Figure 3 from Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers

Broad-spectrum antitumor activity of RMC-6236 in preclinical models of RAS-addicted cancers. A–C, Tumor response waterfall plots of KRASG12X NSCLC (A), PDAC (B), and colorectal cancer (C) xenograft models upon RMC-6236 daily treatment at 25 mg/kg. 29 NSCLC, 22 PDAC, and 23 colorectal cancer xenograft models were included (n = 1–10 per model). Average % mean tumor volume change ± SEM from baseline at response calling date are shown. mRECIST criteria were used to call tumor response as indicated on the right-hand side of each waterfall plot. Oncoplots illustrating gene alterations and expression levels in critical genes linked to the clinicopathologic characteristics of the indicated models are shown below each waterfall. Color coding represents dark green for mutations and light green for the absence of mutations. The ◈ symbol denotes that mRNA expression of corresponding genes not expressed, defined as having a gene-expression value of ≤0.5 CPM. The top row specifically highlights the mutation codon at KRASG12. D–F, Kaplan–Meier analyses of time to tumor doubling on treatment in individual tumor-bearing animals from KRASG12X NSCLC (D), PDAC (E), and colorectal cancer (F) xenograft models upon daily treatment of vehicle control or RMC-6236 at 25 mg/kg for up to 90 days. 29 NSCLC models (n = 135 animals each in control and RMC-6236 treatment groups), 22 PDAC models (n = 95 animals in control, n = 83 in RMC-6236 treatment group), and 23 colorectal cancer models (n = 95 animals in control, n = 93 in RMC-6236 treatment group) were included. Time to event was determined by the time on treatment until tumor volume doubling from baseline on survival plots by Kaplan–Meier analysis. Log-rank test was used to compare vehicle control with treatment groups, Cox proportional hazards models were used to estimate hazard ratios: KRASG12X NSCLC (HR 0.035, 95% interval 0.020–0.061, P < 2 × 10⁻¹⁶), KRASG12X PDAC (HR 0.008, 95% interval 0.002–0.026, P < 2 × 10⁻¹⁶) and KRASG12X colorectal cancer (HR 0.072, 95% interval 0.043–0.120, P < 2 × 10⁻¹⁶). G, Tumor response waterfall plot and Kaplan–Meier analysis of KRASG12X GAC and OVCA xenograft models upon daily treatment of vehicle control or RMC-6236 at 25 mg/kg for up to 90 days. Four models of GAC and 4 models of OVCA tumors were included. Average % mean tumor volume change ± SEM from baseline at the response calling date were plotted. mRECIST criteria were used to call tumor response as indicated on right-hand side of the waterfall plot. Time to event was determined above. H, Bar plots of mean tumor volume % change ± SEM from baseline for xenograft models of NSCLC with KRASG12X and KRASOther mutations. Data for both vehicle control and RMC-6236 treatment groups of 35 KRASMUT NSCLC models (29 KRASG12X and 6 KRASOther models) are shown with each model represented by one symbol. The genotype of each model was represented by color and shapes: KRASG12X (green dot), KRASOther (purple; KRASG13X, square; KRASQ61H, triangle; KRASK117N, star). Mean tumor volume % change from baseline of the vehicle control groups and RMC-6236 treatment groups for KRASG12X models are 708.1% and −13.7% respectively; for KRASOther models are 1,070% and 257.5%, respectively. Vehicle control and RMC-6236 treatment groups were compared by paired t test, with P < 0.001 (***) for KRASG12X models and P < 0.01 (**) for KRASOther models. The dotted line represents mean baseline tumor volume.