Patients who were enrolled under the amended protocol with at least one post-baseline disease assessment achieved a CR of 56% at 3 months (n = 62) and a 62% at 6 months (n = 37), with 4 patients having successfully converted to CR post reinduction. Moreover, all 5 patients who completed the 9-month assessment had a CR.
Regarding safety, detalimogene demonstrated favorable toxicity among patients in the overall pivotal cohort (n = 125). The incidence of treatment-related adverse effects (TRAEs) was 42%, with 1.6% and 0.8% of patients in this cohort experiencing dose interruptions or discontinuations due to TRAE, respectively.
“We are pleased to report an improved 6-month CR rate for patients being treated with detalimogene under our amended protocol,” Hussein Sweiti, MD, MSc, chief medical officer of enGene, stated in a news release. “With a competitive preliminary efficacy profile and potential for best-in-class tolerability and ease of use, we believe detalimogene could emerge as the first-line therapy for patients with high-risk, BCG-unresponsive NMIBC.”
To date, data from LEGEND alongside a differentiated profile continues to support the company’s planned submission of a Biologics License Application (BLA) for detalimogene in the second half of 2026. The Company continues to expect a potential FDA approval in 2027.
“Careful selection of an appropriate bladder-sparing therapy is of utmost importance in creating a long-term strategy to maintain a patient’s disease control and quality of life, while minimizing the logistical burden on patient and practice,” Suzanne Merrill, MD, senior physician, urologic oncologist, and bladder cancer regional lead at Colorado Urology added in a news release. “I am pleased to see the positive trajectory of detalimogene’s efficacy and tolerability data. Combined with its ease of use, detalimogene would be an attractive option to both patients and a busy urology practice.”
What was the design of LEGEND?
Detalimogene voraplasmid is a genetic medicine–based immunotherapy that utilizes a plasmid encoding interleukin-12 (IL-12) and regulators of retinoic acid–inducible gene I (RIG-I).2 The agent is designed to stimulate both innate and adaptive immune responses.
LEGEND (NCT05703955) is a first-in-human, open-label, multicenter, dose-escalation and -expansion trial evaluating detalimogene voraplasmid in patients at least 18 years of age with BCG-unresponsive NMIBC with CIS with or without resected papillary tumors who are ineligible for or who have chosen not to undergo cystectomy.2,3 The study comprises 4 cohorts:
Cohort 1: Patients with Bacillus Calmette-Guérin (BCG)-unresponsive NMIBC and carcinoma in situ (CIS) who experienced persistent or recurrent high-grade disease (Ta, T1, or TIS) within 12 months of at least 1 full induction course and 2 maintenance/rechallenge doses of BCG.
Cohort 2: Patients with BCG-naive NMIBC and CIS.
Cohort 3: Patients with BCG-exposed NMIBC and CIS.
Cohort 4: Patients with BCG-unresponsive, high-grade Ta/T1 papillary disease without CIS.
Patients must also have an ECOG performance status of 0 to 2, adequate bladder function, and either be ineligible for or have refused cystectomy.
Of note, all patients included in the current analysis were enrolled under an amended protocol implemented in Q4 of 2024, aligning LEGEND with American Urological Association (AUA) guidelines and standards.1
The pivotal cohort enrolled 125 patients—exceeding their initial target by 25%. All participants received detalimogene voraplasmid at 0.8 ng/mL in a 50-mL intravesical solution administered at weeks 1, 2, 5, and 6 for up to 4 cycles (12 weeks each).2,3 After cycle 1, patients achieving a CR or non-CR (persistent CIS or recurrent high-grade Ta disease) continued treatment; those with progressive disease discontinued. After cycle 2, only patients with a CR proceeded to cycles 3 and 4. Following cycle 4, patients with a CR could receive maintenance therapy at weeks 1 and 2 of each 12-week cycle for up to 4 additional cycles, with the option for 4 further cycles or study follow-up after 8 total cycles.
The study’s coprimary end points are CR rate and safety. Secondary end points include progression-free survival, recurrence-free survival, CR rate at the end of each treatment cycle and at end of therapy, investigator-assessed CR rate at week 48, duration of response (DOR), cystectomy-free survival, and health-related quality of life. Exploratory endpoints include pharmacokinetics, antidrug antibodies, and biomarker analyses.
What prior data have read out from this trial?
In September 2024, enGene reported preliminary efficacy data from 31 patients in the pivotal cohort of LEGEND, including 21 patients enrolled prior to the 2024 protocol amendment.1 Among these 21 patients, the CR rate at any time and at 3 months was 55% (95% CI, 38%–71%), and the 6-month CR rate was 41% (95% CI, 25%–59%). The 12-month CR rate was notably lower than those reported with other FDA-approved therapies for BCG-unresponsive NMIBC.
Previously presented data from cohort 1 at the 2025 Genitourinary Cancers Symposium also showed that evaluable patients (n = 21) achieved an any-time CR rate of 71%.2 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%.
Following protocol amendment, the company observed improved preliminary 6-month CR rates, suggesting enhanced efficacy under the revised trial design.1
What recent updates have been made to the LEGEND trial?
Following discussions with the FDA, the primary end point for the pivotal cohort has been revised from 12-month CR rate to CR rate at any time, aligning the study design with other recent regulatory precedents. The key secondary end point is now DOR among patients achieving CR.
Enrollment across additional study cohorts includes:
Cohort 2a: BCG-naive NMIBC with CIS (n = 30)
Cohort 2b: BCG-exposed NMIBC with CIS who have not received adequate BCG (n = 45)
Cohort 3: BCG-unresponsive, high-risk NMIBC with papillary-only disease (n = 36)
enGene plans to finalize a statistical analysis plan (SAP) with the FDA to define the efficacy-evaluable population. A data update from the pivotal cohort is anticipated in the second half of 2026, pending accumulation of sufficient 12-month CR data.
References
- Detalimogene demonstrates improved complete response rate of 62% at 6 months. News release. enGene. November 11, 2025. Accessed November 11, 2025. https://engene.com/detalimogene-demonstrates-improved-complete-response-rate-of-62-at-6-months/
- 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
- LEGEND study: EG-70 in NMIBC patients who are BCG-unresponsive and high-risk NMIBC patients who have been incompletely treated with BCG or are BCG-naïve (LEGEND STUDY). ClinicalTrials.gov. Updated September 4, 2025. Accessed November 11, 2025. https://clinicaltrials.gov/ct2/show/NCT04752722
