This is a single arm Phase I/II trial evaluating the safety of the combination of pembrolizumab, gemcitabine, and radiation therapy with an initial safety lead-in cohort of 6 patients. This will be followed by a phase II cohort if toxicity is only seen in 1 or zero patients consisting of 48 patients for efficacy evaluation. The results were presented at ASCO 2021. The chemoradiation consisted of whole bladder radiation therapy (52 Gy in 20 fractions over 4 weeks) with twice weekly gemcitabine at 27 mg/m2 for 4 weeks given concurrent with chemoradiation. Pembrolizumab was given as a single lead-in dose (200 mg). Treatment was followed by maximal TURBT 2- 3 weeks afterwards and pembrolizumab 200 mg intravenously was administered every 3 weeks for a total of 3 doses starting day 1 of radiation therapy.
Chemoradiation is an established treatment for MIBC and this trial is evaluating whether the addition of immunotherapy, specifically, pembrolizumab can improve upon this response. Furthermore, the trial uses an unique endpoint of intact bladder-free survival which minimizes the impact of urinary symptoms and/or recurrence of NMIBC.
The primary endpoint was two-year bladder intact event-free survival (BI-EFS) which is a novel endpoint only measured from the time of treatment initiation to the following events: recurrent/residual MIBC post-chemoradiotherapy, nodal or distant metastatic disease, radical cystectomy, or death due to any cause. Secondary endpoints included safety, complete response rate, overall survival and metastasis-free survival. Complete response rate was defined as the absence of any viable residual cancer.
The initial results are exciting given the complete response rate and high bladder-intact free survival rate, albeit with short follow-up. Of course with further follow-up, these numbers can worsen over time but the regimen appears to be safe and outcomes are initially quite reasonable. Another challenge will lie in knowing the ideal radio-sensitizing chemotherapy agent to use along with the best radiation treatment protocol. To that end, the ongoing randomized clinical trial evaluating the use of pembrolizumab with investigator choice of chemotherapy and radiation therapy (NCT 04241185) is actively accruing and will answer more questions.
Updated results were presented at ASCO 2021. Six patients were enrolled into a safety cohort followed by 48 patients enrolled into an efficacy cohort. A total of 42 patients (85%) completed all protocol therapy and were included in the analysis. The majority of patients had T2N0 disease (70%) and 75% refused cystectomy. At 12 weeks post-radiotherapy, complete response in the entire cohort was 59%. At a median follow-up of 14.6 months, bladder-intact free survival was 88% at 12 months in the efficacy cohort. Nine patients (19%) were treated with steroids for immune-related adverse events. One patient died of a grade 4 colonic perforation.