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While some patients with relapsed or refractory multiple myeloma saw a benefit in a confirmatory trial, the main issue concerning the committee members was a high rate of death in the study.
The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 14 to 2 on Sept. 22, 2022, against whether the benefit risk profile of Oncopeptides’ Pepaxto (melphalan flufenamide) was favorable in adult patients with relapsed or refractory multiple myeloma.
In materials released ahead of the meeting, the FDA indicated that the confirmatory trial (OCEAN) demonstrated a worse overall survival and failed to verify clinical benefit. The committee reviewed data from the OCEAN trial, which compared Peptaxto/dexamethasone with pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. Additionally, there were higher rates of deaths in Pepaxto arm than in the pomalidomide/dexamethasone arm. There were also higher rates of grade 3 and 4 adverse events in the Pepaxto arm.
“There is a need for better drugs but we shouldn’t be using drugs that might actually be harming patients,” Christopher H. Lieu, M.D., associate professor of Medicine, Associate Director for Clinical Research, University of Colorado Cancer Center Aurora, Colorado, said after the vote. “There is analysis which may support the use in a specified patient population that could show benefit and confirmatory trial should be done with this population but the data do not support the use at this time.”
In October 2021, Oncopeptides briefly withdrew Pepaxto from the U.S. market based on preliminary analysis of progression free survival data from the OCEAN study failed to show statistically significant improvement. Oncopeptides rescinded this action on Jan. 13, 2022, but has not marketed the product in the United States.
And In July 2022, the company had announced that it had been in discussions with the FDA to review the data after the therapy received a positive opinion from the European Commission recommending full marketing authorization approval.
The FDA had granted accelerated approval for Pepaxto on Feb. 26, 2021, in combination with dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma. The approval was based on the OP-106 (HORIZON) trial, a single-arm trial. The overall response rate (ORR) in this population was 23.7% with a median duration of response (DOR) of 4.2 months.
At the advisory committee meeting, the FDA indicated that the dose of Pepaxto was not optimized to support a favorable benefit-risk profile. The FDA disagreed with Oncopeptides analysis of the efficacy data, saying it relied heavily on post hoc sub-group analyses. Subgroup analyses, regulators said, should be used for exploratory or hypothesis-generating purpose and are not meant to provide conclusive evidence of efficacy and safety.
Additionally in the OCEAN study, high rates of adverse events and dose modifications were seen in the Pepaxto arm. Almost all patients (99.6%) reported treatment-emergent adverse events, including serious events such a bleeding, infections, thrombocytopenia (low platelet count), and neutropenia (low count of a specific white blood cell). Additionally, 53% of the 491 patients died during the studies with most of the deaths occurring more than 30 days after the last dose of Pepaxto.
Although the OCEAN study demonstrated a positive progression free survival endpoint, agency officials indicated that they look at the entire clinical picture of the data that is presented.
“We don’t look at an isolated fashion at one endpoint,” Nicole Gormley, M.D., Office of Oncologic Diseases at the FDA. “We would never rely on a positive PFS value if there is evidence of detriment in overall survival. When we have used subgroups in the past, the ITT (intent to treat) results have been positive. We do not use a subgroup analyses to find a population that has a favorable benefit when overall, the picture is negative.”
One the committee member who voted yes was Jorge J. Nieva, M.D., associate professor of Clinical Medicine, Section Head, Solid Tumors, University of Southern California (USC), Keck School of Medicine in Los Angeles.
“The OCEAN has a positive trial based on PFS with a prespecified analytical plan,” he said after the vote. “It does appear that the OCEAN study confirms clinical response and benefits seen in Horizon. To say it doesn’t is an exercise in moving the goal posts. I don’t the numerical difference in OS (overall survival) is a safety signal but a lack of efficacy signal. While it may not have been obvious at the time of study design that you shouldn’t use melphalan in a melphalan-resistant patient and population, it certainly seems obvious now. The analysis provided showed that patients may benefit as long as they are not melphalan-resistant.”