Novel Gene Therapy Wows for BCG-Unresponsive Bladder Cancer

Sharon Worcester

December 08, 2020

A novel intravesical gene therapy for bladder cancer has shown such promising results in clinical trials that experts are suggesting that it be considered the "new gold standard," even though it is not yet available.

The product, nadofaragene firadenovec, is being developed by FerGene Inc as a treatment for patients with high-grade bacillus Calmette-Guérin (BCG)–unresponsive non-muscle-invasive bladder cancer (NMIBC).

It is currently under consideration for approval by the US Food and Drug Administration.

The product is an adenovirus vector-based gene therapy containing the gene interferon alfa-2b. It is administered by catheter into the bladder once every 3 months. The vector enters the cells of the bladder wall, the gene turns on, and the cells then secrete high quantities of the interferon alfa-2b protein.

This approach "turns the patient's own bladder wall cells into interferon microfactories, enhancing the body's natural defenses against the cancer," the manufacturer explains.

New clinical results were published online November 27 in The Lancet Oncology.

At median follow-up of 19.7 months, a complete response (CR) was seen in about half of patients (53.4%, 55 of 103 patients) with BCG-unresponsive NMIBC in situ (with or without a high-grade Ta or T1 tumor), who received an initial dose of the investigational therapy in the single-arm, open-label, repeat-dose trial.

For 25 patients (45.5%), response was maintained at 12 months, report the investigators, led by Stephen A. Boorjian, MD, of the Mayo Clinic, Rochester, Minnesota.

These patients were among 151 treated in the trial between September 19, 2016, and May 24, 2019, and were included in a per-protocol efficacy analysis. All CRs occurred within 3 months of the initial treatment. The duration of CR was 9.69 months.

The remaining 48 patients had high-grade Ta or T1 disease. Of these patients, 35 were free of high-grade recurrence at month 3; 21 of these patients remained recurrence-free at month 12. Median follow-up in that cohort was 20.2 months, and median duration of high-grade recurrence-free survival was 12.35 months.

The most common adverse events were discharge around the catheter during placement, fatigue, bladder spasms, and micturition urgency.

In an accompanying editorial, Girish S. Kulkarni, MD, of Princess Margaret Cancer Center, the University of Toronto, Ontario, Canada, explains that BCG-unresponsive NMIBC is a "notoriously difficult to treat" condition for which nonsurgical treatment options are suboptimal. He said the findings by Boorjian and colleagues are encouraging.

"The reported efficacy, manageable adverse event profile, and straightforward dosing schedule all have the potential to make nadofaragene firadenovec the new gold standard for patients with BCG-unresponsive bladder cancer," Kulkarni writes. "At the very least, this study helps establish a new benchmark against which new therapies for this disease can be tested, thus enabling the conduct of future randomized studies."

Hope for Bladder Preservation

Kulkarni also notes that the results support "the oncological safety of an attempt at bladder preservation" in this patient population. Only 5.3% of patients experienced disease progression to muscle invasion during the study. Among those patients, salvage with cystectomy appeared feasible, he writes.

Senior study author Colin P. N. Dinney, MD, further emphasized the importance of the treatment for bladder preservation.

"Once patients with high-grade, non-muscle-invasive bladder cancer no longer benefit from their initial BCG treatments, patients often make an informed decision to decline cystectomy ― a highly complex and life-altering bladder removal surgery ― or are often medically ineligible for this complex operation, leaving them with limited options," Dinney explained in a press statement.

Treatment with this new gene therapy represents an effective alternative, he suggested.

"As a practicing urologist, I'm encouraged by these efficacy and safety data, which demonstrate the potential for a novel treatment option that fits within the urology practice and gives patients the choice of receiving treatment once every 3 months ― which may be a particularly important consideration in this evolving healthcare environment," said Gennady Bratslavsky, MD, president of the Society of Urologic Oncology Clinical Trials Consortium, which has worked with the manufacturer on the clinical trials of the product.

The study is ongoing; a 4-year treatment and monitoring phase is planned.

Boorjian has received consulting fees and personal fees from Ferring, FerGene, Sanofi, and ArTara. Dinney has used shared resources funded by a grant from the National Institutes for Health/National Cancer Institute at MD Anderson Cancer Center and has received grant and personal fees from FKD therapies. He also is a creator of intellectual property owned by UT/MDACC related to the use of genetic alterations as a predictive biomarker for response to nadofaragene firadenovec. Financial disclosures of several coauthors are available in the original article. Kulkarni has disclosed no relevant financial relationships.

Lancet Oncol. Published online November 27, 2020. Abstract, Editorial

Sharon Worcester is a reporter for MDedge News, part of the Medscape Professional Network.

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