Introduction:

Patients with Bacillus Calmette-Guerin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) are at significant risk for recurrence and progression and there is an unmet need for local, effective, bladder-preserving treatment options. Nadofaragene firadenovec, a non-replicating recombinant adenovirus vector-based gene therapy that delivers a copy of the human interferon alfa-2b gene into the bladder epithelium, is approved by the FDA for treatment of adult patients with high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with/without papillary tumors (±Ta/T1). The Phase 3 study of nadofaragene firadenovec met its primary endpoint; 53.4% of patients with CIS±Ta/T1 achieved complete response (CR) at three months. The 24-month follow-up results showed that nadofaragene firadenovec was well tolerated, and 36.4% of the patients with CIS±Ta/T1 who achieved a CR remained high-grade recurrence free (HGRF) at 24 months. Herein, we report 36-month follow-up results from the Phase 3 study for the CIS±Ta/T1 cohort.

Methods:

The open-label Phase 3 study enrolled 107 patients with BCG-unresponsive NMIBC with CIS±Ta/T1 (NCT02773849). The efficacy analysis for this cohort included 103 patients who met the protocol definition of BCG-unresponsive NMIBC. Patients received 75 mL of nadofaragene firadenovec (3x10¹¹ viral particles/mL) once every 3 months for up to 4 doses. The protocol mandated a 5-site biopsy (dome, trigone, right and left lateral walls, posterior wall) at 12 months and patients who were HGRF were offered continued treatment once every 3 months at the investigator’s discretion. Assessments beyond 24 months were performed in accordance with usual clinical practice. The study is ongoing, with a planned 5-year treatment and monitoring phase; the follow-up results reported here are based on the 36-month interim data for the CIS±Ta/T1 cohort.

Results:

Mean (standard deviation) duration of follow-up for the entire cohort was 42.1 (12.6) months*, with a total of 13/107 (12.1%) patients having received 36 months of treatment.

At 36 months, 14/55 (25.5%) patients who had achieved a CR at 3 months remained HGRF. For these patients, the Kaplan–Meier (KM)-estimated probability of duration of CR for at least 12, 24 and 36 months was 46.5%, 36.6% and 34.2%, respectively (Figure).

In the overall CIS±Ta/T1 cohort (N=103), the KM-estimated median (95% confidence interval [CI]) duration of HGRF survival was 6.0 (3.4, 8.3) months, and probability (95% CI) of HGRF survival for at least 12 months was 30.1% (21.5, 39.2). Two patients (1.9%) discontinued due to adverse events, while four (3.9%) experienced progression to muscle-invasive disease. The KM-estimated cystectomy-free survival (95% CI) at 36 months was 53.8% (43.3, 63.1), and the three-year overall survival was 90.4% (82.3, 94.9).

Conclusion:

Intravesical nadofaragene firadenovec, administered once every three months, demonstrated a sustained durability of response in patients with BCG-unresponsive CIS±Ta/T1 papillary disease. Nadofaragene firadenovec represents a novel treatment option for BCG-unresponsive NMIBC with a favorable benefit-to-risk ratio.

*All patients had passed 36 months at data cutoff on 09 September 2021.

Figure. Kaplan–Meier estimated durability of complete response in patients with CIS±Ta/T1 papillary disease.

Funding: The ongoing follow-up of the Phase 3 study is sponsored by Ferring Pharmaceuticals Ltd. The original study was funded by FKD Therapies Oy.