Nadofaragene firadenovec is a non-replicating recombinant type-5 adenovirus vector-based gene therapy that delivers a copy of the human IFNα2b gene. The Phase 3 study assessed its safety and efficacy in 157 patients with high-grade, BCG-unresponsive NMIBC. The study met its primary endpoint with 53.4% of patients with CIS±Ta/T1 achieving a complete response (CR), all by 3 months. 43.6% of these patients remained free of high-grade recurrence at 15 months.
Non-replicating adenovirus vectors are widely used due to their advantages as a gene delivery vehicle. However, a crucial concern is that adenovirus vector-mediated transduction is suppressed in individuals with pre-existing anti-adenovirus neutralizing antibodies.
The most commonly used recombinant adenovirus are based on adenovirus type 5 (Ad5). Most adults have pre-existing antibodies to adenovirus as a result of previous environmental exposure.
This analysis focused on correlation of the anti-adenoviral antibody levels to response rate, a secondary objective of the Phase 3 study.
The multicenter, open-label Phase 3 study enrolled 157 patients into two cohorts: CIS±Ta/T1 (carcinoma in situ with or without high-grade Ta or T1) and high-grade Ta/T1 (High-Grade Ta or T1 without concomitant CIS) with 103 and 48 patients, respectively, included in the efficacy analysis.
Nadofaragene (3x1011 vp/mL [75 mL]) was administered once every 3 months for up 4 doses, with additional dosing at the investigator’s discretion. The protocol mandated a 5-site (dome, trigone, right and left lateral walls, posterior wall) biopsy at 12 months.
Blood sample for anti-adenoviral antibody level assessments were collected between 24 and 1 hour predose on Day 1 and 3, 6, 9 and 12 months or at a withdrawal-from-treatment study visit.
A patient was considered to have a positive immunogenic response if a post-baseline anti-adenoviral antibodies titration demonstrated a >2-fold dilution increase from baseline. This analysis was based on the data cut-off at 15 months.
Of the 151 patients included in the efficacy analysis, 129 had anti-adenoviral antibody titer results and were included in this analysis.
Among the 55 patients who achieved CR in the CIS±Ta/T1 cohort, significantly more patients had positive post-baseline immunogenic response (43 vs 8; p= 0.0033). This was similarly observed in the high-grade Ta/T1 cohort where among the 34 patients who remained free of high-grade recurrence at 3 months, significantly more patients had positive post-baseline immunogenic response (30 vs 4; p= 0.0003).
At 15 months, the same trends were noted among patients who remained free of high-grade recurrence, with 19 vs 3 in the CIS±Ta/T1 cohort and 17 vs 2 patients in the high-grade Ta/T1 cohort who had post-baseline immunogenic response, although the differences were not significant. This could be due to the smaller number of patients in this cohort.
Nadofaragene firadenovec instilled intravesically once every 3 months achieves durable CR in patients with high-grade, BCG-unresponsive NMIBC. These data suggest that a significant anti-adenovirus antibody response does not appear to affect efficacy. Nadofaragene firadenovec demonstrates promising efficacy and is a potential novel therapeutic option in a patient population with urgent unmet medical need.
Clinical trial information: NCT02773849
SIGNIFICANT ANTI-ADENOVIRUS ANTIBODY RESPONSE POSITIVELY CORRELATES WITH EFFICACY IN PATIENTS TREATED WITH NADOFARAGENE FIRADENOVEC FOR HIGH-GRADE BCG-UNRESPONSIVE NMIBC
Bladder Cancer > Non-Muscle Invasive Bladder Cancer
Presented By: VIkram Narayan
Authors: VIkram Narayan
Badrinath R. Konety
Ashish M. Kamat
Seth P. Lerner
Robert S. Svatek
Brant A. Inman
Colin P.N. Dinney