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 | |||||||||
| Patient | Age | Sex | 3 month | 6 month | 9 month | 12 month | 18 month | Terminated Due to | Side Effects |
| 1 | 86 | M | Persistent | Did not reach | Grade 2 AE | Myalgias and arthropathy | |||
| 2 | 77 | M | Persistent | Persistent | Did not reach | Grade 2 AE | Hypothyroidism,Adrenal Insufficiency | ||
| 3 | 69 | M | Persistent | Persistent | Persistent | Persistent | Did not reach | Grade 3 AE | Pneumonia, Adrenal insufficiency |
| 4 | 73 | F | Progress | Progression | Progression | Recurrent infections, NOS | |||
| 5 | 64 | M | Respond | Recurrence | Did not reach | Recurrence | Fatigue | ||
| 6 | 66 | M | Respond | Respond | Did not reach | Ongoing | None reported | ||
| 7 | 85 | F | Persistent | Persistent | Progress | Progression | Progression | None reported | |
| 8 | 75 | M | Did not reach | Grade 4 AE | Sepsis | ||||
| 9 | 75 | M | Did not reach | Ongoing | Fatigue | ||||
| 10 | 82 | M | Persistent | Persistent | Progression | Progression | Progression | None reported | |
| 11 | 66 | M | Respond | Respond | Respond | Respond | Respond | Complete Response | Rash |
| 12 | 79 | F | Persistent | Persistent | Persistent | Persistent | Did not reach | Ongoing | None reported |
| 13 | 61 | M | Persistent | Persistent | Persistent | Respond | Respond | Ongoing | None reported |
| 14 | 74 | M | Persistent | Did not reach | Grade 2 AE | Rash | |||
| 15 | 72 | M | Did not reach | Grade 2 AE | Rash, Infections, Colitis, Myocarditis, Atrial Fibrillation, Heart Failure | ||||
| 16 | 81 | M | Did not reach | Grade 2 AE | Autoimmune Hepatitis | ||||
| 17 | 68 | M | Did not reach | Ongoing | Rash | ||||
| 18 | 90 | F | Persistent | Persistent | Persistent | Progression | Progression | Pneumonitis | |
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