FDA Approves Nogapendekin Alfa Inbakicept for BCG-Unresponsive NMIBC Carcinoma In Situ


Patients with Bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer carcinoma in situ now have a new treatment option following the FDA’s approval of nogapendekin alfa.

  • Nogapendekin alfa inbakicept-pmln (N-803, Anktiva) is now an approved treatment for patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) carcinoma in situ (CIS) with or without Ta or T1 disease.
  • The approval is based on positive results from studies, including the QUILT 3.032 trial (NCT03022825).
  • This trial showed a 71% complete response (CR) rate, a median response duration of 26.6 months, and a 91% cystectomy avoidance rate in patients who had not responded to prior therapies.
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The FDA has granted approval to nogapendekin alfa inbakicept with BCG as a treatment combination for patients with BCG-unresponsive NMIBC CIS with or without Ta or T1 disease.1

Positive results from a series of studies of the investigational treatment, including the open-label, single-arm, multicenter, phase 2/3 QUILT 3.032 trial, support this approval of nogapendekin alfa in patients with BCG-unresponsive NMIBC.2

The QUILT 3.032 study showed improved efficacy and safety with the agent among patients who failed on prior therapies. A total of 71% had a CR and the median duration of response of 26.6 months.2 The cystectomy avoidance rate was 91% with nogapendekin alfa, and the 24-month bladder cancer overall survival rate was 100%. Additionally, no serious adverse events (AEs) were reported.

“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,” 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, told Targeted OncologyTM in an interview.

Bladder Image: © magicmine stock.adobe.com

Bladder Image: © magicmine stock.adobe.com

In May 2023, the FDA issued a complete response letter (CRL) to ImmunityBio regarding the biologics license application (BLA) for nogapendekin alfa for the treatment of patients with BCG-unresponsive NMIBC CIS with or without Ta or T1 disease. The FDA cited insufficient inspection of a third-party manufacturer within the CRL. However, no efficacy or safety issues related to nogapendekin alfa were mentioned. The FDA accepted the BLA resubmission for nogapendekin alfa in October 2023.

Nogapendekin alfa is an IL-15 superagonist that has a mechanism of action resulting in proliferation of natural killer and T cells. This leads to a secondary boost in immunological response from treatment with BCG or other checkpoint inhibitors for other indications.

QUILT 3.032 included patients with persistent or recurrent CIS within 12 months of undergoing adequate treatment with BCG (cohort A) or papillary recurrent high-grade Ta-T1 disease within 6 months of finishing adequate treatment with BCG. Once enrolled, patients received BCG 50 mg plus 400 μg of intravesical nogapendekin alfa every week for 6 weeks or reinduction for 6 weeks plus maintenance up to a maximum of 3 years.3

In cohort A, the primary end point was biopsy-confirmed CR at 3 or 6 months. In cohort B, the primary end point was disease-free rate at 12 months. Secondary end points of the study included duration of CR, cystectomy avoidance, time to cystectomy, and safety.

Updated findings from the study were presented at the 2022 American Society of Clinical Oncology Meeting, and showed that the study met its primary end point with a 99% bladder cancer specific overall survival rate observed at 2 years. There also was a 53% disease-free survival (DFS) rate at 18 months among patients with papillary disease, and 96% showed 24 month bladder cancer specific progression-free survival.2

At 12 months, the DFS rate for papillary patients was 57% and 48% at 24 months. A total of 95% of patients avoided cystectomy with the median time to cystectomy among the 4 responders being 12.9 months vs 7.8 in the 8 non-responders. This resulted in a 5.1 month delay in cystectomy.

Looking at pharmacokinetic data, there were not any systemic levels of N-803 and activity was confined to the bladder.

Moreover, there was no incidence of grade 4/5 treatment-related serious AEs, immune-related AEs, or treatment-related AEs (TRAEs) observed among any patients in the study. Two patients had grade 3 TRAEs, including urinary tract infection and arthralgia. The most common grade 1/2 AEs were dysuria (22%), pollakiuria (19%), hematuria (18%), fatigue (16%), and urgency (12%), and all other AEs were seen at 7% or less.

1. FDA approves nogapendekin alfa inbakicept-pmln for BCG-unresponsive non-muscle invasive bladder cancer. US FDA. April 22, 2024. Accessed April 22, 2024. https://tinyurl.com/3bcnrzwy
2. 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). Presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 2-6, 2022; virtual. Abstract 4508.
3. 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. Updated June 16, 2022. Accessed February 2, 2024. https://clinicaltrials.gov/ct2/show/NCT03022825
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