December 2, 2020 - Patients with high-grade Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer who responded to the investigational gene therapy nadofaragene firadenovec had a lower rate of cystectomy and delayed time to cystectomy compared with those who did not respond.
Patients with high-grade Bacillus Calmette-Guérin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) who responded to the investigational gene therapy nadofaragene firadenovec (rAd-IFN/Syn3) had a lower rate of cystectomy and delayed time to cystectomy compared with those who did not respond, according to additional data from a phase 3 trial (NCT02773849).1
The results, which were presented during the Society of Urologic Oncology 21st Annual Meeting, showed that 26.5% (n = 40) of patients underwent cystectomy; this included 29.1% (n = 30) of those in the cohort of patients with carcinoma in-situ (CIS) with or without concomitant high-grade Ta or T1 papillary disease and 20.8% (n = 10) of those in the cohort of patients with high-grade Ta/T1 disease without concomitant CIS. The median time to cystectomy in the 2 cohorts was 8.87 months versus 8.31 months, respectively.
Patients who achieved a complete response (CR) to treatment experienced a substantially longer median time to cystectomy versus those who did not, at 11.35 months versus 6.36 months, respectively (P = .0432). At 24 months, the estimated cystectomy-free survival among all patients who received treatment was 65.4%; this proved to be similar between the 2 cohorts.2
“These data further reinforce the potential of nadofaragene firadenovec to help with the lack of treatment options available to [patients with] high-grade NMIBC after BCG stops working for them,” study investigator Robert Svatek, MD, MSCI, professor and chair of the Department of Urology at UT Health, stated in a press release.1 “If approved, nadofaragene firadenovec will be used by urologists in their offices giving us a new tool for the management of our patients.”
The multicenter, phase 3 trial enrolled patients who were 18 years of age or older who had CIS, Ta/T1 high-grade disease with concomitant CIS, or Ta/T1 high-grade disease without concomitant CIS. All patients were unresponsive to BCG and had to have a life expectancy of over 2 years and an ECOG performance status of 2 or less.
Previous results from an efficacy analysis of 151 patients who received nadofaragene firadenovec were presented during the Society of Urologic Oncology 20th Annual Meeting. Data were stratified by patients who had CIS with or without Ta/T1 disease (n = 103) and high-grade Ta/T1 papillary disease (non-CIS; n = 48). The primary end point was CR rate in the CIS cohort and high-grade recurrence-free survival (HGRF) rate in the non-CIS cohort.
Data showed that 24% of patients with CIS with or without Ta/T1 disease who received the investigational gene therapy continued to experience a CR at 12 months. Moreover, at 3 months, the HGRF rate was 73% in patients with papillary disease; at 12 months, it was 44%.3
In the CIS cohort specifically, the CR rates at 3 months, 6 months, 9 months, and 12 months were 53.4%, 40.8%, 35.0%, and 24.3%, respectively. In the non-CIS cohort, the HGRF rates at these time points were 72.9%, 62.5%, 58.3%, and 43.8%, respectively. All responses observed at 12 months were confirmed via protocol-mandatory 5-point biopsies.
In November 2019, the FDA granted a priority review to the biologics license application (BLA) for nadofaragene firadenovec as a treatment for this patient population; the decision was partly based on data from the trial.4 However, in May 2020, the regulatory agency issued a response to the BLA, requesting additional information pertaining to manufacturing processes.5
Additional results presented at this year’s meeting revealed that patient characteristics and prior treatment history do not impact response to treatment with the therapy. The post-hoc subgroup analysis of the trial was based on the efficacy population comprised of 151 patients.6
At 3 months and 15 months, no significant differences in response rate was observed between males and females, age groups, those who were relapsed versus refractory to BCG, or those who received less than 3 or more than 3 prior courses of BCG. Moreover, no substantial differences were noted between the subgroups analyzed in terms of duration of response with the exception of the CIS +/- Ta/T1 cohort. In this subset, patients who had previously received 3 or less courses of BCG experienced a significantly longer DOR versus those who received more than 3 courses, at 12.68 months versus 4.96 months, respectively (P = .0172).
Results also indicated that significant anti-adenovirus antibody response did not appear to influence outcomes.7 Of the 151 patients included in the analysis, 129 had anti-adenoviral antibody titer results. Of 55 patients in the CIS +/- Ta/T1 cohort who experienced a CR to treatment, more had a positive post-baseline immunogenic response, at 43 months versus 8 months (P = .0033).
In the cohort of patients with high-grade Ta/T1 disease, results were found to be similar. Of 34 patients who were free of high-grade recurrence at 3 months, more had positive post-baseline immunogenic response, at 30 months versus 4 months, respectively (P = .0003). The same trend was noted at 15 months although this was not found to be statistically significant.
“The research suggests that nadofaragene firadenovec may answer the need for additional targeted treatments that reduce the rate of bladder cancer recurrence and progression in patients where BCG has failed,” study investigator Vikram Narayan, MD, assistant professor of urology at Emory University School of Medicine and director of Urologic Oncology at Grady Memorial Hospital, concluded in the release.