Everolimus (EVE) exposure as a predictor of toxicity (Tox) in renal cell cancer (RCC) patients (Pts) in the adjuvant setting: Results of a pharmacokinetic analysis for SWOG S0931 (EVEREST), a phase III study (NCT01120249).
4566 Background: S0931 is assessing recurrence-free survival in RCC pts randomized to receive EVE versus placebo for one year following nephrectomy. To date, there has been a higher than expected dropout rate due to bothersome tox. Previous reports have shown an association between EVE trough levels and both tox and disease response in RCC pts. Therefore, we have assessed EVE trough levels to evaluate the relationship between measured exposure and probability of tox. This analysis has been approved by the DSMC. Methods: Patients received 10 mg daily EVE or placebo for nine 6-week cycles. Pre-dose whole blood samples collected pre-cycle 2 and pre-cycle 3 were analyzed for EVE. Pts with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. When both trough levels were available, results were averaged. Pts were segregated into quartiles (Q) based on EVE levels and logistic regression was used to model the following adverse event outcomes using EVE trough as a predictor; any grade 3+ tox, grade 2+ triglycerides, grade 2+ hyperglycemia, grade 2+ oral mucositis, grade 2+ rash, and premature stopping of EVE. Hazard and odds ratios were adjusted for age, BMI and performance status. Results: This study reached its accrual goal and closed on 9/15/2016 with 1545 (775 EVE) randomized patients. A total of 386 pts are included in this preliminary analysis. Median EVE trough was 12.8 ng/mL (range 3.1, 75.6) per 10 mg dose. Event rates for tox were: any grade 3+ tox = 46%, grade 2+ triglycerides = 33%, grade 2+ hyperglycemia = 15%, grade 2+ oral mucositis = 34%, grade 2+ rash = 15%, and premature stopping of EVE = 40%. The risk of grade 2+ triglycerides was increased in Q2 and Q3 vs Q1 (OR = 2.95; p = 0.001 and OR = 3.48; p < 0.001). The risk of grade 2+ rash was increased in Q2 and Q4 vs Q1 (OR = 2.95; p = 0.02 and OR = 3.20; p = 0.01). There was also a trend towards an increased risk of any grade 3+ tox in Q3 vs Q1 (OR = 1.72; p = 0.07). Conclusions: This analysis has identified significant associations between EVE exposure and the probability of tox. EVE analysis is ongoing and the final results will be presented. Clinical trial information: NCT01120249.