ABLE-22: Safety and efficacy evaluation of nadofaragene firadenovec alone or in combination with chemotherapy or immunotherapy—A randomized, open-label, phase 2 study.

Abstract

TPS4630 Background: Bacillus Calmette-Guérin (BCG) is the standard first-line therapy for patients with high-risk non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) ± papillary tumors; however, patients whose disease is unresponsive to BCG therapy are unlikely to benefit from further courses of BCG. Bladder-preserving treatment options for patients with BCG-unresponsive NMIBC with CIS ± Ta/T1 include intravesical gene therapy (nadofaragene firadenovec-vncg), intravesical chemotherapy (gemcitabine and docetaxel), and immunotherapy (intravenous pembrolizumab and intravesical nogapendekin alfa inbakicept-pmln). In a pivotal phase 3 study, 53.4% of participants (55/103) with BCG-unresponsive NMIBC with CIS ± Ta/T1 achieved a complete response (CR) within 3 months of a single instillation of nadofaragene firadenovec, and of them, 45.5% (25/55) maintained a CR at 12 months. Nadofaragene firadenovec in combination with chemotherapy or immunotherapy may further improve clinical efficacy. ABLE-22 (NCT06545955) is an interventional study evaluating the safety and efficacy of nadofaragene firadenovec alone or in combination with chemotherapy (gemcitabine and docetaxel) or immunotherapy (pembrolizumab) in participants with high-risk BCG-unresponsive NMIBC. Participants not responding at month 3 will be offered reinduction. Methods: ABLE-22 will include approximately 40 to 75 sites across the United States and Canada; sites in Asia, Australia, and Europe may be included. Participants (anticipated N = 150) will be randomly assigned 1:1:1 to receive nadofaragene firadenovec (n = 50), nadofaragene firadenovec plus gemcitabine and docetaxel (n = 50), or nadofaragene firadenovec plus pembrolizumab (n = 50). Adults aged ≥18 years with documented NMIBC with CIS ± Ta/T1 that is unresponsive to ≥2 courses of BCG therapy within the last 12 months are eligible to enroll. The primary endpoint is CR (defined as absence of low- and high-grade NMIBC) at months 3 or 6, as participants with persistent NMIBC (any CIS, low-grade Ta, and > 3 cm or multifocal high-grade Ta) will be offered reinduction once, at month 3. Secondary endpoints include durability of CR, incidence of muscle-invasive progression, cystectomy-free survival, pathologic staging, overall survival, and safety. Durability of CR will be followed up to month 36 (assessed quarterly for the first 24 months); all other secondary endpoints will be assessed up to and including month 36. Exploratory endpoints include changes in expression of potential biomarkers in blood and urine. Results from this investigational, randomized, multicenter, open-label study evaluating the safety and efficacy of nadofaragene firadenovec alone or in combination with chemotherapy or immunotherapy are expected July 2028. Clinical trial information: NCT06545955 .