ASCO 2021: Pembrolizumab in Combination With Gemcitabine and Concurrent Hypofractionated Radiation Therapy As Bladder Sparing Treatment for Muscle-Invasive Bladder Cancer: A Multicenter Phase 2 Trial

( Curative intent therapy in muscle-invasive bladder cancer includes neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy, whereas trimodality bladder preservation therapy (maximal TURBT followed by concurrent chemoradiation) is a standard treatment option for clinically localized muscle-invasive bladder cancer, also with curative intent. While no randomized trials exist, propensity risk-matched cohort analyses suggest similar DSS and OS outcomes between bladder preservation and radical cystectomy.1 The optimal chemoradiation regimen has not yet been defined, although hypofractionated radiotherapy regimens combined with gemcitabine have demonstrated promising efficacy and safety in phase I/II studies.   Pembrolizumab has shown activity in muscle-invasive bladder cancer in the neoadjuvant setting and may combine well with trimodality bladder preservation therapy to improve outcomes. At the 2021 ASCO annual meeting, Dr. Arjun Balar and colleagues presented results of their phase 2 trial evaluating the safety and efficacy of pembrolizumab added to trimodality bladder preservation therapy in muscle-invasive bladder cancer.

This multicenter phase 2 trial included patients with cT2 – T4aN0M0 muscle-invasive bladder cancer who declined or were ineligible for cystectomy, ECOG performance status 0/1, eGFR > 30 cc/min, and no contraindications to pelvic radiotherapy or pembrolizumab. No perioperative chemotherapy for muscle-invasive bladder cancer was permitted. Patients received pembrolizumab 200 mg x 1 followed 2-3 weeks by maximal TURBT and then whole bladder radiotherapy (52 Gy/20 fractions; IMRT preferred) with twice-weekly gemcitabine 27 mg/m2 and pembrolizumab Q3 weeks x 3 treatments. 12 weeks after radiotherapy, CT/MR abdomen/pelvis, TUR of the tumor bed and cytology were performed to document response. Up to six patients were enrolled to a safety cohort followed by 48 patients in the efficacy cohort. The trial schema is as follows:


The primary endpoint is 2-year bladder-intact disease-free survival, defined as first of muscle-invasive bladder cancer or regional nodal recurrence, distant metastases, or death, assessed by serial cystoscopy/cytology and CT/MRI. The efficacy cohort had 85% power to detect a 20% absolute improvement in 2-yr bladder-intact disease-free survival rate over 60% historical rate.2 Key secondary endpoints were safety, 12 weeks complete response rate, metastases-free survival and overall survival. Tumor tissue was collected at study entry, maximal TURBT and post-treatment TUR of tumor bed with serial PBMCs for correlative analyses:


From May 2016 to October 2020, 54 patients (six in the safety cohort and 48 in the efficacy cohort) enrolled at 5 centers. The median age was 67 (range: 65-89) years for the safety cohort and 74 (range: 51-97) years for the efficacy cohort. The clinical stage was 70% cT2, 26% cT3, and 4% cT4. Overall, there were 39 (72%) patients that declined cystectomy. All six patients in the safety cohort and 42/48 (88%) patients in the efficacy cohort completed all study therapy. 1/48 (2%), 2/48 (4%), and 4/48 (8%) patients discontinued radiotherapy/gemcitabine, gemcitabine or pembrolizumab, respectively, most often due to toxicity.

As of January 2021, with a median follow-up of 40.9 months (range: 38.6-50.8) in the safety cohort and 11.7 months (range: 0.6 – 32.2) in the efficacy cohort, there were no recurrences in the safety cohort, and 12/48 efficacy cohort patients had any recurrence (6 NMIBC, 0 muscle-invasive bladder cancer, 2 regional and 4 distant). The estimated 1 year bladder-intact disease-free survival rate in the efficacy cohort (n=48) is 88% (95% CI: 0.73-0.95):


The estimated 1 year bladder-intact disease-free survival rate in the overall cohort (n=54) is 89% (95% CI: 0.76-0.95):


12 weeks complete response rate was 100% in safety cohort and 83% for the efficacy cohort (1 partial response, 3 no-response, 1 progression, 11 NE; two patients still on active study). The key secondary endpoint of 1-year metastasis-free survival rate in all patients was 85% (95% CI 0.71-0.93):


In the efficacy cohort, 35% of patients had a grade ≥3 treatment-emergent adverse events (grade 3 events included UTI 8%, diarrhea 4%, colitis 4%, bladder pain/obstruction 4%, neutropenia 2%, thrombocytopenia 2%). Notable pembrolizumab grade ≥3 treatment-emergent adverse events included 3 patients (6%) grade 3 GI toxicity and one patient grade 4 colonic perforation. One patient died due to fungemia, unrelated to study therapy.

Dr. Arjun Balar concluded his presentation of this phase 2 trial with the following take-home messages:

  • Trimodality bladder preservation therapy is an effective non-surgical option for patients with muscle-invasive bladder cancer with curative intent
  • Pembrolizumab added to hypofractionated radiotherapy and twice weekly gemcitabine was well-tolerated with promising efficacy in this early analysis: 88% rate of bladder intact disease-free survival at 1 year in the efficacy cohort is noteworthy, but longer follow-up is needed
  • Pembrolizumab-related toxicity was consistent with prior monotherapy trials, including immune-related toxicities requiring steroids, however the majority were manageable
  • Correlative studies on serially collected tumor tissue and blood are underway to interrogate the local and systemic impact of pembrolizumab added to chemoradiation on anti-tumor immunity
  • Ongoing randomized studies including SWOG 1806 and KEYNOTE 992 will better define the role for immunotherapy added to trimodality bladder preservation

Clinical trial information: NCT02621151


Presented by: Arjun V. Balar, MD, Director of the Genitourinary Medical Oncology Program at NYU Langone’s Perlmutter Cancer Center, New York, NY

Co-Authors: Matthew I. Milowsky, Peter H. O'Donnell, Ajjai Shivaram Alva, Marisa Kollmeier, Tracy L Rose, Sean Pitroda, Samuel D. Kaffenberger, Jonathan E. Rosenberg, Kaitlyn Francese, Tsivia Hochman, Judith D Goldberg, Sarah Griglun, Dayna Leis, Gary D. Steinberg, James Wysock, Peter B. Schiff, Nicholas J. Sanfilippo, Samir Taneja, William C. Huang; University of North Carolina Department of Medicine, Division of Hematology/Oncology, Chapel Hill, NC; University of Chicago Comprehensive Cancer Center, Chicago, IL; University of Michigan Rogel Cancer Center, Ann Arbor, MI; Memorial Sloan Kettering Cancer Center, New York, NY; The University of North Carolina at Chapel Hill (UNC-CH) School of Medicine and UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC; University of Chicago, Chicago, IL; University of Michigan, Ann Arbor, MI; Genitourinary Medical Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY; New York University School of Medicine, New York, NY; Department of Surgery, The University of Chicago Medicine, Chicago, IL; Department of Urology, New York University School of Medicine, New York, NY; Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY; Weill Cornell Medicine, New York, NY; NYU Langone Health, New York, NY; NYU Langone Medical Center, New York, NY


  1. Kulkarni GS, Hermanns T, Wei Y, et al. Propensity score analysis of radical cystectomy versus bladder-sparing trimodal therapy in the setting of a multidisciplinary bladder cancer clinic. J Clin Oncol 2017;35(20):2299-2305.
  2. Mak RH, Hunt D, Shipley WU, et al. Long-term outcomes in patients with muscle-invasive bladder cancer after selected bladder-preserving combined-modality therapy: A pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-3909.