As safety signals mount, FDA aims to crack down on PI3K blood cancer nods

After noticing concerning patient survival data across multiple clinical trials, the FDA is losing confidence in the safety profile of the notoriously toxic PI3K inhibitor drug class for blood cancers. Now, the agency aims to put the meds under a more stringent regulatory scope.

Six randomized clinical trials have shown a trend that suggests four marketed PI3K inhibitors might shorten blood cancer patients’ life expectancy because of their toxicity, the FDA said in a briefing document (PDF) ahead of an advisory committee meeting scheduled Thursday.

The “unprecedented” observation raises a red flag for PI3K inhibitor approvals based on single-arm trials. In those studies, drug reviewers cannot properly evaluate the life extension marker known as overall survival, the FDA says. Therefore, the agency says future PI3K nods should use randomized clinical trials with active comparators.

“Single-arm trials do not allow you to take a look at toxicity [because] you don’t have a comparator there, and this is particularly a problem in indolent diseases that people may live many, many years,” Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence, said in a recent interview with Fierce Pharma.

“What we have seen many times is people maximizing dose to get the highest response rate and not really carefully evaluating an efficacy dose-toxicity relationship,” Pazdur added.

In its review document, the FDA’s oncology team noted that the PI3K drug developers in question didn’t do a good enough job exploring lower doses of their products, which could potentially reduce toxicities.

Although the FDA seems to have made up its mind, it’s now asking external experts to weigh in on whether future PI3K inhibitor approvals in blood cancers should strictly use overall survival from randomized trials. Before the public meeting, the FDA has already successfully dissuaded Incyte from pursuing a nod of its PI3K delta inhibitor parsaclisib in certain indolent non-Hodgkin lymphomas based on single-arm data.


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Patient survival is both an efficacy and safety marker, the FDA says. And for these PI3K inhibitors, which have shown favorable effects on anti-tumor efficacy but not eventually on prolonging life, “substantial toxicity” could have tipped the benefit-risk balance against the drugs.

The FDA has approved four PI3K inhibitors for various blood cancers: Gilead Sciences’ Zydelig, Bayer’s Aliqopa, Secura Bio’s Copiktra and TG Therapeutics’ Ukoniq. Novartis’ Piqray, a PI3K alpha-specific inhibitor approved for breast cancer, is not part of the group under FDA scrutiny thanks to its different mechanism of action.

The safety concerns initially cropped up in Zydelig, the first PI3K inhibitor to reach the market. The drug won approvals in chronic lymphocytic leukemia (CLL), follicular lymphoma (FL) and small lymphocytic lymphoma (SLL) with either tumor shrinkage or disease progression data. Gilead halted three randomized clinical trials in CLL or indolent non-Hodgkin lymphoma (iNHL) in 2016 after noticing an increase in patient deaths in the Zydelig arm. The higher death rates weren’t caused by Zydelig being less effective at controlling tumors but by fatal infections, the FDA noted. In February this year, Gilead voluntarily withdrew Zydelig in FL and SLL, citing slow enrollment in a postmarketing trial.

Bayer’s Aliqopa, for its part, appeared to have a win last year in the phase 3 CHRONOS-3 trial in second-line iNHL. That study showed the med’s addition to Roche’s Rituxan cut the risk of disease progression or death by 48%. The Aliqopa arm did show a higher number of severe side effects, and more patients discontinued treatment, but Bayer at that time said most of those problems were manageable.

The drug also cut the risk of death by 13% at an interim analysis. But the FDA noted a concerning trend which showed that the survival curves between the two treatment arms flipped at about two years as more patients on single-agent Rituxan started to live longer than those on the Aliqopa-Rituxan combo. The FDA acknowledged the data were too early given that only very few patients had died; however, potential harm to patients cannot be ruled out, regulators said.

Bayer in December voluntarily withdrew an application for the Aliqopa-Rituxan regimen. The company plans to “reassess the possibility of resubmitting” the therapy after running additional analyses, according to its annual report.

It’s not just Zydelig and Aliqopa facing uncertainty. Secura Bio’s Copiktra also failed to confer a survival benefit in previously treated CLL/SLL over Novartis’ anti-CD20 antibody Arzerra. TG Therapeutics also just recorded an unfavorable overall survival showing for a pairing of its Ukoniq with an investigational CD20 drug. The company has capped development of the combo and is pulling Ukoniq monotherapy from the market in two iNHL subtypes.

The overall survival analyses from these trials either don’t have enough cases to draw conclusions or are simply not powered for formal statistical testing, the FDA said. But the same observation of potential detriment to overall survival across six randomized clinical trials of drugs in the same class is showing a pattern here, the agency said.