Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway

Abstract

Agents inhibiting the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin (PAM) pathway are currently in various stages of clinical development in oncology, ranging from some in early-phase evaluations to others that have already received regulatory approval for treatment in advanced cancers. The administration of PAM pathway inhibitors has been associated with metabolic toxicities of hyperlipidemia and hyperglycemia. The PAM Task Force of the National Cancer Institute Investigational Drug Steering Committee convened an interdisciplinary expert panel to review the pathophysiology of hyperlipidemia and hyperglycemia induced by PAM pathway inhibitors, summarize the incidence of these metabolic toxicities induced by such agents in the current literature, advise on clinical trial screening and monitoring criteria, and provide management guidance and therapeutic goals on occurrence of these toxicities. The overarching aim of this consensus report is to raise awareness of these metabolic adverse events to enable their early recognition, regular monitoring, and timely intervention in clinical trials. Hyperglycemia and hyperlipidemia are generally not acutely toxic and most often reversible with therapeutic intervention. Dose modifications or discontinuation of PAM pathway inhibitors should only be considered in situations of severe events or if progressive metabolic derangement persists after therapeutic interventions have been attempted for a sufficient duration. Specialty consultation should be sought to aid clinical trial planning and the management of these metabolic adverse events.

Fig 1.

Pathophysiology of (A) mammalian target of rapamycin (mTOR) inhibitor–induced hyperlipidemia and (B) phosphoinositide 3- kinase–Akt–mTOR pathway inhibitor–induced hyperglycemia. LPL, lipoprotein lipase; TG, triglyceride; VDL, very low density lipoprotein.

Fig 2.

(A) Treatment of phosphoinositide 3–kinase–Akt–mammalian target of rapamycin (PAM) pathway inhibitor–induced hypertriglyceridemia. (*) Therapeutic lifestyle changes (TLC), if appropriate: weight reduction, physical activity, avoid simple sugars (Table 2) and alcohol, consult registered dietician. (†) For triglyceride levels of 150 to 499 mg/dL, triglyceride lowering is secondary to achieving individual LDL cholesterol target. (‡) High risk defined as those continuing to receive PAM pathway inhibitor agent, with anticipated increase in triglycerides, or those with diabetes or cardiovascular (CV) disease (Table 2). (§) Options: fibrates (fenofibrate or gemfibrozil), fish oil (omega-3-ethyl esters), extended-release nicotinic acid. (B) Treatment of PAM pathway inhibitor–induced hypercholesterolemia, if prognosis > 1 year. (*) CV risk equivalents defined in Table 2. (†) TLC in diet and exercise (Table 2).

Fig 3.

Management of (A) grade 2 hyperglycemia (161 to 250 mg/dL), (B) asymptomatic grade 3 hyperglycemia (250 to 500 mg/dL), (C) symptomatic grade 3 hyperglycemia (250 to 500 mg/dL) or grade 4 hyperglycemia (> 500 mg/dL), and (D) hyperglycemia in previously diagnosed diabetics. NOTE. Recommendations based on experience and expertise of the panel. Some patients are able to stop insulin or sulfonylureas later with therapeutic lifestyle changes (TLC), after acute lowering of blood glucose or after discontinuation of phosphoinositide 3–kinase–Akt–mammalian target of rapamycin (PAM) pathway inhibitors. AC, before meals; DLT, dose-limiting toxicity; IVF, intravenous fluids; QHS, before every bedtime. (*) Do not use metformin if creatine > 1.3 mg/dL (women) or > 1.4 mg/dL (men) or if any state of decreased tissue perfusion or hemodynamic instability is present (eg, heart failure); hold metformin for computed tomography scans; GI symptoms may occur with initiation but usually subside after first week.