A U.S. Food and Drug Administration (FDA) advisory committee overwhelmingly voted that melphalan flufenamide has not demonstrated benefit for treating adult patients with relapsed or refractory multiple myeloma (MM).
After weighing the evidence presented by the FDA and Oncopeptides, the manufacturer of the drug, at its September meeting, the FDA Oncology Drug Advisory Committee voted 14-2 that melphalan flufenamide did not have a favorable benefit-risk profile for its currently indicated patient population.
“There was a questionable benefit in terms of the progression-free survival (PFS) and potential detrimental impact on overall survival (OS), raising safety concerns with this drug,” said FDA advisory committee member Grzegorz Nowakowski, MD, of the Mayo Clinic, while casting his no vote.
In its presentation to the advisory committee, the FDA said that the phase III OCEAN trial failed to meet the trial’s endpoint and to demonstrate the clinical benefit of the drug. The trial compared the performance of melphalan flufenamide with another group of patients who received pomalidomide as the control.
“The data from the OCEAN trial do not support the safety and efficacy of melphalan,” the FDA said, noting that patients in the melphalan flufenamide arm had “unfavorable outcomes” compared to patients in the pomalidomide arm.
At least one of the advisory committee members raised objections to the FDA’s analysis, however. “The OCEAN trial is a positive trial based on the PFS using a pre-specified analytic plan, and I think it’s problematic to have the sponsor submit a [statistical analysis plan] to the FDA and have the FDA see it and have the FDA analyze the data using an alternative methodology,” said FDA advisory committee member Jorge Nieva, MD, of the University of Southern California Keck School of Medicine, while casting his yes vote.
The FDA cited their three main concerns with the OCEAN trial, including:
- A potential detriment in OS between the melphalan flufenamide arm and the pomalidomide arm
- Failure to meet a primary endpoint of a statistically significant improvement in PFS
- Lack of an appropriate dose
Melphalan flufenamide is a lipophilic peptide conjugated alkylating drug that selectively delivers cytotoxic agents into tumor cells, inhibiting proliferation and inducing apoptosis.
The treatment is currently indicated for adult patients with relapsed or refractory MM who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody.
The drug was granted approval through the FDA’s accelerated approval process on February 26, 2021, for use in combination with dexamethasone to treat patients with relapsed or refractory MM based on results of the single-arm HORIZON trial. However, the FDA warned in July 2021 that the OCEAN trial showed an increased risk of death and required that the company suspend enrollment in the trial.
Oncopeptides later withdrew melphalan flufenamide from the U.S. market in October 2021 after it became evident that the FDA did not believe the OCEAN study met the criteria of a confirmatory study.
The FDA will now consider the advisory committee’s vote before making a final determination on melphalan flufenamide.
The drug is currently available in Europe. In August 2022, the European Commission granted marketing authorization to melphalan flufenamide in combination with dexamethasone for adults with MM. The marketing authorization is valid in all European Union states, as well as Iceland, Lichtenstein, and Norway.
Source: FDA Oncology Drug Advisory Committee Meeting, September 2022