NEW YORK – PI3K inhibitors are highly active against B-cell malignancies, but this class of drugs, led by
Idelalisib is a potent inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3K) that in a phase 1 trial was associated at higher dose levels with a median progression-free survival (PFS) of 32 months in patients with CLL who had received a median of five prior lines of therapy, noted Jennifer R. Brown, MD, PhD, director of the CLL center at the Dana-Farber Cancer Institute in Boston.
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Dr. Jennifer R. Brown
“This is really a very effective drug. So what’s happened? Why aren’t we using it more?” she asked rhetorically at an international congress on hematologic malignancies.
“This relates to a pattern of toxicities that has becoming increasingly familiar to us,” she added.
There is increasing evidence to suggest that the toxicities associated with idelalisib are immune mediated, indicating both the need for caution among clinicians who think about prescribing the drug, and a potential future use for this and other PI3K inhibitors as immunomodulatory agents, Dr. Brown said.
Registration trial toxicities
Among 760 patients enrolled in trials for the idelalisib registration programs, grade 3 or greater diarrhea and/or colitis and transaminitis each occurred in 14% of patients, rash occurred in 6%, and pneumonitis of any grade was seen in 3%.
Among patients with relapsed disease, transaminitis was often self-limiting and usually resolved when the drug was withheld, and about 75% of patients were successfully restarted on idelalisib at the same or lower dose, Dr. Brown noted.
Rashes, which can occur any time with therapy, were also successfully managed by withholding drug and then rechallenging, with the addition of corticosteroids as necessary.
Patients who developed drug-related pneumonitis were less likely than those with other toxicities to be rechallenged, and most required steroids until the infections resolved.
“The steroid responsiveness of many of these side effects suggested that they were autoimmune,” Dr. Brown said.
Drugs only work when you take them
The toxicities seen with idelalisib have had a marked effect on the use of the drug. In registration trials for idelalisib in combination with rituximab or ofatumumab (Arzerra), each of which had at least 2 years of follow-up, only 22.5% of 369 patients remained on idelalisib, primarily because of toxicities rather than disease progression. The combined 2-year progression in these trials was 13.3% In contrast, 40.7% of patients discontinued idelalisib because of adverse events.
Out to about 7 months, survival rates for patients who discontinued idelalisib because of disease progression or adverse events were roughly similar, but survival for the patients who stopped because of side effects began to plateau out to 2 years, Dr. Brown noted.
As of March 2016, 23.2% of patients who received idelalisib in clinical trials in combination with other agents as second- or third-line therapy had died, compared with 31% of controls, indicating a clear survival benefit with the drug.
“This is probably because the benefit of disease control in that setting overwhelmed the adverse event or infections problem,” she said.
Many of the deaths in registration trials were related to opportunistic infections, including Pneumocystis jiroveci pneumonia, fungal infection, and cytomegalovirus.
“Idelalisib, I think, is a prototypical delta inhibitor with a pattern of immune-mediated toxicity that remains unpredictable and can be severe. We now have pretty good data, based on the Gilead [sponsor] trials, that younger age and less prior therapy predispose to this toxicity,” Dr. Brown said.
Evidence is less robust, but growing, that mutated IGHV and a decrease in regulatory T cells may be also be risk factors for immune-mediated toxicities with idelalisib. Immune modulation with the drug may also account for associated neutropenia, sepsis, and opportunistic infections seen with idelalisib therapy, she added.
So how to use it?
Currently, the best uses for idelalisib and other PI3K inhibitors in CLL appear to be in single-agent therapy in patients with relapsed disease who cannot tolerate a Bruton’s tyrosine kinase (BTK) inhibitor such as ibrutinib (Imbruvica) or in patients whose disease has progressed on a BTK inhibitor.
“Where I think about this drug is in older, more heavily pretreated patients, who are generally at less risk for toxicities, and if they have significant comorbidities that may impact BTK-inhibitor tolerability, usually cardiac,” Dr. Brown said.
Future expansion of PI3K inhibitors in B-cell malignancies may require identifying a biomarker for tolerance, alternative dosing schedules, or identification of an idelalisib/drug X combination that might mitigate the toxicity, she said.
The immune-activation properties of PI3K-delta inhibitors suggests that they might also play a role as antitumor immunomodulatory agents in treatment of both hematologic malignancies and solid tumors, Dr. Brown concluded.
Idelalisib trials were sponsored by Gilead Sciences. Dr. Brown disclosed serving as a consultant for Gilead and other companies.