Introduction:

The typical treatment for high-risk non-muscle-invasive bladder cancer (HR-NMIBC) is transurethral resection of the bladder tumor with subsequent intravesical instillations of Bacillus Calmette-Guerin (BCG) immunotherapy. Although initial responses to BCG are high, up to 50% of patients have recurrence or become BCG-unresponsive. Pembrolizumab was approved by the US Food and Drug Administration in January 2020 based on the results of the KEYNOTE-057 study for the treatment of patients with BCG-unresponsive, NMIBC with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. Little is known about real-world utilization of pembrolizumab in patients with HR-NMIBC. The present study aims to describe patient demographic and clinical characteristics, real-world time on treatment (rwToT), real-world time to next treatment (rwTtNT), real-world treatment free interval (rwTFI), and on-treatment rates in HR-NMIBC patients initiating pembrolizumab within the Optum Research Database.

Methods:

Eligible patients for this retrospective cohort study included those aged ≥18 years with bladder cancer diagnosis codes who initiated pembrolizumab between January 1, 2020 and September 30, 2021 (index date defined as the first pembrolizumab administration), had continuous enrollment during the 6-month pre-index period, and prior BCG exposure. Adequate BCG therapy was defined as ≥5 induction instillations and a total of ≥7 instillations within 9-months of the first instillation. Patients were followed until the end of database availability (December 31, 2021), end of enrollment or death, whichever occurred first. Patients with evidence of radical cystectomy, muscle-invasive or metastatic-disease pre-index were excluded. Primary outcomes included pembrolizumab rwToT, rwTtNT, rwTFI, and on-treatment rates at 3, 6, 9, and 12-months. Secondary outcomes were demographics, clinical characteristics, and treatment patterns prior to and after pembrolizumab initiation. Kaplan-Meier estimations were used for the time to event analysis. Descriptive analyses were used to evaluate secondary outcomes.

Results:

We identified 107 patients who initiated pembrolizumab for HR-NMIBC (median age 80 years, 96.3% ≥65 years; 75.7% male; 83.2% white; 92.5% insured primarily through Medicare; 49.5% had 5+ Quan-Charleston comorbidities) with a median follow-up of 10.9 months. Prior to initiating pembrolizumab, the median number of BCG instillations was 9 [IQR 6-14] and 44.1% demonstrated adequate BCG therapy. Median time from last BCG until the index date was 4.8 months [IQR 3.3-9.2]. Median pembrolizumab rwToT was 6.5 months (95% CI 4.9-8.5). Median rwTtNT was 18.7 months (95% CI 14.8–NA), and median rwTFI was 11 months (95% CI 4.3–NA). Pembrolizumab on-treatment rates were 76%, 50%, 37%, and 30% at 3, 6, 9, 12 months, respectively. During follow-up, 31% (33/107) patients received subsequent therapies after pembrolizumab initiation. The most frequent subsequent therapies after pembrolizumab were gemcitabine-based regimens (33%; 11/33), radical cystectomy (27%; 9/33), and radiation (18%; 6/33).

Conclusion:

Compared to those enrolled in KEYNOTE-057, patients in the present real-world study were older (KEYNOTE-057: median age 73 [IQR 63-79]; 70% ≥65 years). The median pembrolizumab rwToT reported here was similar in duration to the clinical trial setting (6.5 versus 4.2months). Almost half (44%) of the present cohort achieved an adequate BCG therapy, thereby demonstrating modest heterogeneity of initial BCG treatments prior to beginning pembrolizumab. In KEYNOTE-057, 41% of patients demonstrated complete response at 3-months and continued pembrolizumab therapy. Although response rates and reasons for discontinuation are unavailable in claims data, 76% of real-world patients remained on pembrolizumab at month 3 and 50% at month 6. Longer follow-up may be required to contextualize real-world treatment patterns by further allowing for natural disease progression and use of additional treatments. Future studies are warranted to evaluate the clinical effectiveness of pembrolizumab in the real-world setting including complete response, durability, and progression rates.

Funding: This study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.