Around 75% of patients with bladder cancer are diagnosed with non-muscle invasive bladder cancer (NMIBC). The standard of care for high-risk NMIBC (carcinoma in situ, high-grade Ta or T1 tumors) after transurethral resection (TUR) of the bladder tumor is intravesical therapy, such as Bacillus Calmette-Guerin (BCG). Although the majority of patients achieve complete response (CR) to BCG induction therapy, many eventually develop BCG-unresponsive disease, which is challenging and difficult to treat. While radical cystectomy may be curative in more than 80% of patients, some are ineligible for this procedure due to comorbidities, or a preference for bladder-sparing approaches, such as intravesical chemotherapy, or more recently systemic immunotherapy. However, the efficacy of intravesical chemotherapy is suboptimal and while systemic immunotherapy with the immune checkpoint inhibitor pembrolizumab is effective, treatment may be associated with systemic immune-related adverse events. Thus, there is a critical unmet clinical need for an alternative intravesical therapy that is effective, safe, and induces durable responses.

Innovative intravesical therapy, nadofaragene firadenovec, is a replication-deficient recombinant adenovirus vector-based gene therapy that delivers a copy of the human interferon alfa-2b gene into urothelial cells. Based on preclinical data, and promising efficacy and safety in phase 1/2 clinical trials, a multicenter, single-arm, open-label, repeat-dose phase 3 study in BCG-unresponsive NMIBC was conducted. After TUR of all visible bladder tumors, 157 eligible patients received a single intravesical dose (75mL) of nadofaragene firadenovec (3×10¹¹ viral particles per mL) repeated at 3, 6 and 9 months. Patients were enrolled into two cohorts by diagnosis: carcinoma in situ, with or without concomitant high-grade Ta or T1 NMIBC (carcinoma in situ cohort), and high-grade Ta or T1 tumors without concomitant carcinoma in situ (high-grade Ta/T1 cohort). They were evaluated every 3 months for recurrence with urine cytology and cystoscopy (with biopsy, if warranted). Efficacy assessment at 12 months included biopsy from 5 sites in the bladder. The primary endpoint was CR in the carcinoma in situ cohort at any time within 12 months after the first dose of nadofarogene firadenovec. Median follow-up was 19.7 months for the carcinoma in situ cohort and 20.2 months for the Ta/T1 cohort. Intravesical administration of nadofaragene firadenovec resulted in CR in 53.4% of patients in the carcinoma in situ cohort, all within 3 months of the first dose. Median duration of CR was 9.7 months. At 12 months, 24.3% of patients in the carcinoma in situ cohort remained free of high-grade recurrence. In the Ta/T1 cohort, 72.9% of patients were free of high-grade recurrence at month 3, and 43.8% at month 12. Median duration of high-grade recurrence-free survival (RFS) in this group was 12.4 months. In the entire population, recurrences of any stage were reported in 69% of evaluable patients; most were high-grade NMIBC recurrences while progression to muscle invasive bladder cancer was rare (5%). High grade RFS at 1 year for the entire population was 30.5%. By the month 12 cutoff, 29% of patients in the carcinoma in situ cohort and 21% in the high-grade Ta/T1 cohort had undergone cystectomy, with a median time to cystectomy of 8.9 and 8.3 months, respectively. At 24 months, cystectomy-free survival was 64.5% for the total study population, and OS was 91.2% in the carcinoma in situ cohort and 93.5% in the high-grade Ta/T1 cohort. The most frequent drug-related AEs were discharge around the catheter during installation, fatigue, bladder spasms and micturition urgency. Grade 3/4 AEs occurred in 18% of all patients, and only 4% were considered as study-drug related. Only 3 patients stopped treatment, and there were no treatment related deaths.

The authors conclude that nadofaragene firadenovec is an effective gene therapy for patients with BCG-unresponsive NMIBC, with a favorable dosing schedule and manageable safety profile, and thus represents a new treatment option. In a commentary published alongside the study report, the trial investigators are commended for conducting a well-designed study, and nadofarogene firadenovec is acknowledged as having the potential to become the new gold standard treatment for patients with BCG-unresponsive NMIBC.

References

Boorjian SA, et al. Lancet Oncol. 2020; Nov 27. [Online ahead of print].

Kulkarni GS. Lancet Oncol. 2020; Nov 27 [Online ahead of print].