Detalimogene voraplasmid (EG-70) is a novel, non-viral investigational intravesical gene therapy, designed to induce local innate and adaptive immunity via sustained interleukin-12 expression and retinoic acid-inducible gene I pathway stimulation. In Phase 1 of the LEGEND study (NCT04752722), detalimogene was well tolerated with preliminary efficacy results in patients (pts) with Bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) ± papillary disease. Cohort 1 is a pivotal Phase 2 cohort evaluating efficacy and safety in this population.
Cohort 1 enrolled adults (≥18 yrs) with BCG-unresponsive CIS ± papillary (Ta/T1) tumors who were either ineligible for or declined cystectomy. Pts received four 50-mL intravesical doses of detalimogene at weeks 1, 2, 5 and 6 of each 12-week cycle during Year (Yr) 1. Pts with persistent or recurrent disease after Cycle 1 were eligible for re-induction. Those achieving a complete response (CR) at Yr 1 transitioned to maintenance treatment: doses at weeks 1 and 2 of each cycle for up to two yrs. Efficacy assessments included quarterly urine cytology and cystoscopy, mandatory templated biopsies at the 12-month (mo) assessment, and as clinically indicated. The primary endpoint is CR rate at any time. Secondary endpoints are duration of response (DOR), landmark CR rates and safety.
A total of 125 pts were enrolled (median age 71.0 years (35.0-90.0); 80.8% male. Pts received a median of 12 prior BCG doses (6-50); 24.8% received additional prior therapies; 39.2% had CIS + papillary disease. Median number of prior recurrences was 2 (0-11). CR rate was 54.0% (95% CI 44.9-63.0) at any time and 43.0% (95% CI 34.0-52.3) at 6 mo. Median time to CR was 2.1 mo (1.5-6.2); with 91.0% of CRs occurring at first assessment. At data cut-off, 96.8% remained free from progression to ≥T2 disease. Treatment-related adverse events (TRAEs) occurred in 55.2% of pts, predominantly Grades 1-2 (91.3%). Common TRAEs included fatigue (21.6%), dysuria (13.6%), micturition urgency (12.0%), pollakiuria (12.0%) and bladder spasm (11.2%). Grade x{2265}3 TRAEs (4.8%) and serious TRAEs (1.6%) were infrequent. TRAEs led to dose interruption in 2.4% and discontinuation in 2.4% of pts.
Interim results of LEGEND Cohort 1 demonstrate encouraging activity of detalimogene in a heavily pre-treated BCG-unresponsive NMIBC population. The rapid onset of response, non-viral platform, and favorable safety profile support detalimogene voraplasmid as a promising bladder-sparing option in this setting.
enGene Inc