FDA adcomm takes down Secura Bio’s leukemia drug after final trial results show potential OS detriment

The FDA’s Oncologic Drug Advisory Committee on Friday voted 8-4 against the benefit-risk profile of Secura Bio’s PI3K inhibitor Copiktra (duvelisib), which won approval in Sept. 2018 as a third-line treatment for relapsed or refractory CLL or SLL, but updated pivotal trial results raised safety questions.

Jorge Garcia

In addition to the serious and fatal toxicities of duvelisib, FDA speakers at the ODAC meeting pointed to an evolved treatment landscape for CLL and SLL, with targeted BTK or BCL2 inhibitors (front-line or second-line), and data pointing to a “potential detriment” in overall survival for duvelisib. But some ODAC members noted that the detriment was likely small and that there is some efficacy even as the data are difficult to interpret.

ODAC Chair Jorge Garcia said ultimately these data do not support that this agent prolongs life. Other panelists who voted against it said, “we are playing with fire,” and that it didn’t meet the bar for safety, and that the data are hard to interpret and has concerns about this class of medicines.

Jorge Nieva

But those voting in favor of duvelisib said it should remain an option. Panelist Jorge Nieva of the University of Southern California’s Norris Comprehensive Cancer Center voted “yes” and said it reduces the burden of CLL in many patients, but he thanked the FDA for bringing to light the potential toxicity.

Panelist Ravi Madan of the NIH’s National Cancer Institute also voted “yes” because he said the drug still showed efficacy in the trial and the cross-over may have obscured the OS, and meaning the data can only partially inform opinions on safety.

Ravi Madan

The trial in question, known as DUO, was a Phase III, randomized, open-label trial that compared Copiktra with the mAb ofatumumab in 319 patients with relapsed or refractory CLL or SLL who received at least one prior line of therapy. The primary endpoint was progression-free survival. At the time of initial approval, OS data were limited, FDA said, noting that it required a final analysis of OS at 5 years to evaluate Copiktra’s long-term efficacy and safety.

Nicholas Richardson from FDA’s division of hematologic malignancies explained to ODAC Friday how the final data show there was not only a higher number of deaths in the duvelisib arm of DUO when compared to ofatumumab, but a higher rate of death due to adverse events with duvelisib.

Nicholas Richardson

In response to Secura’s claims that the drug did show some efficacy, and that in general, this third-line patient population doesn’t typically survive longer than about 3.5 months on average, the FDA speakers explained how it isn’t claiming a lack of efficacy signal, but that there are significant safety considerations with higher rates of death due to fatal toxicities.

David Sidransky

In contrast, Secura adviser David Sidransky of Johns Hopkins sought to assure ODAC that the OS data do “not support the conclusion of detriment,” claiming the three-year OS rates were comparable between the arms (59% vs. 60%) but that there’s been “no change in the safety profile since the approval in 2018.”

Secura Bio bought duvelisib in September 2020 from Verastem for $70 million in cash but in a deal valued at up to $311 million with royalties.

This is just the latest warning sign for a class of drugs that have received increased scrutiny this year, with an FDA adcomm in April voting that all approvals for PI3K inhibitors should be supported by randomized data. PI3K inhibitors garnered more scrutiny recently in hematological malignancies after renewed toxicity concerns, inadequate dose optimization, trial design limitations of single-arm studies and these concerning OS trends.

Six randomized trials evaluating PI3K inhibitors show a potential detriment in OS, and all showed a benefit in PFS or response rates initially, FDA’s Richardson said.

The agency previously warned at the end of June that Secura Bio’s final trial results revealed this possible increased risk of death with duvelisib.

Mark Spring

Crossover in the trial from ofatumumab to duvelisib (for 90 patients) complicated the results with confounding, but FDA’s Richardson noted that even despite this crossover, “we’re still seeing a signal for a potential detriment in overall survival.”

Secura in April also pulled an accelerated approval indication for Copiktra as a treatment for relapsed or refractory follicular lymphoma, after the firm failed to run the required confirmatory trial in this indication.

Secura Bio CFO Mark Spring told Endpoints News previously that the decision was a financial one, adding:

We felt that completing the required Phase 3 trial would take too many years and would be too expensive. As you can understand, as a small company we invest our finite research funds in the areas that we feel will benefit patients the most and have a reasonable return on our investment. Secura Bio believes that our research funds are better spent on the development of COPIKTRA for the treatment of patients with relapsed and refractory Peripheral T-cell Lymphoma (r/r PTCL).

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