Dr Martini on the Clinical Significance of Nadofaragene Firadenovec in BCG–Unresponsive NMIBC

“There was no biopsy [required] in the [QUILT-3.032 trial], whereas there was a mandated biopsy at the end of the [CS-003 trial], which found that nearly 1 out of 10 patients had occult disease in the absence of visible disease on cystoscopy.”

Alberto Martini, MD, a urologic oncologist at the University of Cincinnati Medical Center, discussed the clinical significance of nadofaragene firadenovec-vncg (Adstiladrin), the first FDA-approved gene therapy for patients with BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC). *I would just add this to the lower third

Nadofaragene firadenovec was FDA approved for this indication in 2022 based on findings from the open-label, multicenter, single-arm phase 3 Study CS-003 (NCT02773849). In this trial, intravesical nadofaragene firadenovec elicited a complete response (CR) rate of 51% (n = 50/98; 95% CI, 41%-61%) in patients with carcinoma in situ (CIS) with or without concomitant high-grade Ta or T1 disease.

In the per-protocol analysis of the broader study population (n = 151), 59.6% of patients (95% CI, 51.3%-67.5%) achieved a CR at 3 months, with approximately half of these responses maintained at 12 months. Importantly, all patients underwent bladder biopsy at 12 months, and 10% of those without visible disease on cystoscopy were found to have occult disease, underscoring the importance of pathologic confirmation in NMIBC trials, according to Martini.

Martini placed these data in the context of outcomes from research with nogapendekin alfa inbakicept-pmln (Anktiva), an interleukin-15 superagonist evaluated in the phase 2/3 QUILT-3.032 trial (NCT03022825). In this single-arm, multicenter study of 77 patients with BCG-unresponsive, high-risk NMIBC with CIS with or without Ta/T1 papillary disease following transurethral resection, the CR rate was 62% (95% CI, 51%-73%). Among those who achieved a CR, 58% maintained a duration of response (DOR) of at least 12 months, and 40% maintained a DOR of at least 24 months.

Martini noted that although these QUILT-3.032 results suggest encouraging durability, trial design differences complicate direct comparison with the CS-003 study. Specifically, the QUILT-3.032 trial allowed reinduction for patients with early treatment progression and did not mandate 12-month biopsy, whereas the CS-003 study included a mandatory biopsy, which identified subclinical disease in approximately 1 of 10 patients considered disease free by cystoscopy.

According to Martini, nadofaragene firadenovec represents an important advance in bladder-preserving therapy for patients with BCG-unresponsive NMIBC, a historically challenging clinical setting with limited alternatives. However, he emphasized that although both nadofaragene firadenovec and nogapendekin alfa inbakicept have demonstrated meaningful clinical activity, interpretation of efficacy must be grounded in differences in trial design, methodology, and biopsy requirements.