This hypothesis was tested in the phase I clinical study QUILT-3.032. A total of 171 patients with NMIBC were recruited across various clinical sites. Cohorts A and C enrolled patients with histologically confirmed BCG-unresponsive carcinoma in situ (CIS) with or without Ta/T1 papillary disease. Cohort B enrolled patients with histologically confirmed BCG-unresponsive high-grade Ta/T1 papillary NMIBC. 84 Patients were assigned to cohort A, 77 to cohort B, and 10 to cohort C. Patients in cohorts A and B were treated with intravesical NAI and BCG, while patients in cohort C received only intravesical NAI. The median age of patients was 73, 72, and 74.5 in cohorts A, B, and C, respectively. Most patients were male. In cohort A, the median follow-up duration was 23.9 months, and 71% of patients exhibited complete response (CR) at any point. The median duration of CR in responders was 26.6 months. In this cohort, 45% of patients had a CR at 12 months, while 33% had a CR at 18 months. Kaplan-Meier analysis showed that the probability of progression-free survival was 84.7% at 24 months, while overall survival was 94.3% and disease-specific survival was 100%. CR rates varied based on baseline disease: 68% in CIS patients, 81% in CIS/Ta, and 67% in CIS/T1 disease. CR was 69% in patients who had received full doses of BCG before the study and 82% in those who had received reduced doses. Among the 71% of cohort A patients who responded to treatment, 7% subsequently underwent cystectomy. Among non-responders, 33% of patients underwent cystectomy. The median time to cystectomy was 11 months among responders and 7.8 months among non-responders. In cohort B, the median follow-up duration was 20.7 months. Median disease-free survival was 19.3 months. Disease-free survival rates were 55.4% at 12 months, 51.1% at 18 months, and 48.3% at 24 months. The cystectomy rate was 7%. In cohort C, the median follow-up was 7.9 months. CR was exhibited in 20% of patients, and only one patient (10%) maintained CR at 6 months. Cohort C was discontinued at 6 months due to futility.
With respect to safety, expected Treatment-Emergent Adverse Events (TEAEs) associated with BCG were observed, including dysuria, pollakiuria, and hematuria. In cohorts A and B, the incidence of grade 1-2, 3, 4, and 5 TEAEs was 86%, 20%, 2%, and 1%, respectively. Hematuria and urinary tract infections were the most common grade 3 TEAEs. Three patients experienced immune-related TEAEs. Only one patient experienced a grade 5 TEAE, which was cardiac arrest leading to death. Overall, 15% of patients experienced TEAEs that required hospitalization. In cohort C, 70% of patients had at least one TEAE. Of these, one was a grade 3 stroke, while the remaining events were of grades 1 or 2.
This important study demonstrated the efficacy of NAI and BCG combination among high-risk patients, as reflected by the high CR rate, the long median duration of CR, and the avoidance of cystectomy in most responders. Unfortunately, Cohort C of NAI monotherapy included a small number of patients and was stopped. The study is still ongoing and has a target enrollment of 200 patients.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
- Chamie K, Chang S, Kramolowsky E et al. IL-15 Superagonist NAI in BCG-Unresponsive Non–Muscle-Invasive Bladder Cancer. NEJM Evidence. 2022. doi:10.1056/EVIDoa2200167