Melphalan Flufenamide for R/R MM Pulled from US Market Over Efficacy Concerns


Melphalan flufenamide is being removed from the US market after the OCEAN study failed to show an improvement in OS over pomalidomide and dexamethasone. The agent was granted approval for use in R/R MM in February.

The multiple myeloma drug melphalan flufenamide (Pepaxto) has been removed from the United States market by the developer after results of the phase 3 OCEAN study found that the overall survival (OS) in the intent-to-treat population had a hazard ratio of 1.104, indicating no improvement in OS, according to a press release by Oncopeptides AB.1

Melphalan flufenamide, a peptide drug conjugate platform that includes OPD5 and OPDC3, was granted approval by the FDA in February of 2021 for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody. The agent was subsequently added to the National Comprehensive Cancer Network’s Multiple Myeloma Clinical Practice Guidelines in March of 2021. 

“We remain confident in our scientific platform, despite the fact that the OCEAN data didn´t pass the regulatory hurdles to confirm the accelerated approval in the US,” said Jakob Lindberg, Med Lic, CSO at Oncopeptides, in a press release. “Going forward we will further explore our PDC-platform, to develop drugs that potentially can make a significant difference for patients. Oncopeptides is committed to work closely with the regulatory authorities to evaluate the most appropriate possibilities for our pipeline products.”

The phase 3 OCEAN study (NCT03151811) had an actual enrollment of 495 participants. The primary end point of the randomized, parallel assignment study was progression-free survival (PFS). Secondary end points included overall response rate (ORR), duration of response (DOR), OS, and safety and tolerability.2

Patients were randomized into an experimental or control arm. During the experimental arm, patients received melphalan flufenamide until unacceptable toxicity, confirmed progression, or patient/investigator decision. During the control arm, patients received a combination of pomalidomide and dexamethasone under the same parameters.

OCEAN met its primary end point of PFS improvement (HR, 0.792; 95% CI, 0.640-0.979, P = .0311). However, In July of 2021, a partial clinical hold was placed on the agent after mixed OS results in the relapsed or refractory myeloma subgroups (HR, 1.104; 95% CI, 0.846-1.441). This partial clinical hold effectively halted accrual of patients into any study using the agent. Later that month, the FDA issued a warning about a death risk associated with the OCEAN study.

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

Grade ≥3 adverse events occurred in 96% of the 157 patients evaluated. Most commonly, these included neutropenia (79%), thrombocytopenia (76%), and anemia (43%). The most common grade 3/4 nonhematologic event was pneumonia (10%). Reversible thrombocytopenia and bleeding were also observed. 3

“The decision to withdraw Pepaxto from the market has been a difficult decision, that has been made with great consideration and with the best intentions for patients and shareholders," said Marty J Duvall, chief executive officer at Oncopeptides, in a press release.

Oncopeptides will continue to work with the FDA to continue to make melphalan flufenamide available to patients who are deriving benefit.

1.Oncopeptides withdraws Pepaxto® in US, scale down organization and focus on R&D. News release. Oncopepetides. October 22, 2021. Accessed October 25, 2021.
2.A study of melphalan flufenamide (Melflufen)-Dex or pomalidomide-dex for RRMM patients fefractory to lenalidomide (OCEAN). Accessed October 25, 2021.
3.Richardson PG, Oriol A, Larocca A, et al. Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol. 2021;39(7): 757-767. doi: 10.1200/JCO.20.02259
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