Background High-grade non-muscle-invasive-bladder-cancer (NMIBC) has high recurrence rates and potential resistance to intravesical therapies. Anti-PD-L1 immunotherapy with pembrolizumab was approved in January 2020 for treatment of patients with high-risk, BCG refractory NMIBC with carcinoma in situ (CIS) with or without papillary tumors who received adequate BCG therapy and were ineligible for or opted out of radical cystectomy. In this study we report on our single institutional experience using pembrolizumab in BCG refractory patients.

Methods Records of patients with NMIBC treated by pembrolizumab from 01/2020–01/2023 at a single institution were retrospectively reviewed for key demographic and clinical information. Kaplan-Meier curves were used to calculate progression free (PFS) and treatment specific survival (TSS), and combined positivity score (CPS) of PD-L1 on immunochemistry was assessed.

Results Out of 250 screened records of NMIBC in this time period, 18 records with median age of 74.1 (IQR=67.8 – 81.4), male to female ratio of 3.5:1, and a median follow-up of 17.5 months (IQR= 8.1 – 22.5) met the inclusion criteria. All patients had CIS and were treated with intravesical chemotherapy after they became BCG refractory. At start of pembrolizumab, 1/18 (5.6%) was cTa, 6/18 (33.3%) had CIS, and 11/18 (61.1%) had cT1. After an average of 8.9 cycles (SD=6.3), 72.2% of patients (13/18) stopped treatment. Only five patients (38.5%) are still undergoing treatment with an average of 12.6 cycles (SD=10.4 cycles). Only one patient out of thirteen who stopped treatment had a sustained complete response at 19 cycles. Reasons for discontinuation included: Grade 2 or higher toxicity in 7/13 (53.8%), disease progression in 4/13 (30.8%), , and 1/13 stopped due to disease recurrence. Recurrence-free survival rates at 3-, 6-, and 12-months were 16.7%, 11.1%, and 5.6%, respectively. 6- and 12-month PFS rates were 94% and 77.7%, respectively. Kaplan-Meier methods showed a PFS of 19.5 months (SD=2.4) and a TSS of 26.5months (SD=2.9). Four patients ultimately required radical cystectomy with pathologies showing pTa (n=1), pTis (n=1), pT1 (n=1), and pT4 (n=1). PD-L1 positivity, defined as CPS > 10, was noted for only one patient.

Conclusions Our institutional experience using pembrolizumab in the treatment of high risk BCG refractory NMIBC suggests high toxicity leading to early withdrawal from treatment. Similarly, our experience did not confirm previously reported high response rates beyond one year. Additional research is warranted to better identify patients who are likely to benefit from this agent.

Ethics Approval This study was approved by institutional review board of the The Miriam Hospital and Lifespan Hospital System in Providence, RI. Study ID: 1047794. All required consents were acquired prior to data collection.