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Last year, 名媛直播 reported on developments leading to PI3K inhibitors losing multiple indications over safety and efficacy concerns. In this report, we outline what to expect in the coming year.

The PI3K inhibitor drug class had a rough go of it in the regulatory realm during 2022.

In April, participants in an unprecedented FDA advisory committee meeting put the entire class on notice regarding questionable safety and efficacy. Less than 3 months later, the FDA issued a mortality-related safety warning about duvelisib (Copiktra).

The FDA's Oncologic Drugs Advisory Committee (ODAC) subsequently voted not to recommend approval of duvelisib for chronic lymphocytic leukemia/small cell lymphoma (CLL/SLL). Along the way, multiple indications for multiple PI3K inhibitors were voluntarily withdrawn or revoked by the FDA.

The flurry of activity begs the question of whether the drug class has a viable way forward in the treatment of hematologic malignancies.

"We are playing with fire," said Mikkael Sekeres, MD, of the University of Miami's Sylvester Comprehensive Cancer Center, speaking during the September ODAC meeting about duvelisib's bid for a CLL/SLL indication.

The situation arose, in large part, due to accelerated approval of the drugs in lymphoid malignancies on the basis of preliminary evidence of benefits.

"Then subsequently, serious adverse events emerged, with the [indications] being pulled," Sekeres told 名媛直播. "I think these are serious adverse events that can't be ignored."

For example, key data supporting the CLL/SLL application came from a 300-patient trial comparing duvelisib and obinutuzumab (Gazyva). Fatal adverse events (AEs) occurred in 15% of the duvelisib arm versus 3% of the control group. More than 90% of patients randomized to duvelisib had grade ≥3 AEs as compared with about half of the control arm. Treatment discontinuation because of adverse events was 44% with the PI3K inhibitor and 6% with obinutuzumab.

"When you look at these data, you see a drug that has a modicum of activity but not a home run, not allowing people to live longer," Sekeres said. "Then, you see high rates of serious toxicity that's resulting not only in more people dying of fatal adverse events but also in treatment discontinuation, so that patients are not getting the drugs they need to treat their cancer."

"My sense is that this is a class effect and not just limited to duvelisib," he added.

Anecdotally, the hematology community has not rallied around the PI3K inhibitor class, in contrast to the support that existed for another drug that fell out of favor only to make a comeback: gemtuzumab ozogamicin (Mylotarg).

"I haven't heard a lot of enthusiasm for the PI3K inhibitors and how all of this is a terrible affront to the utility of the drugs," said Sekeres. "I did hear that when gemtuzumab ozogamicin was removed from the market and eventually was resurrected based on subsequent studies. I've not heard the same discontent about the decisions for the PI3K inhibitors."

Hematologist Hesitance

Even prior to the negative publicity, hematologists had not embraced PI3K inhibitors as an option for patients with indolent lymphomas, said Paolo Strati, MD, of the University of Texas MD Anderson Cancer Center in Houston.

"Even before the randomized study [with obinutuzumab], there was evidence of a higher mortality for patients who received umbralisib [Ukoniq]," he said. "Overall, both in the U.S. and in Europe, there was very limited use of PI3K inhibitors, definitely for follicular lymphoma and marginal zone lymphoma. If any, there was some use for CLL/SLL ... So I don't think those data [from the randomized trial] are going to meaningfully impact our clinical practice."

What might change is the conduct of industry-sponsored clinical trials and how the FDA will assess a drug's safety.

"Many drugs are now approved based on single-arm, phase II studies, while waiting for confirmatory randomized phase III studies," said Strati. "Now the FDA is requesting industry -- pretty much for every phase I trial -- to evaluate multiple dose levels and multiple dosing schedules. What I'm seeing is multiple ongoing trials being reviewed to reflect this new way to investigate safety in early-phase clinical trials."

Class Concerns

But should all the PI3K inhibitors be lumped together?

Prior to the April ODAC meeting, FDA officials outlined the rationale for evaluating the safety and efficacy of the entire drug class in an article published in . They cited the consistency of the data across multiple clinical trials involving different drugs in the PI3K-inhibitor class as the basis for re-evaluating the approval process.

In a , four U.S. hematologists took issue with the FDA-authored article, citing favorable data from clinical trials with idelalisib (Zydelig), use of PI3K inhibitors as an alternative to Bruton tyrosine kinase inhibitors for patients with cardiac comorbidities, the impact of the COVID-19 pandemic on uptake of the drug class, and the complicating effects of a venetoclax (Venclexta) dose ramp up.

"Finally, we are concerned at the suggestion that drugs in development should be evaluated as a class, rather than on the basis of their individual characteristics," concluded Jennifer R. Brown, MD, of Dana-Farber Cancer Institute in Boston, and coauthors. "Newer-generation drugs might show improvement in target specificity or pharmacological characteristics compared with older drugs, and are being carefully developed to optimise dosing, schedule, and tolerability."

"Such a class-based approach could deprive patients of safe and effective drugs. Furthermore, requiring randomised dose-finding studies is prohibitive in rare diseases. We worry that this approach might dampen research, which ultimately would adversely affect patients' access to life-saving medications, such as PI3K inhibitors."

Strati agreed with Brown and coauthors' statements about indicting an entire drug class when individual members of the class could have important differences. As an example, he said the different PI3K subunits targeted by members of the drug class could result in different safety profiles.

"I agree that in terms of development of new drugs, we shouldn't take these data as a message to interrupt the investigation and [instead] try to understand how differential inhibition or different subunits may translate into a different safety profile," said Strati.

"I still think, though, that the signal has been quite consistent across studies and now for many years," he added. "If anything, we should probably take these data to start investigating other components of the B-cell receptor."

Scapegoating?

The year of negative feedback surrounding PI3K inhibitors did nothing to shake the optimism of Bart Vanhaesebroeck, PhD, of University College London. In an of the PI3K inhibitors published in 2021, Vanhaesebroeck and coauthors cited recent research and clinical advances that set the stage for PI3K inhibitors to become major players in oncology and perhaps other types of diseases.

Acknowledging toxicity issues and the need for continued evaluation of doses and dosing schedules, the authors concluded that "PI3K inhibitors are finally coming of age."

Asked if he still stands by that opinion after the events of 2022, Vanhaesebroeck told 名媛直播, "The title is still valid."

He questioned the regulatory chess game that the PI3K inhibitors got caught up in: "The accelerated approval procedure is a bit of a challenge. The companies do not seem to follow up or do not play the game properly. So I think the FDA probably needed a scapegoat, and I think that's how they've used the PI3K inhibitors. They could have taken something else."

"I think it's a bit odd for the FDA to do this, to start writing opinion pieces," he continued. "If your accountant starts to write about how you should [run] your business -- well, your accountant is your accountant. You have to separate that. [The FDA] can make a decision and articulate their decision, but they should not write opinion pieces. I think something is going on at the FDA, like they want to play the game in a different way."

Pharmaceutical companies also have to shoulder some of the blame for missteps during the early developmental stages, he said, as they did not heed warnings that PI3K inhibitors have immunomodulatory effects or take proper precautions to deal with toxic liver metabolites. In one case Vanhaesebroeck cited, a drug company official proclaimed that his scientists had proof that their PI3K inhibitor was cytotoxic, even though the entire class is antiproliferative, not cytotoxic.

"They didn't listen to anything," said Vanhaesebroeck, who has worked as a consultant to the pharmaceutical industry.

Future Directions

Lessons have been learned, clinicians and developers know more about managing toxicities, and the drugs have improved, particularly PI3K-delta inhibitors. However, penetration in the CLL/SLL market remains modest. Some developers are focusing more on PI3K inhibition in solid tumors. Combination strategies containing PI3K inhibitors are attracting interest.

"PI3 kinase is deregulated in cancer, and if we leave it untouched on solid tumors, that's not good," said Vanhaesebroeck. "If we have immunotherapy opportunities, I think what we will do is take patients who do not respond to immune checkpoint therapy, or who become resistant, and give them a PI3K inhibitor, which has immunomodulatory effects through another mechanism. I think there is a massive market."

Strati suggested some context for evaluating the future role of PI3K inhibitors in hematologic malignancies. Patients are often older and have multiple comorbidities. Interest in avoiding chemotherapy remains high, and cellular therapies have yet to make major inroads into the more indolent lymphomas, despite approval for relapsed/refractory follicular lymphoma.

"While I understand that these biological agents have some toxicity, let's not forget that standard chemotherapy and CAR T-cell therapy may have the same or worse toxicity," he said. "The overall interest from investigators, both preclinical and clinical, to better understand how we can improve these agents needs to persist."

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