Two Food and Drug Administration advisory panels voted 18-6 against use of Mycobacterium phlei cell wall-nucleic acid complex (MCNA), an intravesical drug being evaluated for the treatment of non–muscle-invasive bladder cancer at high risk of recurrence or progression in adults failing prior Bacillus Calmette-Guérin (BCG) immunotherapy.
At a meeting of the FDA’s Oncologic Drugs Advisory Committee (ODAC) and the Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC), several panel members expressed being conflicted in their vote, but said they ultimately felt MCNA did not show a clear risk:benefit advantage based on the data presented from a small, single pivotal trial that failed to meet its primary efficacy end point.
“I think it is an effective drug that would be a nice alternative to BCG, but I wasn’t convinced that there was enough of a difference in mechanism of action to accept a single-arm study that wasn’t overwhelmingly convincing that it was better than what is currently being done for these patients,” said Dr. David L. Bartlett, a CTGTAC member with the University of Pittsburgh Medical Center.
Also voting no was ODAC member Dr. Harold J. Burstein of the Dana-Farber Cancer Institute in Boston, who said the toxicity may be low with MCNA, but that he was unclear how to talk to patients about its benefits.
“What do you tell the patient that it does? I can’t answer that question,” he said. “It’s not clear that it spares the bladder. It’s not clear that it improves their longevity. Most of these patients we’ve been told aren’t going to be candidates for cystectomy for any number of reasons, so it doesn’t seem likely that it’s going to avoid or prevent a cystectomy in these patients.”
Although the data submitted for priority review by Telesta Therapeutics was less than stellar, CTGTAC and ODAC jointly considered the biologics license application because limited treatment options exist for patients with BCG-refractory non–muscle-invasive bladder cancer (NMIBC).
Current U.S. and European guidelines recommend cystectomy for high-risk NMIBC after BCG failure, but not all patients are candidates for or want to undergo bladder removal because of the associated high morbidity and poor quality of life. No new intravesical treatments for NMIBC have been approved since valrubicin (Valstar) in 1998 and it is indicated only for BCG-refractory carcinoma in situ (CIS).
MCNA is a suspension containing M. phlei cell wall fragments complexed with nucleic acid oligomers. It is thought to have a dual mechanism of action: direct anti-proliferative/cytotoxic action and indirect immune stimulant activity.
The clinical evidence for MCNA was based on the single-arm, phase III Study 301 in 129 patients with NMIBC at high risk of progression treated with six weekly instillations of MCNA during induction followed by maintenance therapy up to month 24. The disease-free survival (DFS) rate at 1 year was 23.7%, well short of the 40% target set for the primary endpoint.
Still, responses lasted a median of 34 months in the 28 responders and overall progression rates were similar to historical data in BCG-naive controls, according to Zvi Cohen, Ph.D., director of clinical research at Telesta. The rate of bladder removal at 1 year was almost three times lower among responders than among nonresponders (18% vs. 49.5%). In all, 55 (43%) patients went on to cystectomy.
The key safety concern for the panelists was whether treatment with MCNA would put patients at greater risk of muscle-invasive disease and metastasis by delaying cystectomy, the main treatment option for high-risk NMIBC following BCG failure. Notably, 15 (11.6%) patients in Study 301 developed metastatic bladder cancer, Dr. Cohen said.
In patients with CIS-containing disease, the complete response rate was 27% at 6 months and median duration of response was 15.1 months. Active CIS does not typically regress on its own, suggesting a treatment effect from MCNA.
In the subgroup with papillary tumors only, the DFS rate was 35.1% at 1 year, but it was unclear whether this was due to MCNA treatment or because these patients were required to undergo tumor resection within 56 days of their first dose.
The FDA took issue with statistical considerations in Study 301, including the definition of DFS duration, and conducted its own landmark analysis showing a DFS rate at 1 year of 20.9%. Higher DFS rates at 1 year were seen in papillary only vs. CIS-containing disease (27.8% vs. 18.8%) and in BCG-relapsing vs. BCG-refractory disease (36.4% vs. 17.8%), reported Dr. Kristin Baird, medical officer with the Office of Cellular, Tissue, and Gene Therapies (OCTGT) at the FDA’s Center for Biologics Evaluation and Research (CBER).