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CHICAGO -- Patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) had a high response rate and 2-year cancer-specific survival with an immunostimulatory fusion protein complex plus BCG, a prospective study showed.

The intravesical combination led to complete responses in 71% of patients with carcinoma in situ (CIS), with a median response duration exceeding 2 years. More than 90% of patients with 2 years of follow-up avoided cystectomy. The entire 161-patient study population had a 2-year cancer-specific survival of 99%-100%, reported Karim Chamie, MD, of the University of California Los Angeles.

Pharmacokinetic studies showed no systemic levels of the N-803 fusion protein complex, indicating activity was limited to the bladder, he said in a presentation at the American Society for Clinical Oncology (ASCO) annual meeting.

"We observed clinically meaningful benefit in those with CIS, as 71% of the patients attained a complete remission at any time, a median duration of complete remission of 26.6 months, and 96% avoidance of bladder cancer progression at 24 months, and 89% avoidance of cystectomy at 24 months in responders," said Chamie. "The drug was very safe, as serious adverse events [SAEs] were quite low and acceptable, as would be expected for intravesical agents."

"As for patients with papillary disease, we observed a 55% disease-free survival [DFS] at 12 months, 19.3-month median DFS, 99% overall bladder cancer-specific survival, and 95% of patients avoided cystectomy," he noted. "Efficacy was retained across all pathologic and demographic factors."

BCG, a longstanding standard of care for NMIBC, works by inducing pathogen-associated molecular patterns that lead to oncolysis of tumor cells and stimulation of natural killer (NK) and T-cell production that results in cell death. Chamie and colleagues hypothesized that BCG plus interleukin-15 would increase NK and T-cell recruitment without upregulation of regulatory T cells, further augmenting response and improving DFS.

To test the hypothesis, they conducted a phase II/III trial (QUILT-3.032) of BCG plus the IL-15 super-agonist N-803 in patients with BCG-unresponsive NMIBC. They enrolled separate cohorts of patients with CIS (n=84) and papillary disease (n=77). In the CIS cohort, pure CIS accounted for 70% of patients, followed by CIS/Ta (19%) and CIS/T1 (10%). In the papillary cohort, 45% of patients had T1 disease, 43% had high-grade Ta, and 7% had CIS, Ta, or T1.

The CIS cohort had undergone an average of four transurethral resections (TURBT) and received an average of 16.6 doses of BCG. The papillary group also averaged four TURBT procedures and had received 12.3 instillations of BCG.

The combination of BCG and N-803 was well tolerated, as the 161-patient cohort had a 1% incidence of serious treatment-related AEs.

Efficacy data showed complete responses in 58 of 82 evaluable patients in the CIS cohort. Chamie said 61.6% of responses lasted at least 12 months, 56.3% were ongoing at 18 months, and 53.2% continued for 24 months or longer. During a median follow-up of 23.9 months, 91% of responding patients had avoided cystectomy, and the overall avoidance rate in the cohort was 16%. Bladder cancer-specific progression-free survival was 96.4% at 12, 18, and 24 months, and cancer-specific overall survival was 100%.

Chamie pointed out that the results compared favorably with the 96-patient CIS cohort in the trial of pembrolizumab (Keytruda) in BCG-unresponsive NMIBC. Pembrolizumab led to complete response in 41% of patients, including 29% in U.S. patients. Median duration of response was 16.2 months versus 26.6 months with BCG/N-803. More than twice as many patients underwent cystectomy after treatment with pembrolizumab (41.6% vs 16%).

In the cohort with papillary bladder cancer, 72 of 77 patients had avoided cystectomy during a median follow-up of 20.7 months. The median DFS was 19.3 months, and DFS was 55% at 12 months, 51% at 18 months, and 48% at 24 months.

The data "look really good" in comparison to previous trials, such as KEYNOTE-057, said ASCO invited discussant Michiel Simon Van Der Heijden, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, although he acknowledged the caveats associated with cross-trial comparisons. The results also compare favorably with the recommendations for clinical trials in NMIBC: "substantial delay" in cystectomy, low rate of progression to MIBC, and a high rate of durable responses including ≥30% at 12 months for BCG-unresponsive CIS.

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