Long-term relationship between everolimus blood concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma: a prospective study

Shinya Takasaki,Yoshihide Kawasaki,Masaki Tanaka,Masafumi Kikuchi,Akihiro Ito,Nariyasu Mano,Hiroaki Yamaguchi

doi:10.1186/s40780-019-0135-5

Shinya Takasaki, Yoshihide Kawasaki + Show 5 more

Open Access

https://doi.org/10.1186/s40780-019-0135-5

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Abstract

BackgroundEverolimus is an oral inhibitor of mammalian target of rapamycin, approved for metastatic renal cell carcinoma (mRCC). Recently, personalized medicine through therapeutic drug monitoring (TDM) is recommended in cancer therapy. In this study, the relationship between everolimus blood concentration and clinical outcomes on a long-term were evaluated in Japanese patients with mRCC.MethodsPatients with mRCC were enrolled following treatment with everolimus at Tohoku University Hospital between April 2012 and December 2016. The relationship between everolimus trough blood concentration on day 8 of everolimus therapy and just before discontinuation or dose reduction, and their adverse events were evaluated. Patients were divided into two groups based on the median of everolimus blood concentration on day 8 of treatment, and the profiles of adverse events, and efficacy [time to treatment failure (TTF) and progression-free survival (PFS)] were evaluated.ResultsThe median (range) everolimus blood concentrations on day 8 after starting everolimus administration and just before discontinuation or dose reduction were 15.3 (8.1–28.0) ng/mL and 14.8 (6.4–58.4) ng/mL, respectively, with no significant difference between these values (P = 0.3594). Patients (n = 6) with discontinuation or dose reduction following adverse events in everolimus therapy had significantly higher blood concentrations than patients (n = 4) with dose maintenance on both day 8 (median, 18.0 vs 8.2 ng/mL; P = 0.0139) and just before discontinuation or dose reduction (median, 22.9 vs 9.7 ng/mL; P = 0.0142). Median TTF and PFS of the total patients (n = 10) were 96 days (95% confidence interval [CI], 26–288) and 235 days (95% CI, 28–291), respectively. Subgroup analysis showed that TTF of the patients with > 15.3 ng/mL (n = 5) was not significantly different from that of the patients with ≤15.3 ng/mL (n = 5; P = 0.5622). Similarly, PFS of the patients with > 15.3 ng/mL was not significantly different from that of the patients with ≤15.3 ng/mL (P = 0.3436).ConclusionsThis study demonstrated the long-term relationship between everolimus blood level and clinical outcomes and adverse events in Japanese patients with mRCC. Thus, TDM in everolimus therapy could be a useful tool for the early prediction of adverse events for Japanese patients with mRCC.

Highlights

Everolimus is an oral inhibitor of mammalian target of rapamycin, approved for metastatic renal cell carcinoma
An mammalian target of rapamycin inhibitors (mTORi) everolimus used for metastatic renal cell carcinoma (mRCC) has already been adapted for therapeutic drug monitoring (TDM) in other applications such as the prevention of organ rejection after transplantation [4, 5], and for the treatment of tuberous sclerosis complex [6, 7] and various forms of cancer [8,9,10]
Trough level of everolimus should be maintained at 3–8 ng/mL when used in combination with other immunosuppressive drugs and at 6–10 ng/ mL when used without calcineurin inhibitor [11,12,13,14,15,16]

Summary

Introduction

Everolimus is an oral inhibitor of mammalian target of rapamycin, approved for metastatic renal cell carcinoma (mRCC). Personalized medicine through therapeutic drug monitoring (TDM) is recommended in cancer therapy. Tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors (mTORi) are molecular targeted drugs for metastatic renal cell carcinoma (mRCC) [1]. These targeted drugs of mRCC show higher objective response rate and significantly prolong a median progression-free survival (PFS), various adverse events such as diarrhea, fatigue, vomiting, myelosuppression, and interstitial pneumonia are frequently induced [1]. An mTORi everolimus used for mRCC has already been adapted for TDM in other applications such as the prevention of organ rejection after transplantation [4, 5], and for the treatment of tuberous sclerosis complex [6, 7] and various forms of cancer [8,9,10]. In cancer, there is little evidence of TDM for everolimus in actual clinical practice [11]

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