Novel immunotherapy promising in BCG-unresponsive NMIBC

The combination of an IL-15 cytokine agonist known as N-803 and bacillus Calmette–Guérin (BCG) was well tolerated and offered promising activity in patients with nonmuscle-invasive bladder cancer (NMIBC) who did not respond to BCG therapy, according to phase I and II study results.

“These are exciting preliminary results for patients with BCG-unresponsive disease,” Sam S. Chang, MD, MBA, professor of urologic surgery and oncology and vice-chair of urologic surgery at Vanderbilt University Medical Center in Nashville, TN, told Urology Times. “We do need further follow-up. If further follow-up confirms these findings, then this would represent a breakthrough.”

Dr. Chang presented the phase II study data at the AUA annual meeting in Chicago.

Treatment options for patients with NMIBC who have a recurrence or relapse after BCG therapy are limited. If patients fail to respond to BCG, they eventually often require cystectomy, which carries substantial morbidity and mortality risk.

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N-803 is a first-in-class IgG1-Fc IL-15 cytokine agonist; its mechanism involving activation of the innate and adaptive immune systems could potentially rescue the immune response in BCG-unresponsive disease. BCG uptake into bladder cancer cells causes the cells to present antigens and to produce immune-stimulating cytokines; in unresponsive disease, BCG alone does not trigger enough of a response. N-803 mimics the trans-presentation of IL-15, which can selectively induce CD8+ T cells and natural killer cells and thus boost the immune response.

In a previous report, a phase I trial of N-803 in combination with BCG showed a similar safety profile to that of BCG alone, with adverse events that included hypertension, hematuria, and pollakiuria. All nine patients in that cohort had a durable complete response, and all nine were disease free at 24 months; during his presentation of phase II results at the AUA annual meeting, Dr. Chang noted that BCG alone typically has a response rate of 55% to 75% at 3 to 6 months.

The phase II trial was a single-arm, open-label trial combining intravesical N-803 and BCG. At the time of data cutoff, 35 patients had been enrolled in a cohort of carcinoma in situ patients, and 18 were evaluable for response. Of those, 16 had complete responses (89%); 31 of the 35 patients remained on the treatment.

In a second cohort of 27 patients with high-grade Ta/T1 papillary NMIBC, there was a 6-month recurrence-free survival rate of 77% (10 of 13 evaluable patients). In that cohort, 23 of 27 patients remained on the treatment.

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A safety analysis included all 62 patients enrolled to date; again, the adverse events appeared similar to those typically associated with BCG monotherapy. There were five serious adverse events, including two in the carcinoma in situ group and three in the papillary cohort; all were determined to be unlikely to be related to the combination of N-803 and BCG.

“This combined therapy’s overall morbidity is very attractive,” Dr. Chang said. “It does not require IV or subcutaneous injection. It does not require any other monitoring. And it follows a treatment course that urologic surgeons are quite familiar with.”

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He added that the trial is ongoing, with a target enrollment of 160 total patients. Other trials testing N-803 in other malignancies and in combination with other therapies are also ongoing.

Dr. Chang is a consultant for Altor BioScience.