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SAN ANTONIO -- More than 70% of patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) achieved complete responses to a novel gene therapy, a small preliminary trial showed.

Across a range of doses, 16 of 22 patients had a complete response to detalimogene voraplasmid (EG-70), including 15 at 3 months and 10 at 6 months. Additionally, seven of 10 patients treated with the recommended phase II dose had complete responses. A majority of the responses persisted for 3-6 months.

About half of patients had treatment-related adverse events (TRAEs), only one of which reached grade 3 severity, reported Gordon Brown, DO, of Summit Health in Voorhees, New Jersey, at the American Urological Association annual meeting.

"Interim data from the phase I portion of the study suggest a promising safety, tolerability, and efficacy profile," said Brown. "Reported TRAEs are mostly grade 1/2 and consistent with catheterization/intravesical administration. As a noninfective gene therapy, there are no special handling precautions, patient restrictions post-treatment or ultra-cold chain logistics considerations. The treatment was delivered effectively and easily within our clinics, using our existing infrastructure without burdensome changes."

Updated trial results for an adenoviral oncolytic gene therapy continued to show promising safety and efficacy. Cretostimogene grenadenorepvec led to complete responses in three-fourths of 105 evaluable patients with BCG-unresponsive NMIBC. Among patients followed for at least a year, more than 80% of the responses lasted at least 12 months, reported Mark Tyson, MD, of the Mayo Clinic in Scottsdale, Arizona.

NMIBC accounts for about 80% of all newly diagnosed bladder cancers, and about 30% of the cases have high-risk features. Intravesical instillation of BCG is standard of care for high-risk patients, but the disease recurs or progresses in half of cases (BCG unresponsive). Patients with recurrent/progressive disease have limited options beyond radical cystectomy, which remains standard of care to prevent progression to muscle-invasive bladder cancer, Brown noted in his introductory comments.

EG-70 is a nonintegrating, nonviral gene therapy designed for administration in any urology clinic. The therapy has a simplified preparation and administration process and requires no specialized storage or handling, reducing treatment burden for patients and clinic personnel, he continued.

EG-70 has a containing a DNA plasmid that encodes retinoic acid-inducible gene (RIG) 1 agonist and interleukin (IL)-12. Administered intravesically, the gene therapy transfects and stimulates the immune system in the bladder.

The RIG-1 agonist stimulates NK cells and suppressor cell attenuation to promote tumor killing and also stimulates T-cell recruitment and neo-antigen presentation, Brown explained. IL-12 activates T-cell dependent cytokine response to promote tumor killing and immune memory. Bladder-restricted production has the potential to drive a strong therapeutic effect while reducing the potential for systemic adverse events.

The phase I component of the LEGEND trial included 24 patients (22 evaluable for response), who received two or four doses of EG-70 per 12-week cycle. The primary endpoint was safety, and the secondary endpoint was efficacy at 3 months.

Laboratory studies showed dose-dependent levels of IL-12 protein in the urine of every patient but no clinically significant levels in plasma.

The safety profile of all 24 patients showed that TRAEs occurred in 13 patients, and all but one TRAE was grade 1 or 2. The only grade 3 TRAE was renal failure, which occurred in a patient with a history of renal failure. The most common TRAEs (any grade) were hematuria (12.5%), dysuria (12.5%), and micturition urgency, fatigue, nocturia, and pyrexia (8.3% each).

The efficacy results showed a 3-month complete response rate of 68% (70% in patients who received the recommended phase II dose). Brown said 11 of 15 complete responses at 3 months persisted for at least 3 months, including six of seven responses with the recommended phase II dose.

Enrollment in the phase II component of the study has begun, with an accrual target of 100 patients. Patients will receive four doses of EG-70 at weeks 1, 2, 5, and 8 of a 12-week cycle.

Results after enrollment of 105 patients in the trial of cretostimogene remained consistent with earlier reports after 34 patients and 66 patients. The latest results showed complete responses in 79 (75%) patients at any time during follow-up. Additionally, responses persisted for 12 moths or longer in 29 of 35 (83%) responding patients followed for at least a year, said Tyson.

The results with single-agent cretostimogene compared favorably with those of the trial that combined the gene therapy with pembrolizumab (Keytruda). The combination led to complete responses in 29 of 34 (85%) patients, and 14 of 16 (88%) patients followed for a year had a response duration ≥12 months. Results from other recent trials of novel therapies for BCG-unresponsive bladder cancer showed complete responses in 41-62% of patients.

The collective results with cretostimogene suggest the gene therapy has the potential to become backbone therapy in NMIBC, according to Tyson.