CHICAGO-The prospect that most patients with non-muscle invasive bladder cancer (NMIBC) who fail adjuvant BCG immune therapy could avoid cystectomy by treatment with the novel interleukin-15 superagonist N-803 (IL-15R[alpha]Fc) emerged from a phase II open-label single-arm, multi-center study reported at the 2019 ASCO Annual Meeting (Abstract 456).
"This would result in a significant change in how we treat patients with this disease," noted lead author Karim Chamie, MD, Associate Professor from the Department of Urology at UCLA Medical Center. "BCG alone in this setting [results] in maybe a 10 or 20 percent response rate. We are talking about 60, 70, 75 percent. That's a significant paradigm shift."
Chamie said NMIBC accounted for the "vast majority" of all bladder cancer diagnoses and a third of the cases were high-grade. "The standard of care for those patients was to have this tumor surgically resected [transurethrally] and then [give] adjuvant intravesical BCG that stimulates the immune system to help prevent the cancer cells from coming back."
It was necessary to add BCG (or an alternative immunotherapeutic) even in low-grade tumors (where resection alone was potentially curative) because recurrence rates could still be as high as 50 percent, Chamie explained. The phase II study offered patients the chance of augmenting any immunity to recurrence gained from BCG alone by adding N-803.
He said N-803 had been a laboratory-engineered IL-15 that was a potent cytokine able to stimulate the immune system without needing to have antigen-presenting cells present. "This soluble antibody can stimulate the effector cells in the local bladder tissues so that you can have a better kill rate towards the cancer," Chamie stated. N-803 does this by promoting natural killer and CD8-positive T-cell expansion and activation in vivo without expanding immunosuppressive regulatory T cells.
Study Details
The study included three categories of patients. Those who had persistent or recurrent carcinoma in situ (CIS) with or without papillary disease-non-invasive (Ta) or invading subepithelial tissues (T1). The second category included patients with high grade Ta or T1 disease recurring within 6 months of BCG therapy. And patients who had T1 high-grade disease at first evaluation after an induction BCG course were the third group.
Patients were then studied in two cohorts. One consisted of patients with CIS. The second cohort was with patients who had papillary disease that was either Ta or T1.
The primary endpoint for patients with CIS was complete response (CR) rate. For patients with papillary disease, it was disease-free rate at 12 months. At the time of reporting, 18 out of 20 patients in the CIS cohort had a CR. Twelve out of 16 patients with papillary tumors had CRs.
On average only one adverse event (AE) out of 10 was more severe than grade 2. The most common grade 2 or higher AEs were chills, pain on urination, abdominal cramps, bladder spasms, hematuria, hypertension, nausea, and urgency.
Chamie said the effect of using BCG in combination with N-803 was like exploding a "dirty bomb" in the bladder, causing a massive local inflammatory response. "[The] result is an increased inflammatory and immune response, which [we think] then results in a targeted therapy towards bladder cancer in the bladder."
Among the total of 63 patients in the study, 35 had CIS (with or without papillary disease) and 28 patients had papillary disease, Chamie noted. "We found 90 percent of patients in the carcinoma in situ arm had a complete response. At 3 months, 55 percent of patients responded. But when you gave this drug as an additional induction course at 3 months [to] those who didn't respond [initially], that response rate goes up to 78 percent. And it is maintained. About 75 percent of patients who have papillary disease are disease-free at 6 months."
The study concluded that the treatment was well-tolerated with no immune-related AEs and showed promising evidence of clinical activity in patients with CIS or papillary disease who failed BCG therapy.
Clinical Implications
"Oftentimes, these patients are older and sicker. So what you want to do is avoid an operation that is not likely to benefit a patient who is old and sick and has other comorbidities," Chamie said.
For them, overall survival was not necessarily a primary endpoint because most patients did not die of this cancer, he said. "If you follow them long enough, about 15-20 percent of patients who have BCG unresponsive bladder cancer probably will eventually die of this disease. But that means 80 percent won't. And so with this treatment, we want that number to be as low as possible, but [for patients to] have improved quality of life with bladder preservation."
Enrollment to the trial was continuing, though the data already seemed strongly in favor of the new combination adjuvant immune therapy. "We are talking about 75 percent response rates that are durable. That is very meaningful. The FDA clearly wants a study that has a 30 percent durable complete response rate at 18 months or 24 months. This is twice that. It's early on, but if this is maintained then this is clearly a game-changer," Chamie explained.
"We feel that patients who have BCG unresponsive bladder cancer have a choice. And surgical removal of the bladder doesn't always necessarily need to be the first choice. It may be for patients who are younger, healthy, and want to be cancer-free. For patients who are older and sicker, I think this is a viable alternative," Chamie said. "Taking their bladder out if they are old and sick may not improve their quality of life."
Peter M. Goodwin is a contributing writer.