Detalimogene Voraplasmid Produces Complete Responses in BCG-Unresponsive NMIBC With CIS

Treatment with the novel, non-viral intravesical gene therapy detalimogene voraplasmid (EG-70) led to complete responses (CRs) with a tolerable safety profile in patients with Bacillus Calmette–Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), according to preliminary data from cohort 1 of the phase 2 LEGEND trial (NCT04752722).1

Findings presented at the 2025 Genitourinary Cancers Symposium showed that evaluable patients (n = 21) achieved an any-time CR rate of 71%. The 3-month CR rate was 67% (n = 21), and the 6-month CR rate was 47% (n = 17). Per data from a Kaplan-Meier analysis, the estimated 6-month CR rate was 51%.

“Preliminary data from the ongoing pivotal phase 2 portion of the LEGEND study suggest a promising safety/tolerability profile with treatment-related adverse effects [TRAEs] that were largely consistent with instrumentation/intravesical administration,” lead study author John Arthur Taylor, MD, MS, and colleagues, wrote in a poster presentation of the data.

Taylor is the John W. Weigel Professor of Urology and Cancer Biology; director of basic urologic research in the Department of Urology; and co-leader of the Drug Discovery Delivery and Experimental Therapeutics Program at the University of Kansas Cancer Center in Kansas City.

Detalimogene Voraplasmid Background and LEGEND Design

Detalimogene voraplasmid is a genetic medicine–based immunotherapy that features a plasmid expressing both IL-12 and regulators of RIG-I, and the agent is intended to stimulate both innate and adaptive immunity.

LEGEND is a phase 1/2 trial; in the phase 1 portion, data showed that patients with BCG-unresponsive NMIBC with CIS experienced a CR rate of 73%.2 In the ongoing phase 2 portion of the study, investigators are further evaluating detalimogene voraplasmid in different cohorts of patients with high-risk NMIBC.1 For all cohorts, patients need to be at least 18 years of age and have an ECOG performance status of 0 to 2. Patients must also be ineligible for or decline cystectomy. Adequate bladder function—defined as being able to retain the study drug for at least 60 minutes—is also required.

In cohort 1, patients with BCG-unresponsive NMIBC and CIS need to have persistent/recurrent high-grade disease (Ta, T1, or TIS) within 12 months of treatment with at least 1 course of BCG and at least 2 maintenance/rechallenge doses of BCG. The study’s other 3 cohorts are intended for patients with BCG-naive NMIBC with CIS (cohort 2); those with BCG-exposed NMIBC with CIS (cohort 3); and patients with BCG-unresponsive high-grade Ta/T1 papillary disease without CIS (cohort 4).

All enrolled patients are receiving detalimogene voraplasmid at 0.8 ng/mL in a 50-mL solution given intravesically at weeks 1, 2, 5, and 6 for up to four 12-week cycles. After cycle 1, patients with a CR or non-CR attributing to persistent CIS or recurrent, high-grade Ta disease continue to treatment in cycle 2, and those with progressive disease discontinue treatment. After cycle 2, only patients with a CR are permitted to proceed to cycles 3 and 4. After cycle 4, those with a CR are allowed to receive detalimogene voraplasmid during weeks 1 and 2 of each 12-week cycle as maintenance for up to 4 additional cycles. Patients with a CR after 8 total cycles can receive 4 additional cycles or proceed to study follow-up.

The study’s coprimary end points are CR rate at week 48 and safety. Secondary end points included progression-free survival, recurrence-free survival, CR rate at the end of each cycle and at the end of treatment, investigator-assessed CR rate at week 48, duration of response, cystectomy-free survival, and health-related quality of life. Antidrug antibodies, pharmacokinetics, and biomarkers are exploratory end points.

Efficacy-evaluable patients treated in cohort 1 (n = 21) had a median age of 74 years (range, 59-92), and the majority were above 65 years of age (71.4%), male (71.4%), and White (95%); all patients were non-Hispanic. Additionally, 90.5% of patients had an ECOG performance status of 0, and the remaining 9.5% had a status of 1. Tumor stages at baseline included T1 with CIS (14.3%), Ta with CIS (14.3%), and CIS (71.4%). The median number of prior BCG doses received was 11 (range, 8-33).

Diving into Safety

No grade 3 or higher TRAEs were reported in any patients within the safety-evaluable population (n = 42). The rates of any-grade, grade 1, and grade 2 TRAEs were 47.6%, 40.5%, and 21.4%, respectively.

TRAEs reported in more than 10% of patients included bladder spasm (any-grade, 19.0%; grade 1, 9.5%; grade 2, 9.5%), dysuria (21.4%; 19.0%; 2.4%), fatigue (11.9%; 7.1%; 4.8%), and pollakiuria (11.9%; 11.9%; 0%).

Study authors noted that TRAEs were reversible and largely consistent with catheterization.

Enrollment in LEGEND is ongoing, and investigators have a target accrual of approximately 300 patients across the multiple cohorts.

References

1. Taylor J, Joshi S, Satkunasivam R, et al. Preliminary results from LEGEND: A phase 2 study of detalimogene voraplasmid (EG-70), a novel, non-viral intravesical gene therapy for patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS). J Clin Oncol. 2025;43(suppl 5):802. doi:10.1200/JCO.2025.43.5_suppl.802
2. Kalota S, Joshi S, Bui M, et al. Legend: a phase 1/2 study of EG-70 (detalimogene voraplasmid), a novel, non-viral intravesical gene therapy for patients with BCG-unresponsive non-muscle invasive bladder cancer with carcinoma in situ (CIS). J Urol. 2024;211(5S2):e5. doi:10.1097/01.JU.0001015816.87470.c9.08