Promising single-agent activity from sotorasib and adagrasib in KRAS^G12C-mutant tumors has provided clinical evidence of effective KRAS signaling inhibition. However, comprehensive analysis of KRAS-variant prevalence, genomic alterations, and the relationship between KRAS and immuno-oncology biomarkers is lacking.

Retrospective analysis of deidentified records from 79,004 patients with various cancers who underwent next-generation sequencing was performed. Fisher’s exact test evaluated the association between cancer subtypes and KRAS variants. Logistic regression assessed KRAS^G12C comutations with other oncogenes and the association between KRAS variants and immuno-oncology biomarkers.

Of the 79,004 samples assessed, 13,758 (17.4%) harbored KRAS mutations, with 1,632 (11.9%) harboring KRAS^G12C and 12,126 (88.1%) harboring other KRAS variants (KRAS^non-G12C). Compared with KRAS^non-G12C across all tumor subtypes, KRAS^G12C was more prevalent in females (56% v 51%, false discovery rate-adjusted P value [FDR-P] = .0006), current or prior smokers (85% v 56%, FDR-P < .0001), and patients age > 60 years (73% v 63%, FDR-P ≤ .0001). The most frequent KRAS variants across all subtypes were G12D (29.5%), G12V (23.0%), G12C (11.9%), G13D (6.5%), and G12R (6.2%). KRAS^G12C was most prevalent in patients with non–small-cell lung cancer (9%), appendiceal (3.9%), colorectal (3.2%), tumor of unknown origin (1.6%), small bowel (1.43%), and pancreatic (1.3%) cancers. Compared with KRAS^non-G12C-mutated, KRAS^G12C-mutated tumors were significantly associated with tumor mutational burden-high status (17.9% v 8.4%, odds ratio [OR] = 2.38; FDR-P < .0001). KRAS^G12C-mutated tumors exhibited a distinct comutation profile from KRAS^non-G12C-mutated tumors, including higher comutations of STK11 (20.59% v 5.95%, OR = 4.10; FDR-P < .01) and KEAP1 (15.38% v 4.61%, OR = 3.76; FDR-P < .01).

This study presents the first large-scale, pan-cancer genomic characterization of KRAS^G12C. The KRAS^G12C mutation was more prevalent in females and older patients and appeared to be associated with smoking status. KRAS^G12C tumors exhibited a distinct comutation profile and were associated with tumor mutational burden-high status.