FDA issues refusal to file letter on sBLA for nogapendekin alfa inbakicept

The FDA has issued a refusal to file (RTF) letter to ImmunityBio in regard to their supplemental biologics license application (sBLA) for use of nogapendekin alfa inbakicept-pmln (NAI; Anktiva) in combination with BCG for BCG-unresponsive non–muscle invasive bladder cancer (NMIBC) in the papillary indication, the company announced in a news release.¹

The sBLA was supported by data from the ongoing QUILT-3.032 trial.

According to ImmunityBio, this letter comes after receiving unanimous guidance to submit the sBLA from leadership at the agency during an in-person January meeting.

The company reported, “At this meeting, all key decision makers were specifically asked and unanimously confirmed that ImmunityBio should submit the sBLA as soon as possible based on the data in the single-arm trial. Relying on this unanimous guidance, the company submitted the sBLA in March 2025. The company has already requested an urgent meeting to resolve the inconsistencies between the directives provided at the January meeting and receipt of the RTF letter.”

NAI was previously approved by the FDA in April 2024 for use in combination with BCG for patients with BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary disease. ImmunityBio completed its sBLA for NAI in the papillary indication in March 2025.

Both the previous approval and the submitted sBLA were supported by data from the ongoing QUILT-3.032 trial.

The RTF does not impact the previous approval of NAI in patients with BCG-unresponsive NMIBC with CIS with or without papillary disease.

“Our commitment to NMIBC patients in the papillary indication and our belief in ANKTIVA’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, founder, executive chairman, and global chief scientific and medical officer of ImmunityBio, in a news release from the company.¹ “We are fully determined to work with the FDA as quickly as possible, including having already requested a Type A meeting, to explore the best path forward. We would also welcome an FDA Advisory Committee meeting as part of the regulatory process going forward. We presented our data at the recent 2025 American Urological Association (AUA) meeting and ANKTIVA+BCG was considered best in class and best in disease by the thought leaders in attendance, when compared to all the therapies currently approved or in development. Patients with BCG-unresponsive papillary disease face a life-changing and life-threatening prospect of a total radical cystectomy, as well as the danger of the disease progressing from non-muscle invasive to muscle invasion with consequent progression and mortality. With the data presented of 99% disease specific survival at 12 months and over 82% patients not requiring bladder removal, it is essential that these patients be provided this treatment option, especially with the safety profile of ANKTIVA+BCG and the already approved indication of papillary disease with CIS. The Company presented these data to the agency in person in January and the agency leaders present unanimously encouraged the company to expeditiously submit a supplemental BLA for this indication.”

Soon-Shiong added, “The agency must explain the confounding inconsistency of approving ANKTIVA+BCG for patients with Papillary with CIS disease, while refusing to file the sBLA for patients with papillary without CIS disease—even though both groups were part of the same trial, in the same high-risk population of BCG-unresponsive non–muscle invasive bladder cancer. In both cases, patients received the same surgical procedure for the papillary component, the same therapy at the same dose, with the same excellent tolerability and meaningful clinical benefit: over 82% bladder-sparing and over 96% disease-specific survival at 36 months…On behalf of patients facing a potential loss of a vital organ and high risk of progression of disease, I urge the agency to reconsider and act now.”

Data on NAI

The sBLA for NAI in the papillary indication is supported by data from cohort B of the pivotal QUILT-3.032 trial (NCT03022825), which assessed NAI in combination with BCG in patients with histologically confirmed BCG-unresponsive high-grade Ta/T1 papillary NMIBC.² In total, the cohort included 80 patients with a median age of 72 years (range, 46 to 93 years). The primary end point was disease-free survival (DFS).

Overall, the study found a DFS of 55.4% (95% CI, 42.0% to 66.8%) at 12 months, 51.1% (95% CI, 37.6% to 63.1%) at 18 months, and 48.3% (95% CI, 34.5% to 60.7%) at 24 months, per Kaplan-Meier estimates. The median DFS was 19.3 months (95% CI, 7.4 to NR).

Progression-free survival (PFS) was 97.1% (95% CI, 88.8% to 99.3%) at 12 months, 94.8% (95% CI, 84.3% to 98.3%) at 18 months, and 88.8% (95% CI, 74.1% to 95.4%) at 24 months. Overall survival was 98.6% (95% CI, 90.2% to 99.8%) at 12 months, 94.3% (95% CI, 82.9% to 98.1%) at 18 months, and 91.7% (95% CI, 79.0% to 96.9%) at 24 months. Disease-specific survival was 100% (95% CI, 100% to 100%) and 97.7% (95% CI, 84.6% to 99.7%) at 12 and 24 months, respectively.

At a median follow-up of 20.7 months (range, 2.9 to 37.1), the cystectomy rate was 7% (5 of 72).

According to ImmunityBio, “In 88% and 82% of subjects, the probability of avoiding surgical removal of the bladder was achieved for as long as 2 and 3 years, respectively, following treatment with ANKTIVA plus BCG.”

The majority (86%) of treatment-emergent adverse events (TEAEs) were grade 1 to 2. According to the authors, “The most frequently reported TEAEs for patients who received BCG plus NAI (cohorts A and B, n=161) were those expected for intravesical instillation of BCG and included dysuria, pollakiuria, and hematuria.”

The most common grade 3 TEAEs included hematuria (2%) and urinary tract infection (2%).

Overall, the QUILT-3.032 trial enrolled patients across 3 study cohorts. Cohorts A and C in the trial included patients with BCG-unresponsive bladder CIS with or without Ta/T1 papillary tumors who received NAI plus BCG (cohort A) or NAI alone (cohort C). The trial also enrolled patients with BCG-unresponsive high-grade Ta/T1 papillary NMIBC who received NAI plus BCG (cohort B).

The QUILT-3.032 trial is ongoing, with final completion expected in March 2029.³

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. News release. ImmunityBio. May 5, 2025. Accessed May 5, 2025. https://www.businesswire.com/news/home/20250505409104/en/ImmunityBio-Requests-an-Urgent-Meeting-With-FDA-to-Address-the-Change-in-the-Agencys-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

2. Chamie K, Chang SS, Kramolowky E, et al. IL-15 superagonist NAI in BCG-unresponsive non–muscle-invasive bladder cancer. NEJM Evid. 2023;2(1):EVIDoa2200167. doi:10.1056/EVIDoa2200167

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. Last updated April 13, 2025. Accessed May 5, 2025. https://clinicaltrials.gov/study/NCT03022825