.

Regarding toxicities suspected to be related to pembrolizumab, grade 1 and 2 fatigue, maculopapular rash, alanine aminotransferase, and pruritis were seen in 10% or more of the efficacy cohort. Grade 3 toxicities suspected to be related to pembrolizumab included immune-related protein-losing enteropathy, immune-related polyneuropathy, neutropenia, and urinary tract infection. One grade 4 case of colonic perforation was observed. In addition, 9 patients (19%) were treated with systemic corticosteroids for the management of an immune-related adverse event.

In his concluding remarks, Balar said, “Trimodality bladder preservation therapy is an effective nonsurgical option for patients with muscle-invasive bladder cancer and with curative intent.”

Balar also noted that correlative studies on serially collected tumor tissue and blood are underway; these studies will evaluate the local and systemic impact of pembrolizumab added to chemoradiation on antitumor immunity.

“What we need are randomized studies…and the ongoing studies SWOG 1806 [NCT03775265] and KEYNOTE-992 [NCT04241185] will better define the role of immunotherapy added to bladder preservation therapy,” Balar said.


1. Balar AV, Milowsky MI, O’Donnell PH, et al. Pembrolizumab (pembro) in combination with gemcitabine (Gem) and concurrent hypofractionated radiation therapy (RT) as bladder sparing treatment for muscle-invasive urothelial cancer of the bladder (MIBC): A multicenter phase 2 trial. J Clin Oncol 39, 2021 (suppl 15; abstr 4504).

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