Time-Dependent Bias and Prognostic Confounding in Exposure-Response Analysis of Targeted Therapies: Lessons from...

Exposure-response (E-R) analyses of sunitinib in metastatic renal cell carcinoma (mRCC) have supported concentration-guided dose escalation. However, such analyses may be biased when exposure metrics incorporate post-baseline dose modifications, time-varying apparent clearance, or baseline factors that influence both pharmacokinetics and clinical outcomes. We re-evaluated the E-R relationship of sunitinib in mRCC with explicit assessment of these biases. A population pharmacokinetic analysis of 294 patients from four clinical trials identified time-dependent declines in apparent clearance for sunitinib and SU12662. E-R analyses were performed in 165 cytokine-refractory patients treated with the approved 50 mg 4-weeks-on/2-weeks-off regimen, using time to progression (TTP), overall survival (OS), and tolerability-related outcomes. Baseline albumin and age were identified as shared covariates of exposure and outcome and incorporated as confounders in multivariable multistate survival models. The apparent positive association between higher exposure and improved TTP and OS was attenuated when exposure was defined using early, baseline-anchored metrics rather than time-averaged apparent clearance. It was no longer evident after adjustment for albumin and age. Consistently, simulations with confounders fixed at cohort medians showed overlapping TTP and OS profiles across exposure groups. In contrast, higher exposure remained associated with poorer tolerability, including increased risks of dose reduction and treatment discontinuation driven by adverse-events. These findings indicate that previously reported positive E-R relationships for sunitinib were largely due to time-dependent bias and confounding. The results do not support exposure-guided dose escalation based on total plasma concentrations, but instead suggest the use of therapeutic drug monitoring to identify patients at risk of excessive exposure and toxicity.