N-803 shows promise for BCG-unresponsive NMIBC carcinoma in situ

Intravesical administration of the IL-15RαFc* superagonist N-803 with BCG** demonstrated a strong efficacy and an excellent safety and tolerability profile in patients with BCG-unresponsive high-grade NMIBC*** carcinoma in situ, according to an interim analysis presented at ASCO GU 2021.

This interim analysis reports findings from cohort A of the tri-cohort QUILT 3.032 study comprising adults with histologically confirmed BCG-unresponsive carcinoma in situ with or without capillary disease (n=80; mean age 72.5 years, 86 percent male). All participants received intravesical N-803 400 µg plus full-dose BCG (50 mg). Participants were heavily pretreated, with all receiving prior BCG and 78 percent receiving additional therapy, including chemotherapy, interferon, checkpoint inhibitors, and vicinium. Primary endpoint is the incidence of complete response (CR) at any time. [ASCO GU 2021, abstract 510]

After a median follow-up of 10.7 months, the study met its primary endpoint as reflected by the number of participants achieving CR at any time (n=51/72 evaluable patients), translating to a 71-percent CR incidence at any time. Of those who achieved CR, the probability of maintaining CR beyond 12 months is 56 percent, with an estimated median CR duration of 19.2 months.

The CR rate at any time was higher compared with those observed with pembrolizumab (which is FDA-approved for this indication; 41 percent) and nadofaragene (53 percent), the researchers pointed out. Although the median CR duration was favourable, the shorter median follow-up compared with pembrolizumab and nadofaragene should be taken into context. [https://www.fda.gov/media/133542/download, accessed March 8, 2021; Lancet Oncol 2021;22:107-117]

Only 10 patients proceeded to undergo radical cystectomy, translating to a cystectomy avoidance rate of 88 percent which, according to the researchers, compares favourably with other medications in this disease area.

The most common grade 1/2 treatment related adverse events (AEs) were dysuria (18 percent), haematuria (15 percent), and pollakiuria (14 percent). Nine participants had at least one treatment-emergent severe AE; nonetheless, none were deemed treatment-related. No immune-related AEs, treatment-related grade 4/5 AEs, or discontinuations owing to treatment-related AEs were observed.

“The AE profile was quite favourable … This is not too dissimilar to what is seen in patients receiving BCG intravesical therapy,” explained the researchers. Moreover, systemic responses (eg, extreme pain, arthralgias, myalgias) were relatively rare.

These findings support phase Ib data showing durable CRs with intravesical administration of N-803 with BCG in BCG-naïve patients with NMIBC, without recurrence for 2 years.

“Patients with BCG-unresponsive NMIBC carcinoma in situ have limited treatment options,” they pointed out. Given the strong efficacy and AE rate observed in the current analysis, coupled with the favourable comparisons with pembrolizumab and nadofaragene, “N-803 represents a novel treatment option [in this setting] with a favourable benefit-risk ratio in a therapeutically challenging disease,” they concluded.