FDA Confirms Decision to Withdraw Melphalan Flufenamide Approval in Multiple Myeloma

The FDA has determined that sufficient criteria have been met to withdraw the approval for melphalan flufenamide (Pepaxto; Melflufen), which had previously been indicated for use in combination with dexamethasone for the treatment of patients with multiple myeloma.¹

The regulatory agency judged the basis for withdrawal on having shown that the confirmatory OCEAN trial (NCT03151811) conducted as a condition of accelerated approval did not confirm the clinical benefit of melflufen, 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 final decision, which was issued by the Commissioner’s designee, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, is effective immediately. In accordance with the decision, the agency is expected to publish a Federal Register notice announcing the availability of the decision and remove the agent from the Orange Book of Approved Drug Products With Therapeutic Equivalence Evaluations.1

Manufacturer Oncopeptides will now “thoroughly assess the decision,” which it had previously appealed in 2023.^3,4

“Pepaxto was a drug that did work in certain patients. In the OCEAN trial, melflufen was compared against pomalidomide [Pomalyst] and dexamethasone, which was not how it was or would be used in the US population,” Joshua Richter, MD, said in an interview with OncLive^®. “We would have used the drug in pomalidomide-refractory patients. Also, if you subset out the data in the Fredrik Schjesvold publication, patients who didn’t have a transplant or a transplant more than 3 years ago still benefited from the drug, so I felt that there was a space for it.”

“Did we lose a drug that was going to be great for everybody? No, unfortunately, I don’t think that this will have a major impact on how we approach things. That said, we have a number of patients who exhaust all standard approaches, and we need something [for them],” Richter added. Richter is an associate professor of medicine in the Division of Hematology and Medical Oncology at The Tisch Cancer Institute and director of Multiple Myeloma at the Blavatnik Family-Chelsea Medical Center at Mount Sinai in New York, New York.

Melflufen received accelerated approval from the FDA in February 2021 for use in combination with dexamethasone in patients with relapsed/refractory multiple myeloma who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 CD38-directed monoclonal antibody.⁵

The decision was based on data from the single-arm, multicenter, phase 2 HORIZON trial (NCT02963493) in which treatment with melflufen led to an objective response rate of 23.7% (95% CI, 15.7%- 33.4%) and a median duration of response of 4.2 months (95% CI, 3.2-7.6) in the patient population included in the approval.

“The role of alkylator therapy in myeloma is certainly changing, Richter continued. “We know that alkylators can impact T-cell health and may not be optimal things to use prior to T-cell redirection therapies like bispecific agents and CAR T-cell therapy. We recognize that alkylators can have effects on genomics within myeloma. They can cause and may precipitate secondary malignancies like myeloid cancers [such as] myelodysplastic syndrome and acute myeloid leukemia.”

“Alkylators, to me, in many ways, are like Goldilocks, right? You can give low-dose oral melphalan or oral cyclophosphamide and that porridge can sometimes be too cold and doesn’t really get the job done. You can give high-dose alkylators like high-dose melphalan and transplant and that porridge may be too hot. I liked Pepaxto as the kind of porridge that is just right, almost like an intermediate-dose melphalan. Prior to the drug coming off the market, I did have some patients on it who were doing quite well.”

In July 2021, the FDA released an alert indicating that the combination of melflufen and dexamethasone led to an increased risk of death in the phase 3 OCEAN trial.⁸

In September 2022, the Oncologic Drugs Advisory Committee held a meeting to discuss the results of the confirmatory trial. The committee voted 14 to 2 that the benefit-risk profile of melflufen was not favorable for the indicated patient population based on the results of the confirmatory trial.¹

In December 2022, the FDA requested that Oncopeptides withdraw the US marketing authorization for melflufen based on data from the confirmatory phase 3 OCEAN trial.⁶ At the FDA’s request, the company stopped marketing the agent in the United States on October 22, 2021.

“I recognize and appreciate the FDA’s stance. They’re making the moves that they feel are appropriate based on the data that exist. That said, I always wish we had more drugs, because the further down you go in the treatment paradigm, the risk vs benefit changes,” Richter concluded. “But ultimately, I don’t think [the decision is] going to move the needle that much in myeloma, because there are some other newer therapies that are probably going to have a much bigger impact.”

The FDA’s decision will not affect the marketing authorization for melflufen in the European Union.⁹

References

1. FDA issues final decision to withdraw approval of Pepaxto (melphalan flufenamide). FDA. February 23, 2024. Accessed February 23, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-final-decision-withdraw-approval-pepaxto-melphalan-flufenamide
2. Final decision on the proposal to withdraw approval of Pepaxto (melphalan flufenamide) for injection. FDA. February 23, 2024. Accessed February 23, 2024.
3. Oncopeptides receives 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 23, 2024. https://oncopeptides.com/en/media/press-releases/oncopeptides-receives-decision-from-the-u-s-food-and-drug-administration-confirming-withdrawal-of-pepaxto-from-the-u-s-market/
4. 4.Oncopeptides comments and legal aspects to CDERs response on Appeal Document. Accessed February 23, 2024. https://www.regulations.gov/document/FDA-2023-N-3167-0012
5. Withdrawn: FDA grants accelerated approval to melphalan flufenamide for relapsed or refractory multiple myeloma. FDA. February 23, 2024. Accessed February 23, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/withdrawn-fda-grants-accelerated-approval-melphalan-flufenamide-relapsed-or-refractory-multiple
6. Oncopeptides provides update on Pepaxto US marketing authorization. News release. Oncopeptides. December 7, 2022. Accessed February 23, 2024. https://news.cision.com/oncopeptides-ab/r/oncopeptides-provides-update-on-pepaxto-us-marketing-authorization,c3678754
7. Termination of certain limitations on communications and process for issuing a final decision; Pepaxto. FDA. February 23, 2024. Accessed February 23, 2024.
8. FDA alerts patients and health care professionals about clinical trial results showing an increased risk of death associated with Pepaxto (melphalan flufenamide). News release. FDA. July 28, 2021. Accessed February 23, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-final-decision-withdraw-approval-pepaxto-melphalan-flufenamide
9. European Commission approves Oncopeptides’ Pepaxti for the treatment of patients with relapsed refractory multiple myeloma. News release. Oncopeptides AB. August 18, 2022. Accessed February 23, 2024. https://www.prnewswire.com/news-releases/european-commission-approves-oncopeptides-pepaxti-for-the-treatment-of-patients-with-relapsed-refractory-multiple-myeloma-301608459.html