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Idelalisib (zydelig) is a first-in-class oral inhibitor of the enzyme phosphatidylinositol 3-kinase-δ (PI3Kδ) isoform that was approved by the FDA in July 2014 for the treatment of patients with relapsed or refractory B-cell malignancies (eFigure 62–1.1).1 The PI3Kδ isoform in the PI3K signaling pathway is constitutively activated in many B-cell malignancies, and inhibition of this pathway promotes apoptosis in these cancerous cells. The FDA granted idelalisib accelerated approval for treatment of relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL). Accelerated approval allows a drug to be used to treat a serious or life-threatening disease based on a surrogate end point predictive of a clinical benefit in patients. Idelalisib, in combination with rituximab, was also approved as a “breakthrough therapy” for relapsed chronic lymphocytic leukemia (CLL). Idelalisib, available in 100-mg and 150-mg tablets, is administered orally twice daily. Idelalisib may cause serious and sometimes fatal side effects, including liver toxicity, diarrhea, colon inflammation, lung inflammation, intestinal perforations, and skin toxicity. The drug carries a black box warning to caution patients and healthcare providers about these serious risks, and its use is conditional on employing a risk evaluation and mitigation strategy (REMS).2,3

eFigure 62–1.1.

Chemical structure of idelalisib (also known as CAL-101, UNII-YG57I8T5M0, GS-1101, or 870281-82-6). Chemical name: 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one. Compound CID: 11625818.

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Background and Mechanism of Action. Activation of PI3K and the consequent activation of signaling events through protein kinase B (Akt) and the mammalian target of rapamycin (mTOR) pathway is important in regulation of the cell cycle, metabolism, growth, differentiation, motility, and survival (Figure 62–4).4,5 Excessive signaling through the PI3K pathway is a frequent aberration in many human cancers. The class I PI3K enzymes (PI3Ks are grouped into three classes: I-III) are activated by protein tyrosine kinase receptors and G protein–coupled receptors (GPCRs). These PI3K enzymes are heterodimers composed of a p85 regulatory subunit and a p110 catalytic subunit. The p110 subunit exists in four identified isoforms: p110α, p110β, p110γ, and p110δ. The α and δ isoforms are ubiquitously expressed, whereas the γ and δ isoforms are predominantly expressed in cells of hematopoietic origin. In B-cell cancers, constitutive activation of the PI3Kδ isoform is a common occurrence.5 Idelalisib was developed as a small-molecule inhibitor that selectively targets the catalytic subunit p110δ for the treatment of B-cell malignancies.6,7


Clinical Pharmacology. Idelalisib is a highly selective inhibitor of the PI3Kδ isoform with an EC50 of ~8 nM. Idelalisib is 40- to 300-fold more selective for the p110δ isoform than for other PI3K isoforms (α, β, and γ), and 400- to 4000-fold more selective than for related kinases (e.g., DNA-dependent protein kinase, mTOR).6 In tumor cell lines and cells obtained from patients with different types of B-cell malignancies, idelalisib was shown ...

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