N-803/BCG Approval Signals Paradigm Shift in Management of BCG-Unresponsive NMIBC

The FDA’s approval of nogapendekin alfa inbakicept-pmln (Anktiva; N-803) plus Bacillus Calmette–Guérin (BCG) provides a feasible, effective treatment alternative to patients with BCG-unresponsive non–muscle invasive bladder cancer (NMIBC) who would otherwise undergo radical cystectomy, suggesting that this traditional approach may no longer be necessary for those who achieve durable responses, according to Karim Chamie, MD.

In the phase 2/3 QUILT-3.032 trial (NCT03022825), patients with CIS with or without Ta/T1 papillary disease after transurethral resection who received N-803 plus BCG (n = 77) achieved a complete response (CR) rate of 62% (95% CI, 51%-73%). Fifty-eight percent of responders experienced a duration of response (DOR) lasting at least 12 months, and 40% experienced a DOR lasting 24 months or longer.¹ Previously reported data from cohort A of the trial, which included patients with carcinoma in situ (CIS; n = 82), showed that at a median follow-up of 23.9 months, the CR rate with the regimen was 71% (95% CI, 59.6%-80.3%).²

Based on QUILT-3.032 data, the FDA approved N-803 plus BCG for the treatment of patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors on April 22, 2024.³

“The FDA approval N-803 plus BCG for patients with BCG-unresponsive bladder cancer shows that we are offering an alternative option to patients with what we would oftentimes consider end-stage disease, where they’d [typically] need to have their bladder removed,” said Chamie, who is an associate professor of urology at the University of California, Los Angeles.

In an interview with OncLive®, Chamie highlighted key data from the QUILT-3.032 trial supporting the approval of N-803 plus BCG in patients with BCG-unresponsive NMIBC and discussed ongoing research efforts to utilize this regimen in other disease subtypes.

OncLive: How frequently do you see patients with BCG-unresponsive NMIBC in your own clinical practice?

Chamie: A small number of patients will have] BCG-unresponsive NMIBC based on clinical trial criteria. The vast majority of patients are now getting BCG, but for a long time, only a minority of patients who had high-grade disease were actually getting BCG according to SWOG protocol. More importantly, BCG works very well. Fewer and fewer patients are [progressing on] BCG, because we’re identifying those with multifocal disease earlier with access [to techniques such as] blue-light cystoscopy. We are resecting patients with high-grade T1, sometimes high-grade Ta disease. We’re making sure that there’s limited disease at the time of BCG induction, so we’re seeing fewer [patients progress. However], it’s not as though we had a hard time enrolling patients in this study. It’s a common enough disease, and the FDA did a fantastic job at getting [the combination] approved in a timely fashion so that patients with BCG-unresponsive bladder cancer would have access to it.

Please expand on the eligibility criteria for the QUILT-3.032 trial. How did the study design differ from other investigations in BCG-unresponsive NMIBC?

This cohort mirrors ones we’ve seen for other studies, whether it’s the [phase 2] KEYNOTE-057 trial [NCT02625961] with pembrolizumab [Keytruda] or trials with nadofaragene firadenovec [Adstiladrin]. It’s very similar to some of the other studies that are ongoing of TAR-200 or [cretostimogene grenadenorepvec (CG0070)].

There were some nuances in our trial that differed from [those evaluating] the 2 FDA approved drugs. That is our increasing comfortability with not removing patients’ bladders and, more importantly, offering access to reinduction. In earlier trials, patients [who achieved] even a partial response or very minimal disease were kind of excluded from receiving maintenance therapy. In our trial, we allowed patients who had a response to continue with a reinduction or with maintenance [therapy]. Although most of those patients ultimately [experienced disease progression], it taught us that most patients do not need to proceed with a radical cystectomy. In fact, [approximately] 90% of our patients never went on to [undergo] a radical cystectomy. If you follow these patients 2 years out, the vast majority either didn’t respond or ultimately [progressed] after 2 years. [However,] the lesson we learned is that [a subset of patients who achieve responses] will not need to have their bladder removed.

What efficacy and safety data were seen with N-803 plus BCG in the trial?

The CR rate at any time was 71%, and the median durability was approximately 26 months. This CR rate is much higher than what we’ve seen with the other 2 trials [mentioned above]. More importantly, the durability was twice that [of] what we saw with those other 2 drugs. The median duration of CR in the other 2 trials was approximately 12 months.

[In terms of safety profile], it’s no different than patients who are treated with BCG. I had a couple of patients in the trial who had to stop treatment because the immune response is so profound in the bladder. The good news is that even though we stopped treatments, the durability of the response persisted. We’ve seen similar [outcomes] with systemic immunotherapy for other kinds of cancers, where patients experience immune-related adverse effects [AEs], we stop treatment, and the response persists. We’re seeing the same kind of activity here, in the bladder, with these treatments.

Where do you see this combination being used within the NMIBC treatment paradigm, and what is your advice for integrating this regimen into practice?

[Based on the] FDA approval, [patients] must have CIS with or without papillary disease. The important point is that for these patients to access this drug, they must have received adequate amounts of BCG. A lot of times, patients are referred to me to enroll in this trial because they’ve received 6 doses of BCG, and I [unfortunately] can’t [include] them on the trial because 6 doses isn’t enough; they must have received at least 5 with induction and then 2 of 3 or of 6 maintenance treatments. Adequate amounts of BCG are important—not because you necessarily want to give them this drug, but because BCG works well. Even people who [progressed on] an induction course, about 30% will still have some form of response. Before we start [considering] second-line therapy, it’s important that we try a reinduction of BCG for some of those patients.

As far as safety, it’s important that patients are seen by their urologist and not just put into a clinic for nurses to administer immunotherapy without adequately assessing urinary function. If you start to see some AEs and patients are unable to tolerate [treatment] for a prolonged period, it’s important to give the patient a break for a couple of weeks and then resume therapy once their urinary symptoms improve.

What is the overall significance and impact of this regimen’s approval in this population?

It’s fantastic news for patients with bladder cancer. I’ve said this several times, and I’ll say it again: It’s never ideal to be diagnosed with bladder cancer, but in this era with the number of options we have, [the outcome for a patient with] bladder cancer is promising. This is the third drug that’s been FDA approved in the past few years, and it is probably a best-in-class [agent] at this moment. We’re [likely] going to see many patients seeking access to it.

I’ve got patients who are emailing me who really want to get on N-803 plus BGS, so it’s going to be an exciting period. We not only enrolled patients through the trial, but we enrolled patients through the compassionate use [pathway] because they didn’t necessarily fit the criteria. Now we have an opportunity to offer these patients these drugs without going through the motions of compassionate use or trying to get them onto alternative trials.

Are there any planned or ongoing research efforts to extend the benefit of N-803 plus BCG to other bladder cancer subtypes?

We’ve got the phase 2/3 QUILT-3.032 trial [examining the regimen in] the papillary cohort without CIS; [this] is ongoing. We have the [phase 1/2] QUILT 2005 study [NCT02138734,] which is [evaluating] BCG plus N-803 vs BCG alone for BCG-naive, high-grade NMIBC. I suspect that there will be independent studies looking at partial or split doses of BCG. We’ll have studies looking at patients with muscle-invasive bladder cancer [MIBC]. I suspect that they’re going to be combining N-803 and BCG with systemic immunotherapy to see whether there’s any activity in patients who are unfit for cystectomy and who have MIBC. There are going to be several studies springing from this early trial and FDA approval. I’m optimistic that more options are going to be available for patients with regard to bladder preservation for MIBC, but also for earlier lines of therapy in NMIBC.

References

1. Anktiva. Prescribing information. ImmunityBio, Inc; 2024. Accessed May 1, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761336s000lbl.pdf
2. Chamie K, Chang SS, Kramolowsky E, et al. IL-15 superagonist NAI in BCG-unresponsive non-muscle-invasive bladder cancer. NEJM Evid. 2023;2(1):EVIDoa220167. doi:10.1056/EVIDoa2200167
3. FDA approves nogapendekin alfa inbakicept-pmln for BCG-unresponsive non-muscle invasive bladder cancer. FDA. April 22, 2024. Accessed April 26, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nogapendekin-alfa-inbakicept-pmln-bcg-unresponsive-non-muscle-invasive-bladder-cancer