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Follow-up Trial of Myeloma Drug ‘Flopped,’ Says FDA Panel

A federal advisory panel rejected arguments from drug manufacturer Oncopeptides AB about the merits of its multiple myeloma drug, melphalan flufenamide (Pepaxto), further dimming prospects of preserving the FDA accelerated approval granted in February 2021.

Oncopeptides AB argued that a recent post hoc analysis highlighted the drug’s benefit and aligned with the initial trial results that led to the drug’s accelerated approval; however, the majority of a US Food and Drug Administration (FDA) advisory panel disagreed.

On Thursday, the FDA’s Oncologic Drugs Advisory Committee (ODAC) considered the following question: “Given the potential detriment in overall survival, failure to demonstrate a progression-free survival benefit, and lack of an appropriate dose, is the benefit-risk profile of melphalan flufenamide favorable for the currently indicated patient population?”

Overall, 14 panelists voted “no” while two voted “yes.”

Panelist Mikkael A. Sekeres, MD, MS, explained his vote against the drug, echoing concerns expressed by the majority of ODAC members.

“A critical aspect of accelerated approval is that follow-up trials actually confirm the initial benefit that’s seen,” said Sekeres, of the University of Miami. “Unfortunately, in this case, the follow-up trial flopped. And not only did it not show the magnitude of benefit that we saw initially, but it potentially showed an increased risk of death in patients with significant toxicity.”

The initial accelerated approval for melphalan flufenamide was based largely on overall response rates for 97 patients in the HORIZON study, which did not include a comparator drug.

Concerning signals soon emerged from the follow-up OCEAN study — which compared melphalan flufenamide plus dexamethasone to pomalidomide plus dexamethasone in patients with relapsed and refractory multiple myeloma who had received two to four prior lines of therapy.

In July 2021, the FDA issued a safety alert flagging an increased risk of death observed in the OCEAN trial among patients receiving melphalan flufenamide. Overall, higher rates of deaths occurred in the melphalan flufenamide arm (47.6% vs 43.4%), and the median overall survival was 5.3 months shorter.

In October 2021, Oncopeptides sought to withdraw the FDA’s accelerated approval of melphalan flufenamide, but also kept working with the European Medicines Agency on a bid for the drug’s clearance. In an unusual move, a few months later, Oncopeptides rescinded its voluntary withdrawal request, and in August 2022, the European Commission granted marketing authorization to the drug, also called Pepaxti.

This past Thursday, Oncopeptides argued that a benefit for melphalan flufenamide can be seen by delving into the OCEAN results and weighing several factors, including patient ages and prior autologous stem cell transplant (ASCT). An analysis of OCEAN patients who had not had ASCT, for example, showed a median of 9.3 months of progression-free survival vs 4.6 months for the pomalidomide arm, the company said.

“We still have confidence in our science and data,” said Jakob Lindberg, MSc, chief executive of Sweden’s Oncopeptides, in a statement after the ODAC meeting.

However, most of the ODAC panel was not swayed by the company’s arguments.

“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 ODAC panelist Christopher H. Lieu, MD, of the University of Colorado.

“To me the answer is pretty simple,” Lieu added. “[The] data do not support the use of the agent as this time.”

Sekeres also noted the challenges oncologists would face conveying the data to patients.

“How the heck would I give informed consent to a patient to receive this drug and explain that progression-free survival, which itself is a difficult concept to explain to anyone, may be better by a couple of months, but that that person will live (fewer months) than if he or she didn’t get this drug?” Sekeres said.

ODAC panelist David Mitchell, who serves as the consumer representative, noted that he is a candidate for the drug.

“Frankly, this could be a life-or-death decision for me and others like me, but after listening closely to both the sponsor and FDA presentations, I conclude that [melphalan flufenamide] has demonstrated a lack of confirmed benefit, inferior overall survival and a potential for actual harm,” Mitchell said.

Kerry Dooley Young is a freelance journalist based in Miami Beach. Follow her on Twitter @kdooleyyoung.

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