Dr. Ian Flinn, Medical Oncologist specializing in hematologic malignancies at Tennessee Oncology, discusses the recent FDA approval of duvelisib for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email [email protected] for more information.

TRANSCRIPT

(Intro Music Playing) As a background to today's discussion, the PI3K are a family of lipid kinases that sit at the crossroads of numerous signaling events that drive many malignancies, including certain lymphomas, and chronic lymphocytic leukemia. There are four isoforms of the PI3K-- alpha, beta, delta, and gamma. Isoform specific inhibitors are attractive because they may lead to efficacy without the toxicity of pan inhibitors.

Idelalisib, which is a delta isoform inhibitor, was the first PI3K inhibitor be approved for lymphoma in CLL. The delta isoform is a particular interest in B cell malignancies because its expression is normally restricted to cells of a hematopoietic origin. In data from gene knockout models, show that it has a key role in B cell signaling, development, and survival. Selective targeting of the delta isoform should not alter insulin signaling, which is mediated by the ubiquitously expressed alpha isoform. However, narrow targeting could lead to mechanisms of resistance to upregulation of other isoforms. This has been demonstrated in mantle cell lymphoma where the alpha isoform is expressed in relapse patients.

Duvelisib is a dual inhibitor of both the delta and gamma isoforms of the PI3K. Inhibiting the gamma isoform may be important because of its inhibitory effect, not only in the malignant cell, but also in the micro-environment, which provides important survival signals to malignant cells. Both idelalisib and copanlisib, an inhibitor of the delta and alpha isoforms, are currently FDA approved for third line follicular cell lymphoma. And idelalisib is approved in combination with rituximab in relapse CLL.

On September 24, 2018, the Food and Drug Administration granted approval for duvelisib for patients with relapsed refractory chronic lyphocytic leukemia, small lymphocytic lymphoma, and follicular lymphoma after at least two prior therapies. The approval of duvelisib in CLL was based on the DUO trial, a large international randomized phase III trial comparing duvelisib, at 25 milligrams orally, twice daily, to ofatumumab, given according to the package label. The results of the duo trial have been published in Blood. In a subset analysis of 196 patients receiving at least two prior therapies, the median progression pre-survival was 16.4 months in the duvelisib arm, and 9.1 months in the ofatumumab arm, with a hazard ratio of 0.40. The overall response rate of 78% with duvelisib was twice the 39% seen with ofatumumab.

The follicular lymphoma indication is based on the Dynamo trial, a single arm multi-center trial of duvelisib, which enrolled 83 patients with follicular lymphoma who are refractory to rituximab and to either chemotherapy or radioimmunotherapy. The overall response rate, determined by an independent response committee, was 42%. Of the 35 responding patients, 15, or 43%, maintained responses for at least six months. And 6, or 17%, maintained responses for at least 12 months. The most common adverse reactions with an instance of greater than or equal to 20% were diarrhea, or colitis, neutropenium, rash, fatigue, pyrexia, cough, nausea, upper respiratory tract infection, pneumonia, muscle skeletal pain, and anemia.

Over the last decade, we've seen substantial advances in the treatment of low grade lymphoma and CLL, especially in the front-line setting. Unfortunately for patients with relapse and refractory disease, new agents are needed. The approval of duvelisib is an important addition to our armamentarium for these patients. And we'll have an immediate impact.

However, to have its greatest effect, strategies will need to be devised to move this drug earlier in the natural history of these diseases. Such approaches might include alternative dosing and scheduling, as well as combination regiments. Duvelisib is a novel PI3K inhibitor and is differentiated from other PI3K inhibitors, because it targets both the delta and gamma isoforms. Consequently, it is being studied in a broader array of diseases, including T cell malignancies, where promising activity has been seen.

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