Large-Scale Clinico-Genomic Profile of Non-Small Cell Lung Cancer with KRAS G12C: Results from LC-SCRUM-Asia Study

Abstract

Introduction: KRAS G12C is an oncogenic driver mutation, accounting for approximately 14% of Caucasian patients with non-small cell lung cancer (NSCLC). Recently, several KRAS G12C-targeted drugs have been developed; however, the clinico-genomic characteristics of NSCLC patients with KRAS G12C remain unclear. 

Materials and Methods: Based on the large-scale prospective lung cancer genomic screening project (LC-SCRUM-Asia) database, the clinico-genomic characteristics and therapeutic outcomes of NSCLC patients with KRAS G12C were evaluated. 

Results: From March 2015 to March 2021, 10023 NSCLC patients were enrolled in LC-SCRUM-Asia. KRAS mutations were detected in 1258 patients (14%), including G12C in 376 (4.0%), G12D in 289 (3.1%) and G12V in 251 (2.7%). The proportions of males and smokers were higher in patients with KRAS G12C than in those with KRAS non-G12C mutations (males: 73% vs. 63%, p<0.001; smokers: 89% vs. 76%, p<0.001). KRAS G12C-positive tumors showed a higher tumor mutation burden (TMB) (mean, 8.1 mut/Mb, p<0.001) and a higher percentage of tumors with programmed cell death ligand-1 (PD-L1) expression ≥50% (52%, p=0.08). Among KRAS-mutated patients who received immune checkpoint inhibitors (ICIs), the progression-free survival in G12C-positive patients (median, 3.4 months) was similar to that in G12V-positive patients (4.2 months, p=0.90), but significantly longer than that in G12D- (2.0 months, p=0.02) and other KRAS mutation-positive patients (2.5 months, p=0.02). 

Conclusions: The frequencies of KRAS G12C were lower in Asian than in Caucasian NSCLC patients. Among the KRAS-mutated NSCLC patients, G12C-positive tumors showed increased immunogenicity, such as high TMB and high PD-L1 expression, and potential sensitivity to ICIs.

Note:

Funding Information: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of Interests: Shingo Matsumoto received research grants from Merck Biopharma, MSD and Janssen Pharmaceutical, and personal fees (honoraria) from AstraZeneca, Bristol-Myers Squibb, Merck Biopharma, Takeda, Chugai Pharma, Novartis and Lilly. For all conflicts of interest concerning other authors, refer to the the PDF.

Ethics Approval Statement: This study analyzed the genomic data of a large-scale prospective lung cancer genomic screening project (LC-SCRUM-Asia). The protocol for this study was approved by the institutional review board of each of the participant institutions.

Keywords: Non-small cell lung cancer, KRAS mutation, KRAS G12C, Next-generation sequencing, Tumor burden, PD-L1 expression