SAN FRANCISCO — Pembrolizumab (Keytruda) monotherapy showed encouraging antitumor activity in patients with papillary high-risk non-muscle-invasive bladder cancer (HR NMIBC) that was unresponsive to Bacillus Calmette-Guerin (BCG) treatment.

In a cohort of patients in the KEYNOTE-057 study who had 45 months of follow-up, those treated with pembrolizumab (n=32) had an estimated 12-month disease-free survival (DFS) rate of 43.5% (95% CI 34.9-51.9) and a median DFS of 7.7 months (95% CI 6.5-13.6), reported Andrea Necchi, MD, of the Vita-Salute San Raffaele University in Milan.

The DFS curve plateaued at month 24 resulting in equal estimated 24- and 36-month DFS rates of 34.9% (95% 26.4-43.4), he said in a presentation at the ASCO Genitourinary Cancers Symposium (GuCS).

For any disease recurrence, the estimated 12-month DFS was 41.7% (95% CI 33.1-50.0), with a median DFS of 6.0 months (95% CI 4.3.12.0). Again, the DFS curve plateaued at month 24, resulting in estimated 24- and 36-month DFS rates of 33.0% (95% CI 24.7-41.5).

“This patient population currently represents an unmet need without or with very limited conventional therapies, and with very limited clinical trial options,” Necchi stated. “These results are among the most robust data yet available for any novel systemic therapy in this patient population with papillary high-risk disease, and suggest that pembrolizumab monotherapy may be beneficial in this special patient population.”

The single-arm, multicohort phase II KEYNOTE-057 investigated the safety and efficacy of pembrolizumab monotherapy for patients with BCG-unresponsive HR NMIBC who were ineligible or declined to undergo radical cystectomy.

Results from cohort A, which included patients with carcinoma in situ (CIS) with or without papillary tumors, had demonstrated a clinical complete response rate of 40.6% at 3 months, with a median duration of response of 16.2 months. This led to FDA approval in 2020 of pembrolizumab for this population of patients.

Necchi explained that while additional studies are providing “compelling” data on newer therapies or combinations, “limited data is still available regarding the efficacy of any novel systemic therapy in non-CIS, high-grade papillary T1 or Ta disease.”

Necchi and colleagues focused on cohort B of Keynote-057, which included patients with papillary tumors only, without CIS. These patients had a median age 72, and most (78%) were male, while 43.2% had T1 disease. Overall, patients received pembrolizumab for a median of 9.5 cycles, while prior to enrollment they received a median of 10 BCG installations.

According to the study’s secondary endpoints, estimated 12-month progression-free survival (PFS) to worsening of grade or stage, or death, was 88.2% (95% CI 80.0-93.2), with a median PFS of 44.5 months (95% CI 34.6-not available). The 12-month PFS to invasive or metastatic disease, or death, was 88.2% (95% CI 79.4-93.3), with a median PFS of 46.2 months (95% CI 36.8-NA).

The estimated 12-month overall survival (OS) was 96.2% (95% CI 91.1-88.4%), with median OS not reached.

The researchers also reported that 31 patients (23.5%) went on to have a radical cystectomy after stopping pembrolizumab.

Regarding safety, 73.5% of patients had treatment-related adverse events (AEs) of any kind, 14.4% had grade 3 or 4 treatment-related AEs, and 10.6% discontinued therapy due to a treatment-related AE. The most common AE was pruritus. No treatment-related deaths were reported.

GuCS discussant Michiel Van der Heijden, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, looked at how the trial results compared to other therapies in this space.

For example, a clinical trial of intravesical nadofaragene firadenovec gene therapy demonstrated similar results to pembrolizumab in a cohort of patients with high-grade papillary disease, he noted. Van der Heijden also pointed out that studies evaluating intravesical chemotherapy had higher rates of recurrence-free survival, but were retrospective in nature, “and not in the context of a well-controlled clinical trial.”

“I think pembrolizumab mainly stands out for the robustness of the data, with 132 patients, which is the largest prospective clinical trial in this space,” Van der Heijden said.

The drug “probably has clinical activity in this space, although, unless we have randomized trials in this space, the magnitude of this activity is still unknown,” he added. “These randomized trials are needed, but I acknowledge it will be difficult to find a comparator arm.”

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