eUpdate 62-1: Idelalisib: A First-in-Class Specific Inhibitor of PI3Kδ for the Treatment of B-cell Lymphomas

OVERVIEW

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

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 to ...