A post hoc analysis of the phase 2 KEYNOTE-057 trial (NCT02625961) found bladder-sparing treatment to be equally as effective at preventing disease recurrence as radical cystectomy in patients with high-risk, Bacillus Calmette-Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer (NMIBC) who demonstrated nonresponse to pembrolizumab (Keytruda), according to Roger Li, MD.

“[These are] exciting times in the BCG-unresponsive setting,” Li said in an interview with OncLive^® during the 2024 ASCO Annual Meeting. “A lot of different agents have been approved already, and a lot of studies are being run as we speak. I would expect that there are going to be multiple agents in this disease field, and it's going to be up to us to understand how to sequence these agents and how to use combination therapy for certain patients.”

In cohort A (n = 96) of KEYNOTE-057, patients with BCG-unresponsive, high-risk NMIBC with carcinoma in situ (CIS) with or without papillary tumors who received pembrolizumab achieved a complete response (CR) rate of 41% (95% CI, 31%-51%) and a median duration of response of 16.2 months (range, 0.0+ to 30.4+). Furthermore, 46% of patients had a CR lasting 12 months or longer. These findings supported the 2020 FDA approval of pembrolizumab for patients in this population who are not eligible for or have elected not to undergo cystectomy. ¹

A post-hoc analysis of this trial was conducted to investigate the clinical outcomes of patients with recurrent or persistent high-risk NMIBC despite treatment with pembrolizumab who had subsequently received radical cystectomy or other bladder-sparing treatments. Among the 144 patients included in the analysis, 39 received upfront radical cystectomy, 33 received delayed radical cystectomy, and 72 received no radical cystectomy.²

Efficacy outcomes were similar between the 3 groups. The median progression-free survival (PFS) was not reached (NR) in any group (upfront radical cystectomy, 95% CI, NR-NR; delayed radical cystectomy, 95% CI, 30.6 months–NR; no radical cystectomy, 95% CI, 65.4 months–NR). The median metastasis-free survival (MFS) was also NR in any group (all groups, 95% CI, NR-NR). Similarly, the median overall survival (OS) was NR in any group (upfront radical cystectomy, 95% CI, 43.2 months–NR; delayed radical cystectomy, 95% CI, NR-NR; no radical cystectomy, 95% CI, 51.9 months–NR).

In the interview, Li, a genitourinary oncologist at Moffitt Cancer Center in Tampa, Florida, discussed the reasons for conducting this post-hoc analysis, elaborated on the key efficacy findings from this analysis, and shared how these findings may impact the treatment of patients with BCG-unresponsive, high-risk NMIBC.

OncLive: What results from KEYNOTE-057 have been previously reported?

Li: KEYNOTE-057 was the first study to look at pembrolizumab in the BCG-unresponsive setting. [The trial] was divided into cohorts A and B. Patients in cohort A had CIS-containing tumors, whereas [patients in] cohort B had papillary-only tumors.

The primary end point for cohort A was CR rate at 3 months, which was 41%. The primary end point for cohort B was disease-free survival rate at 12 months, which was reported [in 2023 and was] 43.5%. These key findings from the study won pembrolizumab an approval from the FDA for use in the BCG-unresponsive setting.

What was the rationale for this post-hoc analysis?

Even though pembrolizumab has been approved [for patients with BCG-unresponsive NMIBC], a lot of patients develop disease recurrence after being treated with pembrolizumab. Those patients continue to be elderly and frail, so radical cystectomy is not the best option for some of these patients. Our rationale for pursuing this post-hoc analysis was to see whether patients continuing on a bladder-sparing therapeutic strategy would have poorer outcomes than those who underwent immediate radical cystectomy after they developed nonresponse.

What were the key findings from this analysis?

We evaluated PFS, MFS, and OS. We divided [the population] into 3 different groups of patients, [all of whom had] developed nonresponse to pembrolizumab during therapy. For these 3 groups, we used the 4-month mark after they developed nonresponse. If patients underwent radical cystectomy within the first 4 months [of developing nonresponse], they were classified as [having] immediate radical cystectomy. Patients who underwent radical cystectomy after 4 months [were classified as having] delayed cystectomy. Then there were patients who did not undergo radical cystectomy at all and just pursued bladder-sparing therapy.

Among these 3 different groups, we found that there were no differences in PFS, MFS, or OS. In addition, when comparing the patients who underwent radical cystectomy within the first 4 months with those who underwent it after the first 4 months, we found no difference in the distribution of the pathologic staging.

What are the clinical implications of these findings?

Because there were no significant clinical outcome differences between these 3 different groups, [this indicates that] you can continue to treat patients even after they have developed BCG-unresponsive disease during the first line of salvage therapy. [This finding is] critical because we now have multiple agents approved by the FDA in this setting. We need to know that it's safe to continue to treat these patients in a bladder-sparing manner, rather than taking them straight to radical cystectomy.

References

1. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. FDA. January 8, 2024. Accessed July 30, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-bcg-unresponsive-high-risk-non-muscle-invasive-bladder-cancer
2. Li R, Linscott J, Kulkarni GS, et al. Outcomes of patients with bacillus Calmette-Guérin–unresponsive high-risk non–muscle-invasive bladder cancer who demonstrated nonresponse to pembrolizumab in KEYNOTE-057: a post hoc analysis. J Clin Oncol. 2024;42(suppl 16):4597. doi:10.1200/JCO.2024.42.16_suppl.4597