Phase 2 data highlight potential of detalimogene voraplasmid

In this interview, Rian J. Dickstein, MD, medical director of the Bladder Cancer Program at Chesapeake Urology, discusses the promise and challenges of detalimogene voraplasmid, a novel non-viral, plasmid-based gene therapy under investigation for patients with BCG-unresponsive non–muscle invasive bladder cancer (NMIBC). Unlike viral vectors, the therapy does not integrate into the genome, alleviating concerns about genetic alteration. It is also shelf-stable, easily reconstituted, and does not require specialized storage or handling, making it practical for clinical use.

Preliminary data from the phase 2 LEGEND trial (NCT04752722) showed a 71% complete response (CR) rate, with Kaplan-Meier–estimated 6-month CR at 51%. Although these results compare favorably with other therapies in this setting, Dickstein emphasized caution due to the small patient cohort and the early stage of follow-up. The decline in CR from 67% at 3 months to 47% at 6 months is consistent with patterns seen in other trials. Possible explanations include tumor immune evasion, disease biology, or waning treatment effect. Longer follow-up will clarify whether responses plateau or continue to drop off.

Mechanistically, detalimogene voraplasmid is designed to activate both innate and adaptive immune responses, with the adaptive component—stimulated by IL-12 expression—potentially driving long-term durability. Safety findings have been encouraging, with only grade 1-2 local adverse events such as dysuria, bladder spasm, and fatigue reported, and no systemic immune-related toxicities observed.

Feasibility of the 60-minute drug retention requirement was generally good, even among elderly patients, though urologists should address preexisting urinary symptoms to optimize exposure. For patients who are poor candidates for or decline radical cystectomy, Dickstein expressed hope that this therapy could delay or potentially obviate the need for surgery, though longer-term data are needed before drawing definitive conclusions.