Nadofaragene firadenovec promotes bladder preservation in BCG-unresponsive NMIBC

Nadofaragene firadenovec-vncg helps preserve the bladder in patients with bacillus Calmette-Guérin (BCG)-unresponsive nonmuscle-invasive bladder cancer (NMIBC) at 5 years, with an acceptable safety profile, as shown in a phase III trial.

“Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for BCG-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1,” the investigators said.

This study assessed 157 patients with BCG-unresponsive NMIBC in two cohorts: CIS±Ta/T1 (CIS; n=107) and Ta/T1 without CIS (Ta/T1 cohort; n=50). Participants received nadofaragene firadenovec 75 mL (3×10¹¹ vp/mL) intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment for those remaining high grade-recurrence free (HGRF).

Patients were enrolled from 33 sites in the US, of whom 151 were included in efficacy analyses. Median follow-up was 50.8 months, with 27 percent receiving ≥5 instillations and 7.6 percent receiving treatment for ≥57 months. [J Urol 2024;212:74-86]

At month 57, 5.8 percent (95 percent confidence interval [CI], 2.2‒12.2) of patients with CIS and 15 percent (95 percent CI, 6.1‒27.8) of those with high-grade Ta/T1 were HGRF, with Kaplan-Meier-estimated HGRF survival of 13 percent (95 percent CI, 6.9‒21.5) in the CIS cohort and 33 percent (95 percent CI, 19.5‒46.6) in the Ta/T1 cohort.

At month 60, cystectomy-free survival was 49 percent (95 percent CI, 40.0‒57.1): 43 percent (95 percent CI, 32.2‒53.7) and 59 percent (95 percent CI, 43.1‒71.4) in the CIS and Ta/T1 cohorts, respectively. Overall survival was 80 percent (95 percent CI, 71.0‒86.0): 76 percent (95 percent CI, 64.6‒84.5) and 86 percent (95 percent CI, 70.9‒93.5) in the CIS and Ta/T1 cohorts, respectively.

Notably, only five patients (four with CIS and one with Ta/T1) clinically progressed to muscle-invasive bladder cancer.

“With 5 years of follow-up data, the present study demonstrates that nadofaragene provided nearly half of participants in the CIS cohort and two-thirds of those in the Ta/T1 cohort with bladder preservation at 60 months, representing a safe treatment option for patients with BCG-unresponsive NMIBC,” the investigators said.

“Furthermore, no new safety signals emerged with long-term follow-up, and no deaths were attributed to the study drug, which is noteworthy given that it is a novel, first-in-class intravesical gene therapy,” they added.

Agents

Currently, FDA-approved agents used in the treatment of BCG-unresponsive NMIBC include valrubicin, pembrolizumab, and nadofaragene.

In a previous study, valrubicin had a complete response of 21 percent in patients with BCG-refractory CIS, but this trial was conducted prior to the standardized definition for BCG-unresponsive disease. [J Urol 2000;163:761-767; Cancer Med 2023;12:21944-21968]

On the other hand, a study on pembrolizumab reported a complete response rate of 41 percent at 3 months. However, 22 percent of patients had immune-related adverse events. [Lancet Oncol 2021;22:919-930]

“The current study provides the longest-term follow-up efficacy data to date,” the investigators said.

“[A]lthough long-term efficacy was limited, future investigation will focus on retreatment options for patients who recur, combination therapies, as well as biomarker-directed strategies,” they said. [Eur Urol 2022;81:223-228]