WASHINGTON -- The FDA approved the dual PI3K inhibitor duvelisib (Copiktra) on Monday for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma, drugmaker .
"Copiktra is an important addition to the evolving treatment paradigm for patients with CLL/SLL and follicular lymphoma," Ian Flinn, MD, PhD, of the Sarah Cannon Research Institute in Nashville, Tennessee, said in Verastem's .
Flinn, who was lead investigator of the trials that led to the approvals, called duvelisib a "significant addition to physicians' treatment armamentarium" for patients who have progressed after two prior therapies.
The indication for CLL/SLL came from the multicenter open-label DUO trial that compared duvelisib to ofatumumab. The study randomized patients to oral 25-mg duvelisib twice daily or ofatumumab, which is administered intravenously in a 6-week course.
Among patients that had received two prior therapies (n=196), median progression-free survival favored duvelisib (16.4 versus 9.1 months with ofatumumab), as did the rate of overall response (78% versus 39%, respectively).
Susan O'Brien, MD, of the University of California Irvine, said that duvelisib -- the first approved PI3K-delta and PI3K-gamma inhibitor -- might be "stigmatized" by clinicians' experience with the PI3K-delta inhibitor idelalisib (Zydelig).
"If you look at the toxicity profile for [duvelisib] from a qualitative point of view it doesn't look very different than idelalisib in terms of transaminitis, pneumonitis, colitis," O'Brien said in an interview with 鶹ý prior to Monday's approval. "However, if you look from a quantitative point of view it appears to be less -- with the caveat that there are a lot less patients exposed to [duvelisib] and so smaller numbers and wider confidence intervals -- but it appears to be less."
Idelalisib, a first-in-class PI3K delta inhibitor, burst on the scene with a trio of blood cancer approvals in 2014 -- also CLL/SLL and follicular lymphoma -- but its use has been hampered by dose-limiting toxicities.
"There is a rationale for why inhibiting gamma in addition to delta might reduce the toxicity," O'Brien added.
The approval for follicular lymphoma was based on 83 patients from the single-arm DYNAMO study, which yielded an overall response rate of 42% (95% CI 31%-54%) in duvelisib-treated patients who were refractory to rituximab and either radioimmunotherapy or chemotherapy.
There was one complete response, and 34 partial responses. Of these, 43% had a duration of response of 6 months or more and 17% had responses of a year or longer.
Common adverse events (20% or more) seen in DYNAMO and DUO included anemia, cough, colitis or diarrhea, rash, neutropenia, fatigue, pyrexia, nausea, upper respiratory infection, musculoskeletal pain, and pneumonia. Dose reductions were required in 24% of patients and 35% of patients discontinued the drug due to adverse events.
Serious adverse events occurred in 65% of patients with various blood cancers treated with the drug at the approved dose. The drug will carry a boxed warning due to the risk of fatal and/or serious infections, diarrhea or colitis, skin reactions, and pneumonitis, as well as warnings of neutropenia and hepatotoxicity.