Fig. 3. RMC-7977 is broadly active in RAS-addicted cancer models.
a, Relationship between the area under the curve (AUC) difference (see Supplementary Methods) and negative log-transformed P value (two-sided Wilcoxon test) between cell lines by genotype. Points represent mutated genes. Negative AUC indicates sensitivity; positive AUC indicates resistance. b, RMC-7977 EC50 according to KRAS genotype. Each dot represents a cell line. The centre line is the median, box limits represent first and third quartiles and whiskers depict the range. The number of cell lines in each group is indicated in parentheses. VUS, variants of unknown significance. c, Blood and tumour concentrations of RMC-7977 (green) and DUSP6 mRNA (blue) for NCI-H441 xenograft tumours following one oral dose of 10 mg kg−1 RMC-7977. Data are mean ± s.e.m. of three biological replicates. d, Mice bearing NCI-H441 CDX tumours treated with 10 mg kg−1 RMC-7977 orally once daily for 28 days. ***Adjusted P value = 0.0002; two-way ANOVA (n = 8 mice per group) with multiple comparison Dunnett’s test. The dashed line shows the initial average tumour volume. Data are mean ± s.e.m. for eight mice per group. e, KRAS(G12X) xenograft models treated with RMC-7977 (10 mg kg−1 by oral administration) for 4–6 weeks. Data are mean ± s.e.m. of 3–18 mice per group. One data point for LUAD G12C is beyond the axis range. Shaded boxes in the table indicate gene variants. f, Kaplan–Meier analysis of time to tumour size doubling (n = 90 mice per group) of KRASG12X mutant models treated with 10 mg kg−1 RMC-7977 orally once daily. g, CDX models treated with vehicle control, SHP2 inhibitor (20 mg kg−1 RMC-4550 orally every 2 days), MEK inhibitor (2.5 mg kg−1 cobimetinib orally once daily), combined SHP2 and MEK inhibitors (20 mg kg−1 RMC-4550 orally every 2 days and 2.5 mg kg−1 cobimetinib orally once daily), or 10 mg kg−1 RMC-7977 orally once daily. NCI-H441 (KRASG12V, NSCLC) and HPAC (KRASG12D, PDAC) models were treated for 21 days. SW620 (KRASG12V, CRC) was treated for 28 days. Data are mean ± s.e.m.; n = 8 mice per group for control and RMC-7977, and n = 10 mice per group for RMC-4550, cobimetinib, and RMC-4550 + cobimetinib.