Half of Patients With Post-BCG Bladder Cancer Achieve CR With Nonviral Gene Therapy

WASHINGTON — More than half of patients with previously treated non-muscle invasive bladder cancer (NMIBC) had complete responses (CRs) with an intravesical gene therapy, according to preliminary results from an ongoing study.

The interim data showed that 54% of 125 patients achieved a CR with detalimogene voraplasmid, and the 12-month CR rate was 25%. Among patients attaining CRs, 84% remained in CR at the 9-month evaluation and 59% remained in CR at the 12-months evaluation.

The therapy has been well tolerated, as fewer than 5% of patients had grade ≥3 treatment-related adverse events (TRAEs), reported Ashish Kamat, MD, of the MD Anderson Cancer Center in Houston, at the American Urological Association (AUA) annual meeting.

Kamat highlighted that the “durability data” were encouraging, but also cautioned that the findings are preliminary. Still, he said it was “also encouraging to note that 96.8% of patients were free of progression to T2 or more advanced disease. A primary analysis with longer follow-up is planned in the second half of 2026, and the [therapy developer] is planning to have discussions with the FDA later this year.”

The study involved patients whose disease had proven unresponsive to traditional first-line treatment with intravesical bacillus Calmette-Guérin (BCG). Multiple therapies are in development to meet that need. During a post-presentation discussion, AUA session co-moderator Adam Kibel, MD, of Brigham and Women’s Hospital in Boston, asked how urologic oncologists might use the different treatments.

“We’ve all wrestled with that, and I don’t think there’s going to be one clear winner. It’s not going to be one size fits all,” said Kamat. “We’re going to adapt it to different patients. For example, a patient that doesn’t have the ability to come to the clinic very often might need a treatment that’s once very 3 months, even though the efficacy might not look that high. On the other hand, a patient that has very high risk on BCG nonresposive disease and says, ‘Throw the kitchen sink at me,’ might want some that has a very high CR rate.”

“I think it’s great for our patients to have all these options, but it’s more complicated for us to have that true shared decision-making with the patient,” he added.

Co-moderator David Penson, MD, of Vanderbilt University Medical Center in Nashville, said multiple questions from the online audience revolved around the relative safety and efficacy versus other treatment options.

“If you look at the data at 3-months and the durability data, [they are] pretty much parallel to what we saw with nadafaragene [Adstiladrin], because nadafaragene is proven,” Kamat said. “When we look at viral versus nonviral delivery technique, some people will say that nonviral [such as detalimogene] is less durable, but it seems to have similar results to at least one of the approved gene therapies.”

Kamat referenced an ongoing need for novel, bladder-sparing therapies to treat BCG-unresponsive NMIBC. Many existing therapies are toxic, require frequent follow-up visits and procedures, involve complex administration and storage, and possibly the need for biosafety handling. As many as 80% of patients are not in response after 1 year.

Detalimogene works via plasmid delivery of three genes that activate innate and adaptive immune response within the bladder, he continued. The treatment involves fewer administrations per 12-week cycle with less patient-related preparation and no need for special handling. The product can be stored in a standard freezer and administered by a physician or nurse in an exam room.

The phase I/II LEGEND study involves patients with high-risk BCG-unresponsive NMIBC, defined as carcinoma in situ with or without high-grade Ta/T1 that is persistent or recurrent within 12 months of BCG treatment. Patients receive intravesical doses of the gene therapy at weeks 1, 2, 5, and 6 of a 12-week cycle, each dose requiring a 16-minute dwell time. Patients not in CR after 12 weeks have the option for a second induction. Maintenance consists of doses on weeks 1 and 2 every 12 weeks for a maximum of 3 years.

The primary endpoint is CR at any timepoint. Secondary endpoints include duration of response (DOR), CR at landmarks, and progression-defined survival.

The 125 patients had a median age of 71, and men accounted for 80% of the cohort. About 60% of patients had CIS and the rest had CIS with Ta/T1 disease. More than 90% of the patients had declined cystectomy, and the rest were ineligible. All patients had received BCG (median of 12 doses), and a fourth of the patients had received additional treatment.

The 54% of patients who attained CR had a median follow-up of 5.5 months, and 91% of the CRs occurred at the 3-month assessment. Median time to CR was 2.4 months. Kamat said 22 patients have completed the 12-month evaluation, and 21 others have pending evaluations at 6-12 months and potential to achieve CR.

The most frequent TRAEs were fatigue (21.6%), dysuria (13.6%), micturition urgency (12%), pollakiuria (12%), and bladder spasm (11.2%).