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A candidate therapy for nonmuscle invasive bladder cancer (NMIBC) took a regulatory drubbing from an FDA advisory committee, which expressed reservations about the therapy and the data submitted in support of the application.

The committee voted 19-6 against approval of Mycobacterium phlei cell wall-nucleic acid complex (MCNA) for high-risk NMIBC that has failed Bacillus Calmette-Guerin (BCG) immunotherapy. Panelists who voted against the application cited a modest therapeutic benefit, similarities between MCNA and BCG, and the limited number of patients (N=129) included in data submitted in support of the application.

Committee members also expressed disappointment and frustration with the lack of progress toward more effective options for a condition that constitutes a large unmet need.

"I came away from today's session a little angry that we don't have better therapies for bladder cancer," said , of Dana-Farber Cancer Institute in Boston. "I think there is a compelling argument that this is a disease that needs attention. It is not an orphan disease. It has the same number of cases as gastrointestinal stromal tumor or mantle cell lymphoma, oncologic conditions where we are seeing successful clinical trials. It is clearly a disease where we have dismal outcomes and unacceptable choices for way too many people."

During an open discussion, an unidentified panelist said the information presented did not even begin to point toward specific patients who might benefit from the therapy. Noting the paradox between a great unmet need and difficulty in recruiting patients, the panelist exclaimed, "What are they doing, for god's sake, for these patients?"

The vote occurred during a joint meeting of FDA's Oncologic Drugs Advisory Committee and the . FDA is not bound by the decision but usually follows advisory committee recommendations.

Background of Application

MCNA is a non-infectious mycobacteria that occurs widely in the environment, including tap water and soil. According to a briefing report submitted by the sponsor, , of Pointe-Claire, Quebec, M. phlei is not pathogenic for any species. Available evidence suggests MCNA suspension has both immunomodulatory and antiproliferative activity that result in local, nonspecific inflammatory and immune responses that help prevent bladder cancer progression or recurrence.

The principal supporting data for the application came from an involving patients with high-risk NMIBC that had failed BCG therapy. Eligible patients had pathology-confirmed carcinoma in situ (CIS) with or without Ta or T1 papillary tumors of any grade or high-grade Ta/T1 papillary tumors only. Any resection of papillary tumors must have occurred within 56 days before the start of MCNA treatment.

The trial had a primary efficacy endpoint of 40% disease-free survival (DFS) at 1 year.

Investigators in the multicenter trial enrolled and treated 129 patients, of whom 22 completed the planned 2 years of treatment. The principal reason for discontinuing treatment was disease progression (71.3%), followed by adverse events (6.2%).

A randomized study with an accrual goal of 450 patients was initiated but stopped early because of slow accrual (84 patients in 2 years) and other issues.

Primary Endpoint

The completed trial comprised 54 patients who had CIS, 30 with a combination of CIS and papillary tumor, and 31 with papillary tumor only. The 1-year DFS was 23.7%. Subgroup analysis showed that patients with BCG-relapsing disease (N=22) had a 1-year DFS of 39.0% compared with 20.4% for patients with BCG-refractory disease. The number of prior BCG instillations did not influence DFS.

Patients with high-grade papillary tumors only had better 1-year DFS (33.6%), but the confidence intervals overlapped those associated with the majority of patients who had CIS with or without papillary tumor. Median duration of response also was longer (38.8 versus 26 months for patients with CIS), but several members of the committee pointed out that tumor resection might have influenced the response to MCNA.

Progression-free survival, estimated to decrease by 10% to 15% per year, was 85.0% in the total patient population, 91.9% for patients with high-grade papillary tumors only.

Subsequently, 55 (43%) patients underwent cystectomy a median of 263 days after starting MCNA. Among patients who did not benefit from MCNA, the median time to cystectomy was 173.5 days. Of 28 patients who achieved a complete response to MCNA at 1 year, five (17.9%) underwent cystectomy, as compared with 50 of 101 patients who did not achieve a complete response.

"Approximately 24% of the treated patient were disease-free at 1 year," authors of the Telesta briefing document noted. "Among patient who were disease-free at this time point, the response to MCNA was durable and lasted almost 3 years. In addition, patients treated with MCNA were not placed at greater risk of progression, bladder removal, or death. Most importantly, patients were provided a potentially bladder-preserving treatment without undue risk from a delay in surgery."

Unresolved Questions

Authors of an FDA staff document agreed with the desirability of a therapy that can help patients avoid cystectomy, noting that 27% of patients with CIS-containing disease had complete responses at 6 months and that the responses were durable. However, they also pointed out that cystectomy is "strongly recommended" for high-risk, BCG-refractory NMIBC. A substantial number of patients with CIS subsequently underwent cystectomy, regardless of initial response status, and others developed metastatic disease.

"Therefore, the questions remain whether these subjects had been placed at higher risk for developing invasive and metastatic disease by receiving the MCNA treatment rather than cystectomy upfront, and whether the treatment-effect size would justify that risk," FDA staffers said in the report.

"It appears that patients with CIS-containing disease refractory to BCG therapy might represent a population that could benefit from MCNA therapy ... ," the staff report continued. "However, frequent follow-up and vigilant surveillance would be needed to mitigate the concern that delaying cystectomy may increase the risk of the development of invasive disease or metastatic bladder cancer."

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