Federal advisers have unanimously called for randomized trials for a class of drugs used in the treatment of blood cancers, citing concerns about toxicities of these medicines.

The US Food and Drug Administration (FDA) called on advice from its Oncologic Drugs Advisory Committee (ODAC), which met yesterday to discuss the drugs that act as phosphatidylinositol 3-kinase (PI3K) inhibitors and are used for blood cancers.

The drugs discussed included idelalisib (Zydelig), indicated for use in chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and follicular lymphoma (FL); copanlisib (Aliqopa), indicated for FL; and duvelisib (Copiktra), indicated for CLL, SLL, and FL.

Also discussed at the meeting was umbralisib (Ukoniq), which had been indicated for marginal zone and follicular lymphoma, and was awaiting FDA approval for CLL and SLL (to have been discussed at a meeting the following day). However, the manufacturer announced April 15 that it had voluntarily withdrawn the drug from the market and also voluntarily withdrew the approval application.

The FDA explained that it is considering ways to shift away from use of single-arm trials with PI3K inhibitors following disappointing results seen with this class of drugs in more advanced testing. While initial single-arm studies and randomized tests showed good results on progression-free survival (PFS), disturbing trends were seen on overall survival (OS) in more advanced trials.

"The consistent findings of decrements in overall survival in six randomized trials, in the setting of an advantage or potential advantage in PFS, is unprecedented in oncology," the FDA staff said in its briefing document for the ODAC meeting.

"The overall survival information is early and represents a low number of events, yet we have the same pattern observed across multiple trials," the FDA added. "Further, in each trial, there was a higher rate of death due to adverse events in the PI3K inhibitor arm, suggesting the potential detriment in overall survival may be due to toxicity."

The FDA asked ODAC to vote on this question: "Given the observed toxicities with this class, previous randomized trials with a potential detriment in OS, and a narrow range between effective and toxic doses, should future approvals of PI3K inhibitors be supported by randomized data?"

The vote tally was 16-0 in favor of randomized data to support PI3K inhibitor approvals, with one abstention from panelist Anthony Sung, MD, of Duke University.

Sung said he felt uncomfortable with a shift toward expecting drugs in this class to be supported by randomized clinical data. But Sung said he agreed that the findings for the PI3K inhibitor drugs discussed at the meeting were "highly problematic" and randomization in testing may have helped.

The FDA already has publicly expressed clear concerns about the possibility that patients given PI3K inhibitor drugs for blood cancers might be more likely to die than those taking other medicines. The agency announced in February that it was investigating a potential increased risk of death with umbralisib; this is the drug that is no longer awaiting approval, after the manufacturer voluntarily withdrew the application.