FDA Issues Refusal to File Letter for Nogapendekin Alfa Inbakicept sBLA in BCG-Unresponsive Papillary NMIBC

Papillary NMIBC | Image Credit: © Sebastian Kaulitzki – stock.adobe.com

On May 2, 2025, the FDA issued a refusal to file (RTF) letter in response to the supplemental biologics license application (sBLA) seeking the approval of nogapendekin alfa inbakicept-pmln (Anktiva) plus BCG for the treatment of patients with BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC) with papillary tumors without carcinoma in situ (CIS).1

ImmunityBio Inc., the developer of nogapendekin alfa inbakicept, has accordingly requested a Type A meeting with the FDA to address the discrepancies between the FDA’s recommendations provided at an in-person meeting in January 2025 and the agency’s subsequent decision to reject the regulatory submission.

The company received this RTF letter despite previously receiving unanimous guidance from FDA leadership—including those from the Center for Biologics Evaluation and Research, the Center for Drug Evaluation and Research, and the Oncology Center of Excellence—to submit the sBLA to the FDA at the January meeting.

During this meeting, key decision-makers unanimously agreed that the sBLA should be submitted as soon as possible based on findings—including strong clinical response rates and durable long-term follow-up data—from cohort B of the single-arm phase 2/3 QUILT-3.032 trial (NCT03022825). Among patients with papillary disease without CIS in cohort B, the disease-specific overall survival (OS) rates were 99% and 96% at 12 months and 36 months, respectively. 1,2

Following the guidance from this meeting, ImmunityBio submitted the sBLA for the use of the combination in patients with BCG-unresponsive papillary disease in March 2025.1

Notably, in April 2024, the FDA approved nogapendekin alfa inbakicept plus BCG for the treatment of patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors based on findings from cohort A of the QUILT-3.032 trial. The RTF letter does not affect this prior FDA approval.

“Our commitment to [patients with] NMIBC in the papillary indication and our belief in [nogapendekin alfa inbakicept’s] potential based on the strength of the clinical response and long duration of 5-year follow-up remains unchanged, despite our receipt of a refusal to file letter regarding our supplemental BLA,” Patrick Soon-Shiong, MD , the founder, executive chairman, and global chief scientific and medical officer of ImmunityBio, stated in a news release. “We are fully determined to work with the FDA as quickly as possible…to explore the best path forward. We presented our data at the recent 2025 American Urological Association [(AUA) Annual] Meeting, and [nogapendekin alfa inbakicept plus] BCG was considered best in class and best in disease by the thought leaders in attendance when compared [with] all the therapies currently approved or in development.”

Zooming in on QUILT-3.032

The open-label, multicenter QUILT-3.032 trial evaluated nogapendekin alfa inbakicept alone (cohort C) or in combination with BCG (cohorts A and B) in patients with BCG-unresponsive, high-grade NMIBC. During the initial induction treatment period, patients receive treatment with 400 μg of nogapendekin alfa inbakicept with or without 50 mg of BCG for 6 consecutive weeks via a urinary catheter inserted into the bladder.1,2 Following the first disease assessment, eligible patients receive either 3 weeks of maintenance treatment or 6 weeks of re-induction treatment at month 3, comprising the second treatment period.1 Eligible patients then continue to receive maintenance treatment in a third treatment period at months 6, 9, 12, and 18. Eligible patients then have the option to receive maintenance treatment in a fourth treatment period at months 24, 30, and 36. The total study duration is 60 months.

Updated findings from the trial, which were presented at AUA, showed that in cohort A (n = 100), the 36-month CR rate was 71% (95% CI, 61.1%-79.6%). The median duration of CR among evaluable responders (n = 71) was 53+ months.2 Furthermore, the 12-, 24-, and 36-month cystectomy-free survival rates were 96%, 90%, and 84%, respectively. Moreover, the disease-specific OS rates were 100%, 99%, and 99% at 12, 24, and 36 months, respectively.

In cohort B (n = 80), the 12- and 24-month DFS rates were 58% (95% CI, 46.6%-68.2%) and 52% (95% CI, 40.3%-62.7%), respectively, and the median DFS was 25.3 months (95% CI, 9.8-40.1). Additionally, the respective cystectomy-free survival rates at 12, 24, and 36 months were 92%, 88%, and 82%. The disease-specific OS rates were 99%, 96%, and 96% at 12, 24, and 36 months, respectively.

References

1. ImmunityBio requests an urgent meeting with FDA to address the change in the Agency’s unambiguous guidance on Jan 2025 to submit a sBLA for NMIBC BCG unresponsive papillary disease, following an inconsistent refusal to file letter on May 2, 2025. ImmunityBio, Inc. May 5, 2025. Accessed May 5, 2025. https://ir.immunitybio.com/news-releases/news-release-details/immunitybio-requests-urgent-meeting-fda-address-change-agencys?field_nir_news_date_value[min]=
2. Chang S, Chamie K, Kramolowsky E, et al. An update on QUILT-3.032: complete responses to N-803 plus BCG therapy in BCG-unresponsive bladder carcinoma in situ (CIS) with or without papillary disease. Presented at: American Urological Association Annual Meeting; April 26-29, 2025; Las Vegas, NV. Abstract PD12-12.