Progression-free survival
death
CPH, EVENT, DISEASE PROGRESSION
Figure Kaplan–Meier plot for progression-free survival by average exposure quartiles. Shaded regions represent 95% confidence intervals for each exposure quartile (Q#) of CAVG0T, the predicted average cabozantinib concentration from time zero to the event or censoringA linear CPH model including all 311 patients was used to assess the relationship between disease progression or death and cabozantinib exposure (Supplementary Table S4). This model did not produce a statistically significant reduction in − 2LL compared to the model without cabozantinib exposure, indicating no relationship between cabozantinib exposure and PFS. Therefore, a nonlinear model was not tested.The parameter estimate in the linear PFS base model was used to predict the relative hazard rate for different cabozantinib dose levels. The predicted cabozantinib average concentrations and corresponding dose levels were 386 ng/mL for 20 mg QD, 772 ng/mL for 40 mg QD, and 1157 ng/mL for 60 mg QD. These exposures are based on cabozantinib doses that are constant over the course of the study and do not reflect the observed data where cabozantinib dose modifications may have occurred. There was no statistically significant relationship of PFS with cabozantinib exposure at these three average concentrations (Supplementary Fig. S6). Compared with a reference CAVG0T of 772 ng/mL, the HR (95% CI) was 1.00 (0.78–1.27) for CAVG0T 386 ng/mL and 1.00 (0.79–1.28) for CAVG0T 1157 ng/mL.