FDA Requests Withdrawal of Melphalan Flufenamide for R/R Multiple Myeloma

The FDA has requested a withdrawal of the United States marketing authorization for melphalan flufenamide (Pepaxto) for patients with relapsed or refractory multiple myeloma.¹

The decision is based on the outcome of the confirmatory phase 3 OCEAN trial (NCT03151811). While the study met its primary end point of progression-free survival (PFS) improvement (HR, 0.792; 95% CI, 0.640-0.979, P = .0311), there were mixed overall survival rates in the relapsed or refractory myeloma subgroups (HR, 1.104; 95% CI, 0.846-1.441.

“We respect FDA's accelerated approval regulations,” said Jakob Lindberg, chief executive officer of Oncopeptides, in the press release. “Multiple myeloma remains an incurable disease, and the treatment options for patients with triple class refractory disease will ultimately become exhausted. The OCEAN study demonstrated clinical benefit for multiple myeloma patients, in particular for non-transplanted elderly patients where the unmet medical need remains very high.”

Previously in 2021, melphalan flufenamide was granted accelerated approval when used in combination with dexamethasone for adult patients with relapsed or refractory multiple myeloma who had been given 4 or more prior lines of therapy and whose disease was refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody. This approval was based on positive results from the phase 2 HORIZON study (NCT02963493).

Then, the confirmatory OCEAN trial which evaluated the agent showed there to be worse OS rates. Further, the study failed to verify its clinical benefit which led the FDA to place a partial clinical hold on all trials of melphalan flufenamide in combination with dexamethasone. The FDA also issued a warning about a death risk associated with the OCEAN study.

In October 2021, Oncopeptides A.B. pulled the drug from the market and re-applied for FDA approval of the agent under the new brand name. Then in September 2022, the FDA’s Oncologic Drugs Advisory Committee voted that melphalan flufenamide is not favorable for this currently indicated patient population.

The OCEAN study was a randomized, head-to-head comparison between pomalidomide and dexamethasone, and melphalan flufenamide and dexamethasone in patients with relapsed/refractory myeloma. While the study met its primary end point of PFS improvement (HR, 0.792; 95% CI, 0.640-0.979, P = .0311), the OS results were mixed (HR, 1.104; 95% CI, 0.846-1.441).

In the overall population, the ORR was 29% and was 26% in the triple-class refractory population. Median DOR was 5.5 months and there was a median PFS of 4.6 months. The median overall survival at the median follow-up of 14 months was 11.6 months.

Grade 3 or greater adverse events (AEs) were seen in 96% of the 157 patients evaluated. The most frequently observed AEs included neutropenia (79%), thrombocytopenia (76%), and anemia (43%), and the most common grade 3 or 4 nonhematologic event was pneumonia (10%). Reversible thrombocytopenia and bleeding were also observed in the trial.

While the FDA has requested a withdrawal of the marketing for melphalan flufenamide in the United States, the commercialization of the agent is ongoing in Europe as it received a full approval from the European Medicines Agency on August 18, 2022.

REFERENCE:

Oncopeptides provides update on Pepaxto US marketing authorization. News release. Oncopeptides AB. December 7, 2022. Accessed December 8, 2022. https://bit.ly/3VZYpe3