Detalimogene voraplasmid, a non-viral intravesical gene therapy, was safe and produced encouraging activity in heavily pretreated patients with BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), with or without papillary disease, according to pivotal phase 2 interim results from the phase 2 LEGEND trial (NCT04752722) presented during the
At a median follow-up of 5.5 months (range, 1.0-25.8 months), evaluable patients (n = 125) experienced a complete response (CR) rate at any time of 54.0% (95% CI, 44.9%-63.0%). Ninety-one percent of CRs occurred at the first assessment, with a median time to onset of CR of 2.1 months (range, 1.5-6.2 months). Among 67 patients who achieved a CR, the Kaplan-Meier estimate of 12-month CR was 25% (95% CI, 11%-41%).
As of the April 21, 2026, data cutoff, 46.3% of responders had an ongoing CR, 96.8% of participants remained free from progression to T2 or greater disease, and 90.4% had not undergone radical cystectomy. Among responders who reached landmark assessments, 84% remained in CR at the 9-month assessment, and 59% remained in CR at the 12-month assessment. Investigators noted that 21 patients had not yet reached the 12-month evaluation at the time of data cutoff, leaving additional CR outcomes pending. The re-induction success rate among patients without initial CR was 14.0%.
“In this interim analysis, [detalimogene voraplasmid] was safe and very well tolerated. The durability data [are] encouraging, but it's important to remember that they are preliminary. It's also encouraging to note that 96.8% of patients were free of progression to muscle-invasive or greater disease.” -Ashish M. Kamat, MD, MBBS, endowed professor of urology at The University of Texas MD Anderson Cancer Center in Houston.
Since the FDA adopted its draft guidance for BCG-unresponsive NMIBC in 2016, the therapeutic landscape for bladder cancer has seen a rapid expansion of newly studied and approved agents, Kamat stated. However, current and emerging therapies continue to impose a heavy burden on patients due to treatment-related toxicities, frequent clinic visits, and demanding administration schedules. Community oncology practices face additional operational hurdles, including complex preparation protocols, specialized storage requirements, and biosafety concerns. Beyond these logistical challenges, long-term efficacy remains a critical priority.
Detalimogene voraplasmid was designed to address these practice-level barriers associated with existing intravesical therapies, as it requires no thaw or pre-wash steps, can be stored in a standard freezer, can be administered by a nurse or medical assistant in an exam room, and requires no urine bleaching or decontamination procedures, Kamat explained.
LEGEND is a single-arm, open-label phase 2 study evaluating detalimogene voraplasmid in high-risk NMIBC across multiple cohorts.1,2 The pivotal cohort (cohort 1) enrolled 125 patients with BCG-unresponsive NMIBC with CIS with or without high-grade Ta/T1 disease who experienced persistent or recurrent disease within 12 months of adequate BCG therapy. Patients were required to be at least 18 years of age, have an ECOG performance status between 0 and 2, and be unable or unwilling to undergo cystectomy.
Detalimogene voraplasmid was administered as a 50 mL intravesical instillation at 0.8 mg/mL via catheter with a 60-minute dwell time at weeks 1, 2, 5, and 6 of each 12-week induction cycle. Patients without a CR at first evaluation were eligible for re-induction; those achieving or maintaining response proceeded to maintenance dosing (weeks 1 and 2 every 12 weeks) for years 2 and 3.
The study’s primary end point was CR rate at any time; key secondary end points included duration of response (DOR) at 12 months or longer, CR at landmark time points, safety, and progression-free survival.
Baseline characteristics in the pivotal cohort (n = 125) reflected a heavily pretreated population.1 The median age was 71.0 years (range, 35.0-90.0) and 80.8% of patients were male. In total, 60.8% had CIS only while 39.2% had CIS with Ta/T1 disease. The median number of prior BCG doses was 12 (range, 6-50), and 24.8% of patients had received at least one prior non-BCG therapy, including intravesical chemotherapy (16.8%), systemic immunotherapy (6.4%), and viral gene therapy (4.0%). The median number of prior NMIBC recurrences was 2 (range, 0-11).
TRAEs were reported in 55.2% of patients (n = 125). Of those experiencing TRAEs, 91.3% were grade 1/2, and events resolved after a median of 8 days. The most frequently reported TRAEs (≥10%) were fatigue (21.6%), dysuria (13.6%), micturition urgency (12.0%), pollakiuria (12.0%), and bladder spasm (11.2%).
Grade 3 or higher TRAEs occurred in 4.8% of patients (n = 6), of which 5 resolved at the time of data cutoff. Serious TRAEs were each reported in 2 patients (1.6%); both resolved and did not lead to treatment discontinuation. No grade 5 TRAEs were reported. Dose interruption and discontinuation due to TRAEs each occurred in 3 patients (2.4%).
The drug’s developer plans to discuss these results with the FDA in the second half of 2026. A readout of data from the primary analysis, which incorporates longer follow-up, is also expected in that period.
Disclosures: Kamat reported consulting/advisory relationships with Astellas Pharma, CG Oncology, Cystotech, Immunity Bio, Nonagen, Pfizer, ProTara, and Seattle Genetics; and involvement in a current scientific study or trial for FerGene.
