Everolimus Exposure as a Predictor of Toxicity in Renal Cell Cancer Patients in the Adjuvant Setting: Results of a Pharmacokinetic Analysis for SWOG S0931 (EVEREST), a Phase III Study (NCT01120249).

BACKGROUND

S0931 is assessing recurrence-free survival in renal cell carcinoma (RCC) patients randomized to receive everolimus (EVE) versus placebo for one year following nephrectomy. Due to a higher than expected dropout rate, we assessed EVE trough levels in the adjuvant setting to evaluate the relationship between EVE exposure and probability of toxicity.

METHODS

Patients received 10 mg daily EVE for nine 6-week cycles. Pre-dose whole blood samples were collected pre-cycle 2 and pre-cycle 3 and analyzed for EVE. Patients with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. Patients were segregated into quartiles (Q) based on EVE levels and logistic regression was used to model the most common adverse event outcomes using EVE trough as a predictor. Hazard and odds ratios were adjusted for age, BMI and performance status.

RESULTS

A total of 467 patients were included in this analysis. Quartiles normalized to an EVE dose of 10 mg/day were < 9.0, 9.0-12.9, 12.9-22.8, and > 22.8 ng/mL, respectively. EVE trough levels increased with increasing age (

CONCLUSIONS

We identified significant gender and age-related differences in EVE trough levels in patients receiving adjuvant treatment for RCC. Furthermore, our analysis identified significant associations between EVE exposure and probability of toxicity.

Informations de copyright

© 2019 – IOS Press and the authors. All rights reserved.

Déclaration de conflit d'intérêts

TWS reports a grant from The Hope Foundation through the SWOG Trial Support (STrS) program, during the conduct of this study. EIH reports clinical trial funding support from Genentech/Roche, Merck Sharpe and Dohme, and Bristol-Myers Squibb outside the submitted work. PCM reports grants from Boehringer Ingelheim, personal fees from Novartis, personal fees from AstraZeneca, personal fees from Celgene, personal fees from Lilly, personal fees from Pfizer, personal fees from Guardant Health, and personal fees from Apton Biosystems, all outside the submitted work. MNS reports grants and personal fees from Merck Sharp & Dohme, grants from Janssen Oncology, grants from Advaxis, grants from Bristol-Myers Squibb, and grants from Nektar, all outside the submitted work. PL reports consultant fees from Novartis, during the conduct of this study. NJV reports personal fees from Novartis, during the conduct of this study; personal fees from Pfizer, personal fees from Merck, personal fees from Exelixis, personal fees from BMS, all outside the submitted work. CWR reports non-financial support from Novartis, during the conduct of this study; personal fees from Eisai, personal fees from Exelixis, personal fees from Genentech/Roche, personal fees from Novartis, personal fees from Pfizer, grants from Argos, grants from Bristol-Myers Squibb, grants from CytRx Corporation, grants from Daiichi-Sankyo, grants from Eisai, grants from Exelixis, grants from Genentech, grants from Novartis, grants from Glaxo Smith Kline, grants from Janssen, grants from Karyopharm, grants from MabVax, grants from Merck, grants from Morophotek, grants from Threshold Pharmaceuticals, grants from TRACON, and non-financial support from Bayer, all outside the submitted work. MP, CMT, GSP, MVM, and IMT have nothing to disclose.