FDA Panel Finds Duvelisib Risks Outweigh Benefits in CLL/SLL

The risks associated with taking duvelisib (Copiktra) by patients with certain blood cancers appear to outweigh the benefits, a federal advisory panel said on Friday.

The US Food and Drug Administration (FDA) issued a warning in late June that the PI3 kinase (PI3K) inhibitor may increase the risk of death and serious side effects among adults with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

On Friday, the FDA’s Oncologic Drugs Advisory Committee (ODAC) reviewed the record for duvelisib for this indication to help regulators weigh the next steps for the drug.

Members of ODAC voted on the following question: “Given the potential detriment in overall survival, duvelisib-associated toxicity, concerns with the selected dose, and the safety issues with the PI3K inhibitor class, is the benefit-risk profile of duvelisib favorable in patients with relapsed or refractory CLL or SLL after at least two prior therapies?”

Of the 12 panelists, eight voted “no” and four voted “yes.”

In their deliberations, the ODAC panel reviewed 5-year follow-up data on duvelisib and wrestled with whether the drug was safe.

Duvelisib received FDA approval in 2018 on the basis of the DUO trial, which compared the agent to ofatumumab in 319 adults with CLL or SLL who had previously undergone at least one prior therapy. The trial found an advantage for duvelisib — a median progression-free survival time of 13.1 months, vs 9.9 months in the ofatumumab arm.

However, duvelisib came with significant toxicity, including a risk of serious or fatal infections, diarrhea, colitis, rash, pneumonitis, hepatotoxicity, and neutropenia. As a result, the FDA attached requirements to the 2018 approval to address serious safety concerns with the drug, including requiring 5-year overall survival data from the trial.

When the 5-year follow-up data became available, investigators found a possible increased risk of death associated with duvelisib. The median overall survival among patients who received duvelisib was 11 months shorter compared with those who received ofatumumab: 52.3 months vs 63.3 months. Overall, among patients who had undergone at least one prior therapy, 80 deaths (50%) occurred in the duvelisib arm, compared with 70 deaths (44%) in the ofatumumab arm (hazard ratio [HR], 1.09). Among patients who had received two or more prior therapies, 53 deaths (56%) occurred in the duvelisib arm, and 49 deaths (49%) occurred in the ofatumumab arm (HR, 1.06).

The ODAC members’ recent vote represents more bad news for the entire PI3K inhibitor drug class. At a meeting in April, the ODAC panel reviewed data on the class of PI3K inhibitors and found a trend toward adverse overall survival — which the FDA called “unprecedented in the field of oncology.”

In the latest ODAC vote, panelists weighed the disappointing 5-year data on duvelisib along with the need for more therapeutic options for patients whose CLL and SLL persisted after several lines of treatments, noted ODAC Chairman Jorge A. Garcia, MD, of Case Western Reserve University.

Some panelists who supported the drug focused on the need for additional options for these patients and noted that the available data do not yet provide a definitive answer as to whether duvelisib is detrimental to overall survival.

However, Christopher H. Lieu, MD, of the University of Colorado, Denver, focused more on the known risks of duvelisib and the class of PI3K inhibitors more generally.

“I do have concerns,” Lieu said. “And if we’re not clearly improving overall survival in our patients, but we’re increasing toxicity and treatment-associated death, I’m not sure that we’re truly helping patients.”

Kerry Dooley Young is a freelance journalist based in Miami Beach. She earlier covered health policy and the federal budget for Congressional Quarterly/CQ Roll Call and the pharmaceutical industry and the Food and Drug Administration for Bloomberg. Follow her on Twitter @kdooleyyoung.

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