In Focus: Voxtalisib for CLL and B-Cell Lymphomas

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Voxtalisib is a potent inhibitor of 4 PI3K isoforms (p110α, p110β, p110γ, and p110δ) and a weaker inhibitor of mTOR.
Voxtalisib is a potent inhibitor of 4 PI3K isoforms (p110α, p110β, p110γ, and p110δ) and a weaker inhibitor of mTOR.

A recent phase 2 study of voxtalisib provided mixed results on the efficacy of the pan-PI3K/mTOR inhibitor for the treatment of B-cell lymphomas.1

Although the drug had an acceptable safety profile in patients with relapsed or refractory lymphoma, chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL), efficacy was low in patients with mantle cell lymphoma, diffuse large B-cell lymphoma, and CLL/SLL.

Voxtalisib did, however, have efficacy against follicular lymphoma, leading the researchers to conclude that “no further studies with voxtalisib in chronic lymphocytic leukemia are planned,” but that “investigation of voxtalisib either alone or in combination with chemoimmunotherapy is warranted in patients with follicular lymphoma.”

Overview

Many patients with B-cell Hodgkin lymphoma or CLL treated with chemoimmunotherapy will eventually experience relapsed or refractory disease. PI3K and mTOR are both attractive targets for the treatment of B-cell malignancies, and several drugs targeting these pathways are under active investigation for relapsed or refractory disease.

Idelalisib is a US Food and Drug Administration (FDA)-approved PI3Kδ isoform–selective inhibitor used for the treatment of follicular lymphoma that has relapsed after 2 or more prior therapies, or in combination with rituximab in patients with relapsed CLL.2 Unexpected adverse events, however, including severe bacterial infection and immune-mediated organ damage, caused Gilead Sciences to discontinue clinical trials of idelalisib in patients with B-cell non-Hodgkin lymphoma and CLL.3

Evidence has shown that targeting multiple isoforms of PI3K might increase antitumor activity in both B-cell lymphoma and CLL, and that concurrent targeting of mTOR and PI3K could further increase antitumor activity. Voxtalisib is a potent inhibitor of 4 PI3K isoforms (p110α, p110β, p110γ, and p110δ) and a weaker inhibitor of mTOR.

A preclinical study of voxtalisib tested whether the use of an inhibitor of multiple isoforms of PI3 kinase could lead to deeper remissions.4 The study compared the pan-PI3K/mTOR inhibitor with PI3Kα and PI3Kδ isoform selective inhibitors and found that voxtalisib was more pro-apoptotic to CLL cells. Voxtalisib also blocked CLL cell survival, adhesion, and proliferation.

The drug was also a potent inhibitor of T cell–mediated production of cytokines, which support CLL cell survival. The researchers concluded that, based on these results, voxtalisib should be evaluated further in patients with CLL.

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