N-803 Plus BCG Shows Encouraging Responses in NMIBC

Findings of the QUILT 3032 study (NCT03022825) examining N-803 plus Bacillus Calmette–Guérin (BCG) in patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) showed improved efficacy and safety. The findings exceed that observed with other currently available intravesical and systemic options.

Within this disease space, a significant number of unmet needs remain as a majority of patients with newly diagnosed bladder cancer have NMI disease. For patients with intermediate, high-risk NMIBC, or with carcinoma in situ (CIS), adjuvant treatment with BCG is guideline-recommended. Limited treatment options are available for patients and though cystectomy has been the standard of care in this patient population, it is a highly invasive procedure that experts are always looking to improve upon.

Previous phase 1b trials of BCG-naïve patients with NMIBC have taken place, and to expand on the research, experts started the open-label, 3 cohort, multicenter QUILT 3.032 study to evaluate patients with BCG-unresponsive high-grade NMIBC.

Data presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting examined the 160 patients with BCG-unresponsive NMIBC enrolled in the trial.

Among the enrolled patients, there was a 99% bladder cancer specific overall survival at 2 years after treatment with intravesical N-803 plus BCG. In patients with CIS, a 71% CR rate was demonstrated at 24.1 months. A total of 91% of patients avoided cystectomy and 96% had an absence of progression to MIBC at 24 months.

Patients with papillary tumors demonstrated a 57% 12-month disease-free survival (DFS) rate, 48% a 24-month DFS rate, and 95% avoided cystectomy. Further, 71% of patients who had failed on previous therapies demonstrated an increase of over 50% in response and median duration vs other FDA-approved alternatives like valrubicin and pembrolizumab (Keytruda).

In an interview with Targeted Oncology™, Sam S. Chang, MD, MBA, professor Department of Urology, Patricia and Rodes Hart Professor of Urologic Surgery, and chief surgical officer and chief of the Division of Urologic Oncology at Vanderbilt Ingram Cancer Center, further discussed the background of N-803 plus BCG in patients with BCG-unresponsive non-muscle invasive bladder cancer and what he expects for the future of this space.

TARGETED ONCOLOGY: Can you provide a brief overview of the QUILT 3032 study?

Chang: This trial looked at a combination of BCG, which is a commonly used medication to treat patients with non-muscle invasive bladder cancer and combine it with a novel agent or compound called N-803, which is a formulated agonist or super agonist of IL-15. This combination was used in patients who previously were treated with BCG but did not have a response or had a tumor that came back resistant to BCG.

What we found was in patients with both carcinoma in side 2, as well as papillary disease, that's non-invasive bladder cancer, these patients that were heavily pretreated with this combination therapy had excellent results with very few side effects. That's the bottom line.

What were the methods and design of the trial?

There were 2 cohorts, 1 group that had this carcinoma in situ that may or may not had papillary disease with it. The second cohort was papillary disease [and] T-1 disease. The reason why there was a difference was the FDA is focused on these carcinoma in situ patients, [and this] group patients was just under 100, and [it was] just under 100 [patients] in cohorts as well. These patients all received the combination medication and it was once a week for 6 weeks. Then, there were evaluations to see if the tumor had been eradicated, a complete response for the CIS.

In the papillary group to make sure that disease did not come back, a disease-free period of time that was measured over time. If these patients responded, they also got a maintenance regimen. What they did was get treatments at 3 and 6 months, and then 6 months in different intervals. As long as they responded, they received maintenance as well. That was the setup for the trial. It was an intravesical therapy once a week for 6 weeks with maintenance, and evaluations with cystoscopy and urine tests.

What findings were revealed when you looked at both cohorts?

When you looked at both cohorts, what you found was that there was a very high response rate, either complete response or disease-free response, that lasted for a significant amount of time. At the 1-year mark, you were greater than 60-70% in terms of response, and that was maintained to greater than 50%, or right around 50% of the 2-year mark, for both cohort A and cohort B. Not only CIS, but also the papillary tumors at 2 years had around 50% response rates, or 2-3 events, so a real significant improvement.

We've had agents, 1 in particular that was FDA approved, that was a similar cohort, and we saw responses. But over time, that definitely decreased rather significantly. To have it at the 2-year mark, half the patients still without ever disease is really a step forward.

What treatment options have previously been available for these patients?

If you look at the guidelines for patients who have disease that don't respond to BCG, so they have non-muscle invasive bladder cancer which is huge as 100s of 1000s of patients have non-muscle invasive bladder cancer, then you come down into these patients who receive BCG, but then have diseases that came back, the guideline recommended next step is bladder removal. That is in the NCCN guidelines, the AUA guidelines, the European guidelines. The recommended treatment is bladder removal.

If you don't have bladder removal, and many of these patients are older, have more comorbidities, and more issues, if you don't have that as an option, patients are looking for the non-cystectomy, non-bladder removal option. Other options include intravesical therapy. There's a chemotherapy agent called valrubicin that was FDA approved as well for this group. I would bet that that is a choice 1% of the time, maybe even less than that. At our institution, we haven't gotten valrubicin in more than 10 years, even though it's an FDA approved medication.

So, you've got the recommendation of bladder removal, you have the FDA approved valrubicin that is basically never used, then, the most recent FDA approved medication or treatment for this group of patients is pembrolizumab [Keytruda] which is an immunotherapy agent. A totally different mechanism, not anything put in the bladder, but it's an intravenous, that's recommended to be given for at least a year for patients with BCG, unresponsive, non-muscle invasive bladder cancer. Those are the 3 options that are out there that are either guideline recommended, or FDA approved, but the vast majority of times, patients hopefully will get enrolled in clinical trials just as this one that I have been talking about.

Then what many people try are different agents that are put into the bladder. Its most common gemcitabine, which is a chemotherapy agent, or gemcitabine, and docetaxel, which is another chemotherapy agent. Other chemotherapy we use include mitomycin. There are different options out there, but ones that are definitively better and have a big chance for success, the statistics have not been great compared to cystectomy. But then you weigh all the comorbidities of cystectomy, so patients are definitely looking for non-cystectomy alternatives.

What unmet needs still exist in the space?

In terms of patients who receive BCG therapy and don't respond, it's still a huge unmet need. That's what this trial addresses. If you go beyond that, from a non-muscle invasive bladder cancer standpoint, it's a true alternative to BCG. BCG is a very effective treatment, but it has side effects. Those include local problems with urination and frequency of bleeding. A small percentage of patients can get BCG sepsis, where the bacterium could get absorbed and you get sick, febrile, and require strong antibiotics and hospitalization. We don't have a true alternative to BCG.

In addition, we have a BCG shortage that's ongoing, that is sporadic, and that is inconsistent. There are times where you have BCG, a supply that comes in and then you find out from the supplier, you won't get BCG for a couple months or 6 weeks, or [it is] unknown when you would get another batch. Physicians are looking for a BCG alternative, not only because of their side effects and somewhat difficult at times to receive, but also because there is unreliability of it being available. If we don't have BCG, what do we use? A true alternative that we know is effective or has less side effects would be great.

Separate from therapy, an unmet need all bladder cancer patients would love is a diagnostic test that is non-invasive. You leave a urine sample, and you find out yes or no, do you have bladder cancer or do you not? We have never had that. There are our tests out there that are getting to the point where we can say that you are less likely to have cancer or more likely to have cancer, but we don't have anything yet to replace cystoscopy, which is an invasive procedure.

I [hope] in the foreseeable future that we would have that capability of a urine- based test that is effective and accurate. That would be fantastic. I think those are unmet needs in the non-muscle invasive bladder cancer space.

What excites you the most in regard to the future of this space?

I think a screening test would be very exciting. I think anything that helps predict how effective a certain treatment is, or predicts when you can stop a treatment, or predicts who needs additional therapy in the future is helpful. Then prognostic ones in terms of, you've got this cancer and it's not dangerous, you don't have to worry about it. This is really dangerous and we need to be as aggressive as possible. So, biomarkers are really exciting, and the screening tools are really exciting.

Then I think what's exciting in the future is that we have got a lot more [therapeutic] options than we have ever had in the past. More and more studies are being done for urothelial cancer, so those are all exciting.

References:

1. Chamie K, Chang S, Gonzalgo M, et al. Final clinical results of pivotal trial of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive CIS and papillary nonmuscle-invasive bladder cancer (NMIBC). J Clin Oncol. 2022;40(suppl 16):4508-4508. doi:10.1200/JCO.2022.40.16_suppl.4508

2. QUILT-3.032: A multicenter clinical trial of intravesical bacillus calmette-guerin (BCG) in combination with ALT-803 (N-803) in patients with BCG unresponsive high grade non-muscle invasive bladder cancer. ClinicalTrials.gov. Accessed July 7, 2022. https://clinicaltrials.gov/ct2/show/NCT03022825?term=QUILT+3.032&draw=2&rank=2