(UroToday.com) Curative intent therapy in muscle invasive bladder cancer (MIBC) can be accomplished by either cisplatin-based chemotherapy followed by radical cystectomy, or trimodality bladder preservation therapy via maximal transurethral resection of the bladder tumor (TURBT) followed by chemoradiation. No randomized trials have compared these two options, though propensity risk-matched cohort analyses suggest similar outcomes. Furthermore, the optimal chemoradiation regimen has not been defined, and hypofractionated radiotherapy combined with gemcitabine has shown promising efficacy and safety. Given there is potential synergy between immune checkpoint blockade and chemotherapy, Dr. Balar and colleagues designed a multicenter phase 2 clinical trial to assess the safety and efficacy of pembrolizumab added to standard trimodality bladder preservation therapy using gemcitabine and hypofractionated radiotherapy. The schema for this trial is shown below.
The biomarker sample collection schema is shown below. Tissue was collected at baseline, at the time of maximal TURBT, and at the time of repeat TUR after chemoradiation. Blood was collected at multiple timepoints for analysis of plasma. 
The radiation therapy and chemotherapy regimens, as well as allowed chemotherapy dose levels are indicated below. 
Per FDA recommendations, a 6 patient phase 1 safety lead in was designed, followed by a phase 2 efficacy cohort of 48 patients. The primary endpoint was 2-year bladder-intact disease-free survival (BIDFS). The study was designed with 85% power and two-sided alpha of 0.05% to detect a 20% absolute improvement in BIDFS to 80%.
Baseline characteristics including PD-L1 expression of the enrolled cohort is shown below. The majority of patients had cT2 disease. 75% of patients enrolled because they did not want to undergo radical cystectomy.
Response rates were assessed by TUR/biopsy of the tumor bed, urine cytology and CT as well as MRI of the abdomen and pelvis. At 12 weeks post radiotherapy, the complete response rate in the overall cohort was 59%. At a median follow-up of 14.6 months, the 1-year estimated BIDFS rate was 88% in the efficacy cohort (48 patients). 
With regards to toxicity, one patient developed a grade 4 colonic perforation that was treated but unfortunately the patient developed sepsis and passed away.
Dr. Balar concluded that trimodality bladder preservation therapy with pembrolizumab, gemcitabine and hypofractionated XRT is safe, well-tolerated, and has demonstrated promising efficacy in early analysis with an 88% bladder-intact free survival at 1 year. Correlative studies are ongoing, and on-going randomized studies such as S1806 (NCT03775265) and KEYNOTE-992 (NCT04241185) will further define the role for immunotherapy added to bladder preservation treatment with trimodal therapy.
Presented by: Arjun V. Balar, MD, NYU Langone Health
Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021