TY - JOUR
T1 - Everolimus Exposure as a Predictor of Toxicity in Renal Cell Cancer Patients in the Adjuvant Setting
T2 - Results of a Pharmacokinetic Analysis for SWOG S0931 (EVEREST), a Phase III Study (NCT01120249)
AU - Synold, Timothy W.
AU - Plets, Melissa
AU - Tangen, Catherine M.
AU - Heath, Elisabeth I.
AU - Palapattu, Ganesh S.
AU - Mack, Philip C.
AU - Stein, Mark N.
AU - Meng, Maxwell V.
AU - Lara, Primo
AU - Vogelzang, Nicholas J.
AU - Thompson, Ian Murchie
AU - Ryan, Christopher W.
N1 - Publisher Copyright:
© 2019 - IOS Press and the authors. All rights reserved.
PY - 2019
Y1 - 2019
N2 - 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 (p<0.001). Furthermore, EVE trough levels were higher in men than women (19.4 versus 15.4 ng/mL, p=0.01). Risk of grade 2+triglycerides was increased in Q2 and Q3 vs Q1 (OR=2.08; p=0.02 and OR=2.63; p=0.002). Risk of grade 2+rash was increased in Q2 and Q4 vs Q1 (OR=2.99; p=0.01 and OR=2.90; p=0.02). There was also an increased risk of any grade 3+tox in Q2 vs Q1 (OR=1.71; p=0.05). 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.
AB - 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 (p<0.001). Furthermore, EVE trough levels were higher in men than women (19.4 versus 15.4 ng/mL, p=0.01). Risk of grade 2+triglycerides was increased in Q2 and Q3 vs Q1 (OR=2.08; p=0.02 and OR=2.63; p=0.002). Risk of grade 2+rash was increased in Q2 and Q4 vs Q1 (OR=2.99; p=0.01 and OR=2.90; p=0.02). There was also an increased risk of any grade 3+tox in Q2 vs Q1 (OR=1.71; p=0.05). 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.
KW - Adjuvant chemotherapy
KW - Everolimus
KW - Pharmacokinetics
KW - Renal cell carcinoma
KW - Therapeutic drug monitoring
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U2 - 10.3233/KCA-180049
DO - 10.3233/KCA-180049
M3 - Article
AN - SCOPUS:85078987708
SN - 2468-4562
VL - 3
SP - 111
EP - 118
JO - Kidney Cancer
JF - Kidney Cancer
IS - 2
ER -