Approved Myeloma Drug in Limbo After Negative ODAC Review

The FDA’s Oncologic Drugs Advisory Committee (ODAC) may have dealt a decisive blow to the dangling accelerated approval of melphalan flufenamide (Pepaxto) for multiple myeloma.

By a decisive 14-2 margin, ODAC voted on Thursday that the benefits do not outweigh the risks for patients with relapsed or refractory disease, after data from the confirmatory OCEAN trial showed an increased mortality risk in patients treated with the peptide-drug conjugate.

Based on overall response data from the HORIZON trial, melphalan flufenamide (formerly melflufen) had been granted accelerated approval for relapsed or refractory multiple myeloma in patients treated with at least four prior lines of therapy, including at least one proteasome inhibitor, an immunomodulatory agent, and a CD38-directed monoclonal antibody.

“A critical aspect of accelerated approval is that follow-up trials actually confirm the initial benefit,” said Mikkael Sekeres, MD, MS, of the University of Miami Sylvester Comprehensive Cancer Center, explaining his vote against the drug.

“Unfortunately, in this case the follow-up trial flopped,” said Sekeres. “Not only did it not show the magnitude of benefit shown originally, but it potentially showed an increased risk of death in patients, with significant toxicity.”

“There’s certainly a need for better drugs — we all feel that, but we shouldn’t be using drugs that might actually be harming patients,” said Christopher Lieu, MD, of the University of Colorado Cancer Center in Aurora, who also voted against the drug.

“To me, the answer here is pretty simple,” he said. “The data do not support the use of this agent at this time.”

Drug developer Oncopeptides pulled melphalan flufenamide off the market late last year following the readout of OCEAN and discussions with the FDA, but then reneged.

On Thursday, the company made its case that a post-hoc analysis of the phase III study indicated benefit in certain subgroups, but that wasn’t enough to sway panel members.

“The post-hoc analysis really should be used for hypothesis generation as opposed to labeling and indication for use,” said Lieu.

Nor did that argument sway staff at the FDA.

“We do not use subgroups to carve out indications,” said Nicole Gormley, MD, of FDA’s Office of Oncologic Diseases.

“Given what is currently known, we would not have granted accelerated approval to melflufen,” she said.

An OS Detriment and Disagreement on PFS

In its efficacy analysis, the OCEAN trial demonstrated a median overall survival (OS) of 19.7 months in patients receiving low-dose dexamethasone plus melphalan, as compared with 25.0 months with low-dose dexamethasone plus pomalidomide (Pomalyst), leading to a hazard ratio of 1.104 (95% CI 0.846-1.441). Median progression-free survival (PFS) was 6.8 months and 4.9 months, respectively (HR 0.79, 95% CI 0.64-0.98).

Sponsor Oncopeptides made the case that autologous stem cell transplant (ASCT) heterogeneity confounded the OS analysis. Patients treated within 3 years of receiving ASCT had a median OS of 15.7 months with melphalan compared with 28.7 months with pomalidomide, according to the company’s post hoc analysis.

Meanwhile, patients who had never undergone transplant or who progressed 3 years after ASCT appeared to have an OS benefit with melphalan (23.6 vs 19.8 months with pomalidomide). The company said it aimed to communicate this potential risk as a limitation of use.

“We would wholeheartedly endorse … a prospective randomized trial in the population [the company] deems would not experience harm, but that should be done before an indication is granted,” said Gormley.

Oncopeptides also argued that the study met its primary endpoint of PFS, a point that committee member Jorge Nieva, MD, of the Keck School of Medicine of University of Southern California in Los Angeles, agreed with in explaining why he was one of the two committee members to vote that the benefits of melphalan flufenamide did outweigh the risks.

“The OCEAN trial was a positive trial based on PFS using a prespecified analytic plan,” Nieva said.

“It does appear that the OCEAN study confirms clinical response and benefit seen in HORIZON,” he said. “To say it does not looks to me like an exercise in moving the goal post.”

However, FDA reviewers conducted their own analysis and did not agree that statistical significance for PFS was demonstrated.

“But please note, even if we did, we would have significant concerns, and this trial would not provide a demonstration of safety and effectiveness,” said Gormley. “Overall survival is the paramount endpoint that is needed for determination of clinical benefit.”

While the FDA is not required to follow the advice of its advisory committees, it usually does.