FDA Revokes Melphalan Flufenamide Approval, Citing Efficacy/Safety Concerns


Approval for melphalan flufenamide has been withdrawn by the FDA due to the failure of its confirmatory trial to demonstrate its clinical benefit and the lack of evidence supporting its safety and effectiveness.

  • The FDA has withdrawn the approval of melphalan flufenamide (Pepaxto; Melflufen) due to the confirmatory OCEAN trial (NCT03151811) not showing its clinical benefit and the lack of demonstrated safety and effectiveness.

  • The decision was made by Peter Marks, MD, PhD, representing the FDA’s Center for Biologics Evaluation and Research and takes immediate effect.

  • The FDA will remove melphalan flufenamide from the Orange Book of Approved Drug Products With Therapeutic Equivalence Evaluations, and Oncopeptides, the manufacturer, will assess the decision, which they previously appealed in 2023.

The FDA has decided to withdraw the approval of melphalan flufenamide, which had previously been granted approval for use in combination with dexamethasone for the treatment of patients with multiple myeloma, as grounds for withdrawal were met.1

The basis for withdrawal was determined as the confirmatory OCEAN trial did not prove the clinical benefit of melphalan flufenamide, and that the available evidence demonstrates that the agent has not been shown to be safe or effective under its conditions of use.1,2

The ultimate decision was issued by Peter Marks, MD, PhD, acting as the commissioner's representative for the FDA’s Center for Biologics Evaluation and Research. This decision takes immediate effect.

The FDA intends is to release a Federal Register notice announcing the availability of the decision and remove melphalan flufenamide from the Orange Book of Approved Drug Products With Therapeutic Equivalence Evaluations.1 Now, the manufacturer, Oncopeptides, will “thoroughly assess the decision,” which it had previously appealed in 2023.3,4

“Continued vigilance regarding safety and long-term follow-up remains key, with well-designed future studies developed in close collaboration with investigators and regulatory authorities being a clear way forward,” Paul Richardson, MD, told Targeted OncologyTM in an interview regarding melphalan flufenamide.

Paul Richardson, MD

Paul Richardson, MD

In February 2021, the FDA granted accelerated approval to melphalan flufenamide in combination with dexamethasone for the treatment of patients with relapsed/refractory multiple myeloma who have received 4 or more prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 CD38-directed monoclonal antibody.

Findings from the single-arm, multicenter, phase 2 HORIZON trial (NCT02963493) supported this FDA decision as among those treated with melphalan flufenamide, the overall response rate was 29% (95% CI 22%-37%) in the overall population and 26% (95% CI, 18%-35) in the triple-class refractory population.5 Responses included 1 stringent complete response, 17 very good partial responses (VGPRs), 28 partial responses (PRs), and 25 minimal responses for a clinical benefit rate (CBR) of 45% (95% CI, 37%-53%) in the overall population vs 13 VGPRs, 18 PRs, and 16 minimal responses in patients with triple-class refractory disease, which equated to a CBR of 39% (95% CI, 31%-49%).6

The median duration of response was 5.5 months in the all-treated population (95% CI, 3.9-7.6 months) and 4.4 months (95% CI, 3.4-7.6 months) in the triple-class refractory population.

In July 2021, the FDA requested a partial clinical hold on studies of melphalan flufenamide as the combination of melphalan flufenamide and dexamethasone led to an increased risk of death in the phase 3 OCEAN trial.5 While the study met its primary end point of progression-free survival improvement (HR, 0.792; 95% CI, 0.640-0.979, P = .0311), the key secondary end point of overall survival improvement greatly differed across the prespecified subgroups treated with either melphalan flufenamide plus dexamethasone or pomalidomide (Pomalyst) plus dexamethasone (HR, 1.104; 95% CI, 0.846-1.441).

“[OCEAN] was a randomized trial looking at a head-to-head comparison between pomalidomide and dexamethasone, and melphalan flufenamide and dexamethasone in relapsed/refractory myeloma, but critically in a much less heavily pretreated population. It was looking specifically at a population of patients in whom lenalidomide had failed them,” explained Richardson, a hematologist/oncologist, clinical program leader of the Jerome Lipper Multiple Myeloma Center, director of clinical research at the Jerome Lipper Multiple Myeloma Center, and institute physician at Dana-Farber Cancer Center, as well as the RJ Corman professor of medicine at Harvard Medical School, in an interview with Targeted OncologyTM.

The Oncologic Drugs Advisory Committee then met in September 2022 to discuss the results of the confirmatory OCEAN trial.

“The focus of the oncology drug advisory meeting was to review the results of the phase 3 OCEAN trial, which had been developed as a confirmatory study conducted internationally to support the accelerated approval of [melphalan flufenamide] as a novel, first-in-class peptide drug conjugate,” said Richardson.

In a 14 to 2 vote, the committee decided that the benefit-risk profile of melphalan flufenamide was not favorable for the indicated patient population based on the results of the trial.

Most recently, the FDA requested that the company withdraw the US marketing authorization for melphalan flufenamide in December 2022, based on the results of the OCEAN trial.6 Based on the FDA’s request, marketing of the agent was halted in the United States on October 22, 2021.

  1. FDA issues final decision to withdraw approval of Pepaxto (melphalan flufenamide). FDA. February 23, 2024. Accessed February 27, 2024. http://tinyurl.com/mtfrdyn4
  2. Oncopeptides receive a decision from the U.S. Food and Drug Administration confirming withdrawal of Pepaxto from the US market. News release. Oncopeptides. February 23, 2024. Accessed February 27, 2024. http://tinyurl.com/5e4966pe
  3. Oncopeptides comments and legal aspects to CDERs response on Appeal Document. Accessed February 27, 2024. https://www.regulations.gov/document/FDA-2023-N-3167-0012
  4. Withdrawn: FDA grants accelerated approval to melphalan flufenamide for relapsed or refractory multiple myeloma. FDA. February 23, 2024. Accessed February 27, 2024. http://tinyurl.com/2hpk9twp
  5. Richardson PG, Oriol A, Larocca A, et al. Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol. Published online December 09, 2020. doi: 10.1200/JCO.20.02259
  6. Oncopeptides provides updates on Pepaxto US marketing authorization. News release. Oncopeptides. December 7, 2022. Accessed February 27, 2024. http://tinyurl.com/46avvwmk

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