FDA puts the microscope on 2 more cancer approvals without voluntary withdrawals

The FDA’s oncology department has lately been tightening its act around accelerated approvals and stressing the importance of patient survival data. Several companies immediately fell in line, withdrawing problematic indications when the agency mounted its pressure. But some companies have decided to put up a fight.

Secura Bio’s PI3K inhibitor Copiktra and Oncopeptides’ first-in-class blood cancer therapy Pepaxto are the latest two drugs that will be scrutinized at an upcoming FDA advisory committee meeting, as the drugmakers haven’t pulled indications off the market despite red flags from clinical trials.

During a two-day event in September, external experts for the FDA will discuss whether Copiktra’s use in third-line chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and Pepaxto’s use alongside dexamethasone for fifth-line treatment of multiple myeloma should stay on, according to an FDA filing.

Both drugs have shown concerning signs of potential detriment to patients’ lives in their confirmatory trials, and the FDA has alerted the public of those risks related to Pepaxto and Copiktra.

Last October, Oncopeptides had decided to voluntarily take Pepaxto off the U.S. market but changed its mind this January after conducting additional analyses of patient survival data from the phase 3 OCEAN study. The company has put marketing of Pepaxto on hold “until a mutual understanding” with the FDA.

In the original analysis of OCEAN data, Pepaxto’s combo with dexamethasone was linked to a 10% increased risk of death compared with Bristol Myers Squibb’s Pomalyst and dexamethasone in a group of patients with relapsed or refractory multiple myeloma after two to four lines of prior therapy. The peptide-drug conjugate originally got its accelerated approval last February based on data from the phase 2 HORIZON trial showing Pepaxto triggered a 23.7% response rate in a small group of patients who had received at least four prior lines of therapy.

For Copiktra, the extra safety signals of the entire PI3K inhibitor class had already previously caught the FDA's attention and were discussed extensively during an advisory committee meeting back in April. Before that, Secura had voluntarily withdrawn Copiktra in third-line follicular lymphoma.

But in the larger CLL and SLL indications, Secura is apparently unwilling to give up without a fight. Copiktra got that full third-line approval in 2018 based on data from the phase 3 DUO trial showing it could stall disease progression or death versus Novartis’ Arzerra in patients who had received at least two prior lines of therapy.

However, the final five-year survival results from DUO showed what the FDA believes is a “possible increased risk of death” for Copiktra, according to a drug safety alert the agency issued three weeks ago. By the time of the analysis, Copiktra takers lived a median 52.3 months, versus 63.3. months for the Arzerra group. As previously discussed at the PI3K meeting in April, serious side effects were noted as the reason behind the longer-term patient survival issue.

The effect of the FDA’s PI3K scrutiny is wide-ranging. In addition to Copiktra, Gilead Sciences earlier this year withdrew two indications for its PI3K inhibitor Zydelig—follicular lymphoma and SLL—after failing to meet confirmatory trial requirements.

Incyte in January rescinded a drug application seeking accelerated approval for its PI3K inhibitor parsaclisib for relapsed or refractory follicular lymphoma, marginal zone lymphoma and mantle cell lymphoma after the FDA made clear it wants to see phase 3 data first. The agency later made the same request with MEI Pharma’s application for Kyowa Kirin-partnered zandelisib. And Bayer also pulled filings for its Aliqopa in indolent non-Hodgkin lymphoma.

Before the PI3K drugs, the FDA had launched an industrywide review of accelerated approvals granted to PD-1/L1 immuno-oncology agents. That process saw Merck, BMS, AstraZeneca and Roche pull various indications of their drugs including triple-negative breast cancer, small cell lung cancer, bladder cancer and others.

Editor's Note: The story has been updated with the corrected information that Copiktra's third-line CLL/SLL indication is a full approval, not an accelerated approval.