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
Category
Bladder Cancer > Non-Muscle Invasive Bladder Cancer
Description
Presented By: VIkram Narayan
Authors: VIkram Narayan
Stephen Boorjian
Mehrdad Alemozaffer
Badrinath R. Konety
Leonard Gomella
Ashish M. Kamat
Seth P. Lerner
Robert S. Svatek
Lawrence Karsh
Daniel Canter
Yair Lotan
Brant A. Inman
Mindy Yang
Viviana Garcia-Horton
David Sawutz
Nigel Parker
Colin P.N. Dinney