A multicentre, open-label Phase-3 study investigating nadofaragene firadenovec for high-grade, Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) achieved encouraging, durable, high-grade, recurrence-free survival.
Dr. Neal Shore (Carolina Urologic Research Center, USA) presented the outcomes of the papillary disease (PD) cohort from the trial . Nadofaragene firadenovec is a novel intravesical-administered adenovirus-mediated gene therapy (rAd-IFN) delivering the human interferon (IFN) α2b gene. When combined with the excipient Syn3, rAd-IFN/Syn3 has been shown in a phase-2 trial to be well tolerated and to lead to sustained localized IFNα2b gene expression.
The phase-3 trial enrolled 157 patients (mean age 71 years), 50 of whom had PD. Intravesical administration of nadofaragene firadenovec (3×1,011 viral particles/mL [75 mL]) was planned every 3 months for up to 4 doses during 12 months. All patients with an absence of high-grade disease recurrence at month 12 were offered continued treatment every 3 months. The primary endpoint was complete response (CR) at any time for the carcinoma in situ cohort (CIS ± Ta/T1, or PD [Ta/T1 alone]) unresponsive to BCG. Key secondary endpoints included the rate and durability of high-grade recurrence-free survival as well as safety in patients with PD.
The efficacy population consisted of 48 patients with PD. Of those, 35 (72.9%) achieved recurrence-free survival at 3 months, 30 (62.5%) at 6 months, 28 (58.3%) at 9 months, and 21 (43.8%) at 12 months. The primary endpoint was met; 55 (n=103; 53.4%; 95% CI 43.3-63.3) patients in the CIS cohort achieved CR during the 12-month period. The total cohort (n=151) had 59.6% CR, whereas 72.9% of the PD subgroup (n=48) achieved CR. All CRs occurred in the first 3 months. Patients with CIS demonstrated 24.3% HGRF at month 12, 43.8% of PD patients. In PD patients, the median duration of HGRF was 12.35 months (95% CI 6.67, months-not reached).
The most common drug-related treatment-emergent adverse events were instillation site discharge (33.1%), fatigue (23.6%), bladder spasm (19.7%), micturition urgency (17.8%), and hematuria (16.6%). No patient died.
In short, nadofaragene firadenovec demonstrated clinical response in patients with high-grade BCG-unresponsive NMIBC for both CIS and PD cohorts. Responses remained durable for at least one year, and the safety profile and dosing schedule were acceptable. “These data represent a significant therapeutic advancement for BCG-unresponsive patients”, concluded Dr. Shore.
1. Shore N, et al. Results from the phase III study of nadofaregene firadenovec: Safety and efficacy in patients (pts) with high-grade, BCG-unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC). EAU20 Virtual Congress, 17-26 July 2020, Game-Changing Session 2.