ODAC gives a big thumbs-down to Oncopeptides' dangling accelerated approval in multiple myeloma
ODAC on Thursday voted overwhelmingly against keeping the accelerated approval for Oncopeptides’ Pepaxto, 14 voting “no,” and 2 “yes” to the FDA’s question of: “Is the benefit-risk profile of melphalan flufenamide favorable for the currently indicated patient population?”
It’s been more than 15 months since Sweden-based Oncopeptides first presented to the FDA its failed results from a confirmatory trial, known as OCEAN, following its 2021 accelerated approval of Pepaxto (melphalan flufenamide) as a fifth-line therapy for multiple myeloma.
The FDA sounded no closer on Thursday to coming around on the company’s re-analyzed benefits too, and several ODAC members expressed serious reservations.
ODAC panelist Andy Chen of Oregon Health & Science University questioned the negative overall survival benefit in announcing his “no” vote, while Anthony Sung of Duke University said he didn’t think the benefit outweighs the risks.
The road has been a rocky and unorthodox one for Oncopeptides, which nearly a year ago told FDA it would withdraw this indication before deciding to rescind that withdrawal request, finding a new reanalysis of data that showed some statistically significant PFS.
“We shouldn’t be using drugs that may actually be harming patients,” ODAC panelist Christopher Lieu, from University of Colorado Cancer Center, said in announcing his “no” vote. “The data do not support the use of this.”
And the FDA’s presentations and comments made clear at Thursday’s meeting it would be difficult to budge.
“Sponsors need to provide substantial evidence. Not post-hoc analyses,” OCE head Richard Pazdur said at one point in the early afternoon discussion.
FDA reviewer Alexandria Schwarsin presented findings to ODAC from the confirmatory OCEAN RCT results that said the median OS remained shorter in the melphalan arm than the standard of care arm from the trial. FDA also conducted its own analyses on revised PFS results that Oncopeptides claimed were positive, and found a lack of robust treatment effect, with Schwarsin noting that given the OS detriment, any positive PFS would still not support clinical benefit.
Oncopeptides CMO Klaas Bakker presented the company’s take on the confirmatory results, concluding that Pepaxto does show benefit in a subset of patients — with no autologous stem cell transplantation (ASCT) or post ASCT progression greater than 36 months, seeking to keep approval under a revised label with certain “proposed limitations of use.”
But the FDA made clear that Oncopeptides’ subgroup analysis was not prespecified, and FDA’s Schwarsin noted how subgroup analyses can be misleading as the agency identified survival differences in subgroup analyses from OCEAN based on the month of randomization.
ODAC chair Jorge Garcia and panelist Scott Waldman of Thomas Jefferson University noted the wide gaps between the Oncopeptides and FDA perspectives, but committee members made clear the sub-hoc analyses were hypothesis-generating and did not change the OS result.
Nicole Gormley, director of the FDA’s division of hematologic malignancies II, told ODAC multiple times that from FDA’s perspective, there were “several concerns” with the altered PFS and the company’s unprecedented reassessment, which she also called “highly unusual” and “data dredging.” Regardless, she added, this change still represents a very small difference in PFS, and the change did not impact the negative overall survival.
“We don’t agree a PFS that’s statistically significant was indicated. But even if we did, this trial did not provide a demonstration of safety and effectiveness,” Gormley said. Unlike some other endpoints, OS is both a safety and efficacy endpoint, she said, and “we can have discussions on PFS meeting statistical significance — that’s not the most germane issue. That’s the worse OS.”
The FDA does not have to follow ODAC’s advice but often does.
And even if Pepaxto is pulled in the US, that may not spell its end. Outside the US, the European Medicines Agency’s CHMP in June recommended a full marketing authorization approval for melphalan flufenamide in the EU.
Earlier on Thursday, ODAC also voted against Spectrum Pharmaceuticals’ potential lung cancer drug poziotinib’s benefit-risk profile, by a vote of 9-4.