Figure 1.

Schematic representation of the modeling framework for axitinib in metastatic renal cell carcinoma (mRCC). Axitinib daily area under the curve (AUC_daily) was used as a driver of the timecourses of biomarkers (the vascular endothelial growth factor VEGF and its soluble receptors sVEGFR‐1, ‐2, and ‐3) and diastolic blood pressure (dBP). Biomarker timecourses were described by indirect response models where axitinib inhibits the loss of VEGF response and the production of sVEGFR‐1, ‐2, and ‐3 responses. sKIT was not affected by axitinib. The model describing tumor size (sum of longest diameters, SLD) included an exponential growth and an effect of the relative change in sVEGFR‐3 from baseline over time (sVEGFR‐3_rel(t)) that induces tumor size reduction and washes out over time. The SLD timecourse (SLD(t)) was predictive of overall survival. K_G, first‐order growth rate constant; k_out, first‐order rate constant for the degradation or loss of response; k_sVEGFR‐3, tumor size reduction rate constant related to sVEGFR‐3 response; λ, tumor resistance/regrowth appearance rate constant; R_in, zero‐order rate constant for the production of response. Dashed arrows represent relationships identified as significant.