FDA Issues Refusal to File for Nogapendekin Alfa Plus BCG in Papillary NMIBC

• The FDA has issued a refusal to file (RTF) letter for the supplemental biologics license application (sBLA) seeking approval of nogapendekin alfa inbakicept (Anktiva) in combination with Bacillus Calmette-Guérin (BCG).
• This indication is for patients with BCG-unresponsive non–muscle invasive bladder cancer (NMIBC) with papillary disease without carcinoma in situ (CIS).
• A Type A meeting has been requested to address discrepancies between prior FDA guidance and the RTF.

The FDA has issued an RTF letter for the sBLA seeking approval of nogapendekin alfa in combination with BCG for patients with BCG-unresponsive NMIBC with papillary disease without CIS.¹

The sBLA was submitted based on data from cohort B of the single-arm phase 2/3 QUILT-3.032 trial (NCT03022825) and followed a January 2025 in-person meeting with the FDA, where leadership from the Center for Biologics Evaluation and Research, Center for Drug Evaluation and Reserach, and Oncology Center of Excellence reportedly provided unanimous guidance and encouragement to proceed with the submission. Despite this prior feedback, the agency declined to file the application in its current form.

In response, the sponsor has requested a Type A meeting with the Agency to clarify the discrepancy between the January 2025 verbal recommendations and the recent refusal. This underscores the inherent complexities in regulatory expectations, especially for novel agents supported by nonrandomized trial data.

“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,” said Patrick Soon-Shiong, MD, the founder, executive chairman, and global chief scientific and medical officer of ImmunityBio, in a press release.

ImmunityBio submitted the sBLA for the use of nogapendekin alfa in combination with BCG when given to patients with BCG-unresponsive papillary disease in March 2025. Notably, the FDA approved nogapendekin alfa inbakicept plus BCG in April 2024, for BCG-unresponsive NMIBC with CIS with or without papillary tumors. This was based on findings from cohort A of the QUILT-3.032 trial. The press release states that this RTF letter does not affect this previous FDA approval.

Clinical Evidence Supporting the Submission

In the open-label, multicenter QUILT-3.032 trial, investigators evaluated nogapendekin alfa inbakicept alone (cohort C) or in combination with BCG (cohorts A and B) for the treatment of patients with BCG-unresponsive, high-grade NMIBC. Updated data from the study were presented at the American Urological Association (AUA) 2025 Annual Meeting.²

Among patients in cohort A (n = 100), the 36-month complete response (CR) rate was 71% (95% CI, 61.1%-79.6%). The median duration of CR among evaluable responders (n = 71) was 53+ months.² At 12, 24, and 36 months, the cystectomy-free survival rates were 96%, 90%, and 84%, respectively, and the disease-specific overall survival (OS) rates were 100%, 99%, and 99%.

In cohort B (n = 80), the 12- and 24-month disease-free survival (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.

“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,” Soon-Shiong added in the press release.¹

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 6, 2025. https://tinyurl.com/5aeb7apz

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.