Indirect Comparison Favors Nogapendekin Alfa Inbakicept + BCG Over Nadofaragene in BCG-Unresponsive NMIBC

Nogapendekin alfa inbakicept-pmln (Anktiva) plus BCG (NAI+BCG) showed potential efficacy advantages, including response duration and bladder preservation, over nadofaragene firadenovec-vncg (Adstiladrin) in patients with BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ, with or without papillary disease, according to an indirect treatment comparison (ITC) sponsored by ImmunityBio that was shared at the 2026 AUA Annual Meeting.¹

Clinical Context

BCG-unresponsive NMIBC is one of the most clinically challenging scenarios in urologic oncology. The approval of multiple agents in this space over the past several years, including pembrolizumab (Keytruda), nadofaragene firadenovec, NAI+BCG, and gemcitabine intravesical system (Inlexzo), has given clinicians and patients more options; however, without randomized comparisons across these agents, treatment selection in shared decision-making conversations has relied largely on single-arm trial data from each agent's registration study.

ITCs offer a methodology to bridge this evidence gap, using statistical techniques to adjust for differences in patient populations across separate trials and generate comparative estimates of relative efficacy. The current analysis compared NAI+BCG, evaluated in the phase 3 QUILT-3.032 trial, against nadofaragene firadenovec, evaluated in the phase 3 study NCT02773849, using 2 validated ITC methodologies: matched-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC).

Source Trial Data: QUILT-3.032 and NCT02773849

NAI+BCG received FDA approval in April 2024 for BCG-unresponsive NMIBC with CIS, with or without papillary tumors, based on data from QUILT-3.032. In that trial, the 12-month CR rate among CIS patients was 55.7% (95% CI, 45.1%-65.9%), with a median DOR of 22.1 months among complete responders.²

Nadofaragene firadenovec was approved by the FDA in December 2022 for BCG-unresponsive NMIBC with CIS. In its pivotal trial (NCT02773849), the 3-month CR rate in the CIS cohort was 53.4% (95% CI, 43.3%-63.3%), with 24.3% of complete responders maintaining response at 12 months and a median DOR of 9.7 months.³

ITC Methodology

Investigators conducted feasibility assessments to confirm suitability of the 2 trials for ITC on efficacy endpoints. Despite minor baseline differences between the two study populations, standardized mean differences were less than 0.25 for all assessed variables, indicating adequate comparability supported by clinical expert review.

Five mutually reported baseline characteristics (age 65 years or older, sex, ECOG performance status, race, and tumor stage) were included in the weighting model to minimize confounding. Effective sample size and E-values were calculated to assess weighting adequacy and robustness to unmeasured confounding, with E-values supporting model robustness. Importantly, the analysis was limited to efficacy endpoints; a safety comparison was not feasible due to the absence of disease-specific cohort adverse event reporting in the nadofaragene trial.

Efficacy Results

After propensity score matching, NAI+BCG demonstrated a numerical trend toward a higher overall CR rate compared with nadofaragene (68.0% vs 53.5%; OR, 2.01; 95% CI, 0.94-3.64), though this difference did not reach statistical significance. The CR rate advantage, while not statistically significant, translates to an odds ratio of 2.01.¹ This suggests that patients treated with NAI+BCG had approximately twice the odds of achieving a complete response, a clinically relevant magnitude even in the absence of statistical significance.

There was a statistically significant difference in duration of response (DOR) favoring NAI+BCG. After weighting, the median DOR was 22.1 months with NAI+BCG versus 9.7 months with nadofaragene, a difference of 12.45 months (95% CI, 8.17-17.09).

Bladder preservation outcomes also favored NAI+BCG. At 12 months, only 11% of NAI+BCG patients had undergone cystectomy compared with 29% of nadofaragene patients, representing a nearly threefold difference in the rate of surgical bladder removal. Cystectomy-free survival was significantly prolonged with NAI+BCG (HR, 0.40; 95% CI, 0.21-0.75), reflecting a 60% reduction in the risk of cystectomy or death.

Overall survival was not statistically different between the 2 arms (HR, 0.85; 95% CI, 0.22-3.31), though the wide confidence interval reflects the limited power of indirect comparisons to detect OS differences.

Interpreting the Findings

Investigators appropriately urge caution in interpreting these results, acknowledging the inherent limitations of unanchored, population-adjusted ITCs. Unlike randomized controlled trials, ITC analyses cannot fully account for unmeasured confounders, differences in trial conduct, patient selection practices across sites, or the impact of subsequent therapies on outcomes. The inability to conduct a parallel safety comparison further limits the completeness of the comparative picture.

Nevertheless, the convergence of findings across multiple efficacy endpoints consistently favoring NAI+BCG provides a coherent directional signal that investigators believe is informative for shared clinical decision-making.

REFERENCES

1. Jayram G, Ly C, Moradian H, et al. Indirect treatment comparison of nogapendekin alfa inbakicept-pmln plus BCG and nadofaragene firadenovec-vncg in patients with BCG-unresponsive non-muscle invasive bladder cancer CIS ± papillary (NMIBC). J Urol. 2026;215(5 suppl):e711. doi:10.1097/01.JU.0001191716.05440.37.15

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):EVIDoa2200167. doi:10.1056/EVIDoa2200167

3. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(1):107-117. doi:10.1016/S1470-2045(20)30540-4