Introduction:

Nadofaragene firadenovec is a recombinant adenoviral vector-based intravesical therapeutic capable of expressing the human interferon alpha-2b transgene in treated urothelium. A recent phase 3 trial in high-grade bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) reported a 60% complete response rate in the efficacy population at 3 months, and this response was maintained in 51% of patients at 12 months. This study examined the value of anti-adenovirus antibody level as a predictor of therapeutic response durability in patients receiving nadofaragene firadenovec.

Methods:

157 BCG-unresponsive NMIBC patients were treated on a single-arm, open-label phase 3 trial. 75 mL nadofaragene firadenovec (3 x 10¹¹ vp/mL) was instilled intravesically for one hour once every three months for up to four doses, with additional dosing at the investigator’s discretion. Serum antibody levels were assessed 1-24 hours pretreatment at baseline, and 3, 6, 9 and 12 months or at study-withdrawal visit. Assays were performed at laboratories certified per Clinical Laboratory Improvement Amendments (CLIA) standards. Fold change was calculated as the ratio of on-treatment to baseline antibody level. Final treatment response was assessed at 12 months or time of disease recurrence, whichever was earlier.

Results:

91 (58%) patients in the treatment population had evaluable antibody titers. 47 (52%) patients were high-grade recurrence-free at month 12. On-treatment antibody titers for all patients were at or higher than baseline levels. While baseline titers were not associated with response, high baseline levels were associated with higher frequency of 3-month and peak post-treatment titers >800 [Figure 1]. On-treatment titers >800 were seen in 89% and 59% of responders and nonresponders, respectively (p=0.001). Sensitivity of this test for detecting responders was 89% (negative predictive value, 78%) [Figure 2]. On-treatment antibody fold change >8 from baseline was seen in 51% and 27% of responders and nonresponders, respectively (p=0.02). Elevated on-treatment antibody titers and fold change from baseline were noted in 47% and 18% of responders and nonresponders, respectively (p=0.004). Specificity of the combined test for detecting responders was 82% (positive predictive value, 73%) [Figure 2].

Conclusion:

Secondary analysis of the prospective, multicenter phase 3 nadofaragene firadenovec trial in BCG-unresponsive NMIBC indicates a role for assaying baseline and on-treatment antibody titers. A combination of antibody titer and fold-change levels can potentially predict durable treatment response to this novel therapeutic in a patient population with an urgent unmet clinical need.

Funding: FKD Therapies Oy, AI Virtanen Institute for Molecular Sciences.