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
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.
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 inhibit p110δ, decrease Akt phosphorylation levels, and induce apoptosis.7 In CLL cells and Hodgkin lymphoma cells, idelalisib was shown to downregulate chemokine secretions; inhibit chemotaxis and cell migration beneath stromal cells in B cell–stromal cell co-cultures; and inhibit B-cell receptor–(BCR) and chemokine receptor–induced activation of Akt, mitogen-activated protein (MAP) kinases, and extracellular signal–regulated kinases (ERKs).8,9
The efficacy and dose-limiting toxicity of idelalisib (dose range 50-350 mg 1 to 2 times daily) was evaluated in Phase I studies in 64 patients with relapsed indolent non-Hodgkin lymphomas (iNHL),10 in 40 patients with relapsed or refractory mantle cell lymphoma (MCL),11 and in 54 patients with relapsed or refractory CLL.12 All patients had received a median of 4-5 previous regimens. Idelalisib showed an acceptable safety profile and promising clinical efficacy with an overall response rate (ORR) of 47% in patients with iNHL and one patient achieving a complete response.10 In MCL patients, the ORR to idelalisib was 40%, with two patients achieving a complete response.11 In patients with refractory CLL, the ORR was 72%.12 Cells obtained from patients with refractory CLL receiving the 100-mg or 150-mg dose twice daily were noted to exhibit a significant reduction in phosphorylation levels of Akt within 1 week of therapy.12
Idelalisib as monotherapy was granted accelerated FDA approval for the treatment of FL and SLL based on promising data from one Phase II open-label study of 125 patients with previously treated iNHL who were not responsive to rituximab and chemotherapy that included an alkylating agent, or who had a relapse within 6 months after receiving therapy. Rituximab is an anti-CD20 antibody, and in combination with other chemotherapy agents, is a mainstay of iNHL therapy. Patients were given idelalisib 150 mg, orally twice daily. The ORR was 57%, with 6% achieving a complete response. The median time to response was 1.9 months, and the median duration of response was 12.5 months. The median progression-free survival (PFS) was 11 months, with 47% of patients remaining progression free at 48 weeks.13
The FDA designated idelalisib in combination with rituximab as “breakthrough therapy” for relapsed CLL based on data from the Phase III, multicenter, randomized, double-blind, placebo-controlled study that assessed the efficacy and safety of idelalisib in combination with rituximab or placebo.14,15 In this study, 220 patients with CLL were randomly assigned to receive rituximab plus idelalisib (150 mg) or rituximab plus placebo twice daily. The primary end point was PFS. The study was terminated early on the recommendation of the data and safety monitoring board due to the significant efficacy of idelalisib in improving PFS. The ORR was 81% in the idelalisib group versus 13% in the placebo group. Overall survival was 92% in the idelalisib group versus 80% in the placebo group. The median PFS in the placebo group was 5.5 months but was not reached by the end of the study with the idelalisib group.15
Several clinical studies are in progress to assess the efficacy and safety of idelalisib in combination with other chemotherapeutic and immunomodulatory agents. These trials include evaluating idelalisib in combination with rituximab in patients with previously treated iNHL; idelalisib in combination with ofatumumab in patients with previously treated CLL; and idelalisib in combination with bendamustine and rituximab in patients with previously treated CLL, in patients with previously treated iNHL, and in patients with previously untreated CLL.16
Clinical Use and Pharmacokinetics. The recommended dose of idelalisib is 150 mg administered orally twice daily and reduced if necessary on the basis of toxicity.2 Drug absorption is not affected by food. Steady-state is achieved in 8 days.10 Idelalisib is metabolized by aldehyde oxidase, CYP3A, and UGT1A4. Its major metabolite is GS-563117, which is inactive against PI3Kδ. Elimination is mostly through feces (~80%) and urine (~15%). There is no difference in pharmacokinetics between Japanese and Caucasian populations.2
Idelalisib inhibits P-glycoprotein (P-gp) and the organic anion transporters OATP1B1 and OATP1B3. Idelalisib and GS-563117 inhibit CYP3A and are substrates of P-gp and the efflux transporter breast cancer resistance protein (BCRP/ABCG2) in vitro. Idelalisib increased plasma levels of midazolam (a CYP3A substrate) but did not affect plasma levels of digoxin (a P-gp substrate) or rosuvastatin (an OATP1B1/B3 substrate). Rifampin (a strong CYP3A and P-gp inducer) decreased plasma levels of idelalisib, whereas ketoconazole (a strong CYP and P-gp inhibitor) increased plasma levels of idelalisib. Therefore, patients receiving strong CYP inhibitors may be at increased risk for idelalisib toxicity. Idelalisib had no effect on QTc interval in healthy volunteers. Dosage adjustment is not recommended for patients with baseline renal or hepatic impairment. However, in patients with hepatic impairment, the AUC increased by 60%, and patients may be at increased risk for toxicity.2
Adverse Effects. Idelalisib is marketed under a REMS program consisting of a communication plan for prescribers and a medication guide for patients to reinforce that the drug is associated with potentially fatal toxicities.2,3 These include liver toxicity (14%), diarrhea and colitis (14%), pneumonitis, intestinal perforations, cutaneous toxicity, anaphylaxis, and neutropenia.1,2 Patients taking idelalisib should avoid other hepatotoxic drugs, and idelalisib should be withheld or the dose reduced if significant toxicities occur.2,3
Other common side effects include fever, chills, cough, pneumonia, fatigue nausea, abdominal pain, rash, hyperglycemia, and elevated levels of triglycerides and liver enzymes.10,11,12,13 Idelalisib is teratogenic in rats and may cause embryo-fetal toxicity; it is characterized as FDA pregnancy risk category D, and breast feeding during therapy is contraindicated because of the potential for serious adverse reactions in nursing infants.2
Inhibitors of the PI3K/Akt/mTOR Pathway for Cancer Therapy
The PI3K/Akt/mTOR pathway is an attractive target in cancer therapy. Ongoing Phase I and Phase II clinical trials are evaluating the safety and efficacy of novel molecular inhibitors that target the PI3K/Akt/mTOR pathway in various types of malignancies. Examples of inhibitors being evaluated include pan-PI3K inhibitors [inhibitors of all four p110 isoforms, including BKM120 (buparlisib) and PX-866]; the isoform-specific PI3Kα inhibitor (BYL719); Akt inhibitors (e.g., MK2206 and GSK 2141795); dual PI3K/mTOR inhibitors (e.g., BEZ235); and mTORC1/mTORC2 inhibitors (e.g., AZD2014 and CC-223). Currently, only the PI3Kδ inhibitor, idelalisib, and the mTORC1 inhibitors, sirolimus (rapamycin), everolimus, and temisirolimus, are approved for clinical use.
Idelalisib is the fifth new drug approved with the FDA’s “breakthrough therapy” designation, and it joins obinutuzumab (gazyva; approved in November 2013) and ofatumumab (arzerra; approved in April 2014) as the third breakthrough drug to be approved for CLL. Despite its potential toxicity, idelalisib is a much needed new treatment option for patients with CLL and indolent FL or SLL who have few if any other treatment options.