Figure 6 from Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers

PK/PD/Efficacy modeling to predict clinically active dose range. A, Comparison of observed and predicted tumor growth data at multiple dose levels of RMC-6236 in the NCI-H441 xenograft tumor model. Tumor growth was predicted using the Simeoni tumor growth model. The dotted line indicates the initial average tumor volume. B, Comparison of observed and predicted tumor growth data at multiple dose levels of RMC-6236 in the Capan-2 xenograft tumor model. Tumor growth was predicted using the Simeoni tumor growth model. The dotted line indicates the initial average tumor volume. C, Comparison of observed vs. simulated PK and PD data at multiple dose levels of RMC-6236 in mice bearing NCI-H441 xenograft tumors. Single-dose data from all dose levels are presented from 0 to 24 hours, whereas repeat-dose data from 25 and 40 mg/kg repeat daily dosing is presented from 216 to 240 hours. Simulated blood and tumor PK data are indicated by the solid and dashed green and blue lines, respectively. Simulated PD data are indicated by the solid purple lines. Observed data are indicated by dots (blood PK and PD) or squares (tumor PK). The dotted line indicates the 10% expression level of DUSP6 mRNA as normalized to the vehicle control group. D, Predicted profiles of human whole blood and tumor PK as well as tumor PD at clinical dose levels at steady state. Blood PK and tumor PK are indicated by the solid and dashed green lines whereas tumor PD is indicated by the solid purple lines. Repeat dose data are presented from 336 to 360 hours after two weeks of simulated daily dosing. The dotted line indicates a 10% expression level of DUSP6 mRNA as normalized to the vehicle control group.