Pembrolizumab Could Delay Radical Cystectomy in BCG-unresponsive, High-risk NMIBC

Treatment with pembrolizumab (Keytruda) may potentially delay the need for additional therapy or radical cystectomy in patients with Bacillus Calmette-Guérin (BCG)–unresponsive, high-risk non–muscle invasive bladder cancer (NMIBC), according to Eric A. Singer, MD.

Findings from cohort B of the phase 2 KEYNOTE-057 trial (NCT02625961) presented at the 2023 American Urological Association (AUA) Annual Meeting showed that at a median follow-up of 45.4 months (range, 14.9-77.1), patients with BCG-unresponsive high-risk NMIBC with high-grade Ta or any-grade T1 papillary tumors without carcinoma in situ (CIS; n = 132) experienced a median disease-free survival (DFS) of 7.7 months (95% CI, 5.5-13.6).

Additionally, the 12-month DFS rate was 43.5% (95% CI, 34.9%-51.9%). The 24- and 36-month DFS rates were both 34.9% (95% CI, 26.4%-43.4%).

Furthermore, 53% of patients received subsequent treatment. Twenty-seven percent of patients underwent radical cystectomy, and other therapies or additional procedures included local procedure (26%), intravesical therapy (16%), systemic therapy (8%), and unknown (2%).

“Systemic therapy with the immune checkpoint inhibitor pembrolizumab is a feasible and reasonable option for many patients who are looking to avoid radical cystectomy for their recurrent, high-grade NMIBC,” Singer explained.

Prior results from cohort A of KEYNOTE-057 supported the January 2020 FDA approval of pembrolizumab for the treatment of patients with BCG-unresponsive, high-risk, NMIBC with CIS with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.² Findings from cohort A demonstrated that pembrolizumab elicited a complete response rate of 41% (95% CI, 31%-51%).³

In an interview with OncLive^®, Singer discussed the results from cohort B of KEYNOTE-057 and explained why this approach could be beneficial for patients with BCG-unresponsive, high-risk, papillary-only NMIBC who hope to avoid radical cystectomy. Singer is a professor of Urology and Bioethics, and director of the Division of Urologic Oncology at The Ohio State University Wexner Medical Center and The Ohio State University Comprehensive Cancer Center–James in Columbus, Ohio.

OncLive^®: What unmet needs did KEYNOTE-057 aim to address for patients with BCG-unresponsive, high-risk NMIBC?

Singer: The standard of care for patients with high-grade NMIBC is transurethral resection of bladder tumor followed by an induction course of BCG. For patients who have recurrence after BCG, limited options are available. One of those options includes radical cystectomy, and many patients are not eager to lose their native bladders.

The idea with KEYNOTE-057 was to use pembrolizumab systemically, so not just going into the bladder with intravesical therapy, but giving [pembrolizumab] intravenously to see if patients who had been previously treated with 2 induction courses of BCG—a heavily pretreated population—would [experience] a benefit and a good disease-free interval. We had previously published and presented on cohort A of KEYNOTE-057. That was the group that included CIS.

What were the key efficacy findings from cohort B presented at the 2023 AUA Annual Meeting?

Cohort B [consisted of patients with] papillary-only tumors, so no CIS. We met our primary objective [with a 12-month] DFS [rate] of [43.5%]. DFS [rates] remained stable at [34.9%] at both year 2 and year 3.

This is another option for patients who have high-grade NMIBC who have received BCG and have had recurrences. Many patients in this study were able to avoid or considerably delay the need for radical cystectomy.

Although they are different histological subtypes, could you elaborate on how the outcomes compared between cohort A and cohort B?

[The outcomes] were very similar. [Cohort A] was a different group, and the CIS group does have additional challenges because of the way the CIS can sometimes be hard to detect, be multifocal, and it [may] not be amenable to complete endoscopic resection. However, with papillary tumors, we're usually able to [conduct a complete endoscopic resection].

[These were] very similar findings, the same toxicity profile, the same adverse effects, and a very similar patient-reported quality of life. [This is] a treatment that does have toxicity but, for most patients, was manageable. It does provide another treatment option for patients who are considering radical cystectomy.

How did treatment with pembrolizumab affect the need for additional treatment and delays in cystectomy?

[Forty-seven percent] of patients required no additional therapy, which means [53%] of patients did need [additional treatment]. Of those patients who needed something else, 27% of patients had a radical cystectomy. Of those, 4 patients had upstaging and went from a non–muscle invasive to a muscle invasive disease state.

This seems to indicate that using pembrolizumab as a [systemic] therapy could potentially delay the need for additional therapy and potentially delay the need for cystectomy. If cystectomy is needed, the risk of progression is low. We saw [progression] in [11.1%] of patients [who underwent radical cystectomy].

Editor’s note: Dr Singer reported serving in a consultant/advisory role for Merck, Johnson & Johnson, and Aura; and receiving research funding from Astellas/Medivation and Merck Sharp & Dohme.

Funding for KEYNOTE-057 was provided by Merck Sharp & Dohme.

References

1. Singer EA, Necchi A, Roumiguié M, et al. Pembrolizumab for patients with high-risk non-muscle-invasive bladder cancer unresponsive to Bacillus Calmette-Guerin: efficacy and evaluation of subsequent cystectomy from cohort B of the phase 2 KEYNOTE-057 study. Presented at: 2023 AUA Annual Meeting. April 27-May 1, 2023; Chicago, IL. Abstract LBA03-08.
2. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. News release. FDA. January 8, 2020. Accessed May 5, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
3. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021;22(7):919-930. doi:10.1016/S1470-2045(21)00147-9