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Poor Recurrence-Free Survival and High Toxicity in Patients Receiving Pembrolizumab for BCG Refractory Non-Muscle Invasive Bladder Cancer
Borivoj Golijanin, BS1, Vikas Bhatt, MD1, Ali Amin, MD2, Andre De Souza, MD3, Galina Lagos, MD3, Anthony E. Mega, MD3, Dragan Golijanin, MD1.
1Minimally Invasive Urology Institute at the Miriam Hospital and Warren Alpert Medical School of Brown University, Providence, RI, USA, 2Department of Pathology and Laboratory Medicine at the Miriam Hospital and Warren Alpert Medical School of Brown University, Providence, RI, USA, 3Lifespan Cancer Institute at the Miriam Hospital and Warren Alpert Medical School of Brown University, Providence, RI, USA.

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. Early discussion on radical surgery remains an important part of our guidelines for treatment of BCG refractory NMIBC.
Table 1: Breakdown of patients receiving pembrolizumab for high-risk NMIBC. Follow-up disease monitoring and side effects are listed. M=male, F=female, AE=Adverse Event.

Follow-Up Cystoscopy and Cytology
PatientAgeSex3 month6 month9 month12 month18 monthTerminated Due toSide Effects
186MPersistentDid not reachGrade 2 AEMyalgias and arthropathy
277MPersistentPersistentDid not reachGrade 2 AEHypothyroidism,Adrenal Insufficiency
369MPersistentPersistentPersistentPersistentDid not reachGrade 3 AEPneumonia, Adrenal insufficiency
473FProgressProgressionProgressionRecurrent infections, NOS
564MRespondRecurrenceDid not reachRecurrenceFatigue
666MRespondRespondDid not reachOngoingNone reported
785FPersistentPersistentProgressProgressionProgressionNone reported
875MDid not reachGrade 4 AESepsis
975MDid not reachOngoingFatigue
1082MPersistentPersistentProgressionProgressionProgressionNone reported
1166MRespondRespondRespondRespondRespondComplete ResponseRash
1279FPersistentPersistentPersistentPersistentDid not reachOngoingNone reported
1361MPersistentPersistentPersistentRespondRespondOngoingNone reported
1474MPersistentDid not reachGrade 2 AERash
1572MDid not reachGrade 2 AERash, Infections, Colitis, Myocarditis, Atrial Fibrillation, Heart Failure
1681MDid not reachGrade 2 AEAutoimmune Hepatitis
1768MDid not reachOngoingRash
1890FPersistentPersistentPersistentProgressionProgressionPneumonitis


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