FDA Requests Partial Clinical Hold on Melflufen Studies Following Mixed OS Results in R/R Myeloma Subgroups

The FDA has placed a partial clinical hold on clinical trials evaluating the first-in-class peptide-drug conjugate, melphalan flufenamide (melflufen;Pepaxto), pending a full benefit/risk profile on the agent for use as an early line of therapy in patients with relapsed/refractory (R/R) multiple myeloma, according to a press release from Oncopeptides AB.¹

A decision to halt studies of melphalan was based on data from the randomized phase 3 OCEAN study (NCT03151811) of melflufen plus dexamethasone versus pomalidomide (Pomalyst) plus dexamethasone in patients with R/R multiple myeloma who have received 2 to 4 prior lines of therapy. Although the study met its primary end point of progression-free survival (PFS) improvement (HR, 0.792; 95% CI, 0.640-0.979, P = .0311) as determined by independent review committee, the key secondary end point of overall survival (OS) improvement greatly differed across the pre-specified subgroups treated with either melflufen plus dexamethasone or pomalidomide plus dexamethasone (HR, 1.104; 95% CI, 0.846-1.441).

“The is a head-to-head comparison of 2 different treatment modalities and hence we saw striking differences between the performance of both drugs across different patient populations,” said Klass Bakker, chief medical officer of Oncopeptides AB, during a virtual press conference.²

OCEAN enrolled a total of 495 patients with multiple myeloma who failed 2 to 4 prior lines of therapy, which may have included patients who were refractory to lenalidomide (Revlimid) within 18 months or who have progressed on lenalidomide within 60 days of randomization. Patients were required to be at least 18 years of age or older with measurable disease, a life expectancy of at least 6 months, an ECOG performance status of 2 or lower, and show adequate laboratory values at baseline screening.

Topline results from the study were announced in May 2021 and showed a trend toward PFS improvement and an objective response rate (ORR) of 31.1% in the melflufen arm compared with 26.5% in the control arm. In terms of safety, it was reported that both treatment arms had a similar discontinuation rate resulting from adverse events. Further, melflufen demonstrated a safety profile consistent with what has been shown in prior studies.³

The partial clinical hold placed on the clinical development of melflufen will halt recruitment to multiple ongoing clinical trials including the LIGHTHOUSE (NCT04649060), ANCHOR (NCT03481556), PORT (NCT04412707), BRIDGE (NCT03639610), ASCENT (NCT04115956), and COAST trials. Patients who are already enrolled in these studies are permitted to continue their treatment, but continued therapy during the partial clinical hold is subject to the investigator’s opinion.²

Oncopeptides AB plans to continue communication with the FDA while gathering information of the benefit/risk profile of melflufen, and results from the OCEAN study will be presented

“We are very pleased to have met superiority on the primary end point in the intent-to-treat population…In addition, we know the ORR, clinical benefit rate and duration of response are solid data favoring melflufen, but it is that OS important secondary end point where the results are mixed. We look forward to Q3 and the IMWG meeting to present new data,” said Marty J. Duvall, chief executive officer, Oncopeptides AB, during the press conference

A late-breaking abstract has been submitted for presentation during the 18th International Myeloma Workshop, which will be held in September 2021 in Vienna, Austria. Commercialization for melflufen will continue despite the partial clinical hold based on the HORIZON clinical trial (NCT02963493).

_References:

_{1. Updated results from phase 3 OCEAN study shows melflufen met primary endpoint of superior PFS – Overall Survival data lead to partial clinical hold. News release. Oncopeptides AB. July 8, 2021. Accessed July 8, 2021. https://bit.ly/36lEBKb}

_{2. Updated OCEAN Results and Partial Clinical Dvelopment Hold. Presented at. Oncopeptides AB Press Conference. July 8, 2021.}

_{3. Phase 3 OCEAN study demonstrates that melflufen is at least as efficacious as pomalidomide, the most used medicine in relapsed refractory multiple myeloma. News release. Oncopeptides AB. May 25, 2021. Accessed July 8, 2021. https://bit.ly/2SWbyd7}