Comprehensive Clinical and Molecular Characterization of <i>KRAS</i> ^G12C-Mutant Colorectal Cancer.

Abstract

<i>KRAS</i> p.G12C mutations occur in approximately 3% of metastatic colorectal cancers (mCRC). Recently, two allosteric inhibitors of <i>KRAS</i> p.G12C have demonstrated activity in early phase clinical trials. There are no robust studies examining the behavior of this newly targetable population. We queried the MD Anderson Cancer Center data set for patients with colorectal cancer who harbored <i>KRAS</i> p.G12C mutations between January 2003 and September 2019. Patients were analyzed for clinical characteristics, overall survival (OS), and progression-free survival (PFS) and compared against <i>KRAS</i> nonG12C. Next, we analyzed several internal and external data sets to assess immune signatures, gene expression profiles, hypermethylation, co-occurring mutations, and proteomics. Among the 4,632 patients with comprehensive molecular profiling, 134 (2.9%) were found to have <i>KRAS</i> p.G12C mutations. An additional 53 patients with single gene sequencing were included in clinical data but excluded from prevalence analysis allowing for 187 total patients. Sixty-five patients had de novo metastatic disease and received a median of two lines of chemotherapy without surgical intervention. For the first three lines of chemotherapy, the median PFS was 6.4 months (n = 65; 95% CI, 5.0 to 7.4 months), 3.9 months (n = 47; 95% CI, 2.9 to 5.9 months), and 3.0 months (n = 21; 95% CI, 2.0 to 3.4 months), respectively. <i>KRAS</i> p.G12C demonstrated higher rates of basal EGFR activation compared with <i>KRAS</i> nonG12C. When compared with an internal cohort of <i>KRAS</i> nonG12C, <i>KRAS</i> p.G12C patients had worse OS. PFS is poor for patients with <i>KRAS</i> p.G12C metastatic colorectal cancer. OS was worse in <i>KRAS</i> p.G12C compared with <i>KRAS</i> nonG12C patients. Our data highlight the innate resistance to chemotherapy for <i>KRAS</i> p.G12C patients and serve as a historical comparator for future clinical trials.