Foreseeing the Moments of Occurrence of Everolimus Long-term Side Effects by Follow up of Trough Blood Concentrations

Everolimus is an oral inhibitor of mammalian target of rapamycin (mTOR), a key signal transduction molecule of the phosphatidylinositol 3-kinase/Akt pathway. This pathway, which regulates cellular growth, proliferation, metabolism, survival and angiogenesis, is frequently dysregulated in human cancers and thus is a rational target for anticancer therapy. Everolimus is currently approved by the European Medicines Agency (EMA) and U.S. Food and Drug administration (FDA) for the treatment of different solid malignancies.

Metastatic (Hormone-Receptor [HR]-positive, HER2-negative) breast cancer (BC), advanced or unresectable neuroendocrine tumours of pancreatic (pNET), gastrointestinal or lung origin and metastatic renal cell carcinoma (mRCC) are diseases with poor outcome. Everolimus is part of palliative treatment and increases patients' median progression-free survival (PFS) with 4.6 months in metastatic BC (mBC), 7 months in pNET and 3 months in mRCC. However, serious adverse events (AEs) occur frequently; stomatitis up to 67%, non-infectious pneumonitis (NIP) up to 15%. This reduces effectiveness of everolimus, because AEs are managed with dose reductions, treatment interruptions or even complete discontinuation of everolimus.

Everolimus shows a large inter-individual pharmacokinetic variation in whole blood concentrations, due to variability in oral drug availability, patient non-compliance (e.g. due to drug-related toxicity, forgetting and/or overuse), drug-drug interactions with co-medication and many other factors. Furthermore, variation in the population pharmacokinetics of everolimus is caused by everolimus' hematocrit effect. This effect is present at high everolimus concentrations in combination with low hematocrit values, which is likely to be the case in the oncologic population. High incidences of anemia in oncologic patients treated with everolimus have been described, respectively being 32.1% (CI=17.5-51.3%) for all-grade (grades 1-4) toxicities and 6.9% (95% CI=4.1-11.3%) for high-grade (grades 3-4) toxicities. Therefore, studies have recommended to correct the everolimus whole blood concentrations for hematocrit determination.

The very different whole blood concentrations between individuals can result in supratherapeutic or subtherapeutic exposure levels and consequently in over- or undertreatment, respectively. Despite the inter-patient variability in systemic exposure, everolimus is currently prescribed at a fixed dose. Given the narrow therapeutic index and a positive exposure-efficacy relationship, there is a rationale for pharmacokinetically guided dosing also known as therapeutic drug monitoring (TDM) of everolimus. Such an approach could theoretically contribute to a tailor-made everolimus treatment with improved therapeutic efficacy and decreased risk for toxicity. Since daily everolimus dosing demonstrates dose proportionality and linear pharmacokinetics, this seems to be easily applicable. Furthermore, requirements for dose reduction at physicians discretion can be supported when it is known at what everolimus trough level a dose reduction is recommended.

Therapeutic-drug-monitoring (TDM) (i.e. measurement of everolimus whole blood levels after venipuncture) is used to adjust the prescribed daily dose, to maintain effective everolimus whole blood concentrations, with the lowest possible risk of AEs. In addition, TDM is a useful tool for early detection of non-adherence, and might also be used to monitor the effects of drug-drug interactions and food effects. While TDM, according to international consensus, has been common in transplantation medicine for 10 years, it has not been implemented in oncology. The importance of TDM in oncology is, however, supported by previous research that showed a 2-fold increased trough concentration (Cmin) of everolimus whole blood with a short-term risk of grade ≥ 3 pulmonary events (relative risk [RR] 1.9; 95% CI 1.1-3.3], stomatitis events (RR 1.5; 95% CI 1.1-2.1) and metabolic events (RR 1.3 95% 1.0-1.7). Moreover, an exposure-toxicity relationship of everolimus in patients with thyroid cancer was observed, since initial everolimus concentrations could be associated with early toxicity (< 12 weeks), i.e. stomatitis. However, the association between initial everolimus measurements and long-term AEs (≥ 12 weeks, e.g. pneumonitis, anorexia and anemia) of any grade and the need for everolimus dose reductions could not be made. Since a trough concentration of approximately 18 µg/L was associated with toxicity, the investigators assume that the upper therapeutic window of everolimus in the oncologic setting will be ±18 µg/L. Therefore, an upper threshold of >18 µg/L was considered for this study.Similarly, a tendency to improved PFS and overall survival (OS) was noted when CminSS was above 14.1 μg/L. This might be the lower limit of the therapeutic window.