Nadofaragene Firadenovec Sustains Efficacy in Advanced NMIBC in Longer-Term Follow-Up

Nadofaragene firadenovec, a novel intravesical gene therapy for patients with bacillus Calmette-Guérin (BCG) unresponsive non–muscle invasive bladder cancer (NMIBC), demonstrated sustained durability according to findings from 2 cohorts of a phase 3 study (NCT02773849) presented at the 2021 American Urologic Association Annual Meeting.¹

In 2-year follow-up data, investigators reported that among 103 patients with carcinoma in situ (CIS) with or without Ta/T1, 20 patients (19.4%) remained free from high-grade recurrence. Further, of the 55 patients who achieved a complete response (CR) at 3 months following their first dose of nadofaragene firadenovec, 20 (36.4%) remained disease free at 24 months.

In the cohort of patients with high-grade Ta/T1 without CIS (n = 48), 16 patients (33.3%) did experience disease recurrence and 16 (47.5%) of the 35 patients who achieved a complete response at 3 months did not experience high-grade recurrence at 24 months.²

As of the September 2020 data cutoff, 62.1% (n = 64/103) of patients with CIS with or without Ta/T1 remained on study. The rate was similar in the high-grade Ta/T1 cohort (68.8%; n = 33/48).^1,2

“Nadofaragene [firadenovec] represents a potential novel treatment option for patients with high-grade BCG-unresponsive NMIBC,” said Anne K. Schuckman, MD, in a presentation of the data for the first cohort of patients. She added that the therapy holds the potential to “advance the current treatment paradigm” for these patients. Schuckman is an assistant professor at the Keck School of Medicine at the University of Southern California (USC), and director of urologic oncology at the Los Angeles County + USC Medical Center.

Yair Lotan, MD, who presented the results of the high-grade Ta/T1 cohort, concurred, adding that “[nadofaragene firadenovec] demonstrates sustained durability of response.”

Lotan is a professor of urology and holds the Helen J. and Robert S. Strauss Professorship in Urology at UT Southwestern Medical Center. He is also chief of urologic oncology and the Jane and John Justin Distinguished Chair in Urology as well as the medical director of the urologic clinic at UT Southwestern and Parkland Health and Hospital System.

The multicenter, open-label study enrolled 157 patients with high-grade BCG-unresponsive NMIBC to 2 cohorts: those with CIS with or without Ta/T1 (n = 107) and high-grade Ta/T1 without CIS (n = 50); 103 and 48 patients were included in the efficacy analysis, respectively.^1-4

Nadofaragene firadenovec was administered as a single intravesical 75-mL dose of (3 × 1011 viral particles/mL) over 1 hour and was given once every 3 months for up to 4 doses, with additional dosing permitted at investigator’s discretion. The intravesical delivery of the agent prolongs the exposure of the bladder to the human recombinant interferon α-2b (INFα-2b).4 In preclinical studies, IFNα-2b production resulted in tumor regression, presenting a potential avenue for treatment of patients whose tumors do not respond or recur after BCG.⁵

BCG-unresponsive disease was defined as persistent high-grade T1 recurrence occurring within 12 months of BCG initiation, relapse with CIS after initial CR less than or equal to 12 months after last BCG treatment, or relapse with high-grade Ta/T1 NMIBC after last BCG treatment.

Baseline characteristics differed slightly between the 2 cohorts.

Patients in the CIS cohort had a median age of 72 years, 89% of patients were men, and 99% received 2 or more prior courses of BCG prior to enrollment. Specifically, 42% of patients received 2 courses and 57% received 3 or more courses of BCG. In terms of disease stage at study entry, 76% had CIS only, 20% had Ta plus CIS, and 5% had T1 plus CIS. The median time from initial diagnosis of bladder cancer was 20 months.¹

Those in the Ta/T1 cohort had a median age of 71 years, 68% of individuals were men, and 90% of patients received 2 or more prior BCG courses; 56% received 2 courses and 34% received 3 or more courses. The time from initial diagnosis of bladder cancer was 15 months and 70% of patients had Ta disease and 30% had T1 disease.²

^{At 12 months, protocol mandated a 5-site biopsy, which includes the dome, trigone, right and left lateral walls, and the posterior wall. The primary end point was CR in patients with CIS with or without high-grade Ta/T1 papillary disease.1-3}

The trial met its primary end point of CR within 12 months. Specifically, 53.4% (95% CI, 43.3%-63.3%) of patients in the CIS cohort (n = 103) had a CR, all of which occurred at 3 months. The median duration of CR was 9.69 months (95% CI, 9.17-not estimable [NE]); 25 patients (24.3%; 95% CI, 16.4%-33.7%) were free from high-grade recurrence at 12 months.⁴

Twelve-month data for the high-grade Ta/T1 cohort (n = 48) trended slightly higher with 72.9% (95% CI, 58.2%-84.7%) of patients achieving a CR at 3 months and 21 patients (43.8%; 95% CI, 29.5%-58.8%) were recurrence free at 12 months. The median duration of CR was 12.35 months (95% CI, 6.67-NE).⁴

In terms of patients who proceeded to cystectomy at 24 months of the 20 patients in the CIS cohort who had a durable CR at 24 months, 50% went on to cystectomy; for those who did not achieve a CR (n = 48), 23 underwent cystectomy by 24 months. Of the 48 patients who did not achieve a CR, 40 had high-grade recurrence, 7 did not meet the sponsor definition of CR at 3 months, and 1 patient discontinued treatment.¹

Overall, the cystectomy-free survival rate for this cohort was 64.6% (95% CI, 54.1%-73.3%). Further, the overall survival (OS) rate was 94.4% (95% CI, 87.0%-97.6%).¹

For the patients in the high-grade Ta/T1 cohort, of those who were high-grade recurrence free at 24 months (n = 16), 7 had cystectomy by 24 months. For those patients who were not high-grade recurrence free at 3 months (n = 13), 4 proceeded to cystectomy by 24 months. The cystectomy-free survival rate was 69.8% (95% CI, 53.4%-80.9%) and the OS rate was 93.2% (95% CI, 80.4%-97.8%).2

^{Finally, in terms of safety, both investigators reported that most drug-related adverse effects (AEs) were transient and localized with a median duration of 2 or fewer days. Additionally, most drug-related AEs were grade 1/2 and no grade 4 or 5 AEs were reported in either cohort.1,2}

The most common AEs observed in the CIS cohort were discharge around the catheter (24%), fatigue (23%), bladder spasm (18%), micturition urgency (17%), chills (12%), dysuria (10%), and pyrexia (10%).1 The rates for these AEs in the Ta/T1 cohort were 26%, 12%, 14%, 14%, 10%, 16%, and 10%, respectively.²

Two patients in this cohort discontinued because of drug-related AEs in the CIS cohort and 1 patient discontinued treatment in the Ta/T1 cohort.^1,2

References

1. Shuckman AK, Lotan Y, Boorjian SA, Cilwa KE, Dinney CPN. Efficacy of intravesical nadofaragene firadenovec for patients with carcinoma in situ (CIS), BCG-unresponsive non-muscle invasive bladder cancer (NMIBC): longer-term follow-up from the phase III trial. J Urol. 2021;206(suppl 3):e296. doi:10.1097/JU.0000000000002001.01
2. Lotan Y, Shuckman AK, Boorjian SA, Cilwa KE, Dinney CPN. Phase III trial of intravesical nadofaragene firadenovec in patients with high-grade, BCG-unresponsive, non-muscle invasive bladder cancer: two year follow-up in the Ta/T1 cohort. J Urol. 2021;206(suppl 3):e296. doi:10.1097/JU.0000000000002001.02
3. Instiladrin in patients with bacillus Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC). ClinicalTrials.gov. Updated September 10, 2021. Accessed September 11, 2021. https://clinicaltrials.gov/ct2/show/NCT02773849
4. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22(1):107-117. doi:10.1016/S1470-2045(20)30540-4
5. Shore ND, Boorjian SA, Canter DJ, et al. Intravesical rAd-IFNα/Syn3 for patients with high-grade, bacillus Calmette-Guerin-refractory or relapsed non-muscle-invasive bladder cancer: a phase II randomized study. J Clin Oncol. 2017;35(30):3410-3416. Published cor-rection in J Clin Oncol. 2019;37(24):2187.