The FDA approved duvelisib, a PI3Kδ/PI3Kγ inhibitor, for patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma who have received at least two prior therapies. The agency also granted the drug an accelerated approval for patients with relapsed/refractory follicular lymphoma following at least two other therapies.

The FDA has approved the PI3Kδ/PI3Kγ inhibitor duvelisib (Copiktra; Verastem) for patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have received at least two prior therapies. The agency also granted the drug an accelerated approval for patients with relapsed/refractory follicular lymphoma (FL) following at least two other therapies.

Duvelisib, which works by interrupting B-cell receptor signaling, is the first approved PI3K inhibitor that selectively inhibits both the δ and γ isoforms. The FDA previously approved the PI3Kδ inhibitor idelalisib (Zydelig; Gilead) in combination with rituximab for patients with relapsed CLL, and as a monotherapy for relapsed SLL and FL. The agency has also approved the pan–class I PI3K inhibitor copanlisib (Aliqopa; Bayer) for patients with relapsed FL.

The duvelisib approvals were based on results from the phase III DUO and the phase II DYNAMO trials. In DUO, patients with CLL/SLL treated with the drug had a median progression-free survival of 16.4 months and an overall response rate of 78%, compared with 9.1 months and 39% in patients who received the CD20 monoclonal antibody ofatumumab (Arzerra; Novartis). In DYNAMO, patients with FL treated with the drug had an overall response rate of 42%.

For Matthew Davids, MD, MMSc, of Dana-Farber Cancer Institute in Boston, MA, duvelisib represents another option, in addition to idelalisib, for patients with CLL/SLL who relapse following first- and second-line therapies such as chemotherapy, venetoclax (Venclexta; AbbVie/Genentech), and ibrutinib (Johnson & Johnson and Pharmacyclics). “We have some good options for patients, and yet it's still an incurable disease in most cases, and so patients continue to need new mechanisms and new lines of therapy,” he says.

He notes, however, that it is not yet clear whether the drug's ability to inhibit both δ and γ isoforms will translate into a clinical benefit over a PI3Kδ inhibitor such as idelalisib. “That difference seems be important when the drug is used preclinically in model systems, but in clinical practice, the differences have not been as clear as we might have predicted,” he says.

Davids is also interested in understanding the optimal sequencing of drugs for patients with CLL/SLL: He is currently leading an investigator-initiated trial testing duvelisib plus chemotherapy as a first-line therapy, and another exploring duvelisib plus venetoclax for patients with relapsed/refractory disease.

Nitin Jain, MD, of The University of Texas MD Anderson Cancer Center in Houston, agrees that duvelisib will join idelalisib as an option for patients with CLL/SLL after chemotherapy and other targeted therapies, noting that the drugs had similar efficacy in their respective trials. He adds that because PI3K inhibitors can cause immune-related toxicities such as colitis and hepatitis, the safety profile may ultimately determine which drug clinicians choose. “It's unlikely that there will be a head-to-head trial, but I think that we'll have to go across trials and compare the toxicity profile of these drugs,” he says. –Catherine Caruso