Exposing KRAS G12C: Not Your Usual Suspect in NSCLC
KRAS G12C–mutant NSCLC Is Unique
KRAS G12C Is a Prevalent Oncogenic Driver Mutation in NSCLC, the Most Common Form of Lung Cancer1,2,4
Infographic illustrating the epidemiological landscape of KRAS G12C–mutant NSCLC. NSCLC comprises approximately 85% of all lung cancer diagnoses. Among patients with lung adenocarcinoma—a major NSCLC subtype—approximately 25% harbor KRAS mutations. Within this group, the KRAS G12C variant emerges as the most common mutation.
Patients with KRAS G12C–mutant NSCLC are a heterogenous patient population who typically exhibit a unique profile, with distinct clinical features and tumor characteristics.4,5,7,8,11,14
Graphic representation of the unique features that are associated with KRAS G12C tumors, including smoking history, higher PD-L1 levels, an elevated TMB, co-mutations, and sensitivity to immunotherapy.
The KRAS G12C mutation is associated with:
Unlike other oncogenic driver alterations, targeted therapy is not the standard in the first line (1L) setting:
In KRAS G12C–mutant NSCLC, IO with or without chemotherapy remains the standard of care, with exceptions such as where patients are ineligible for IO/chemotherapy. 1L systemic therapy is often guided by PD-L1 expression.10
KRAS G12C–mutant NSCLC Is Associated With Poor Prognosis
Poor survival outcomes compared to patients with other oncogenic drivers treated with approved targeted therapies4
Comparable median overall survival (OS) compared to patients with KRAS wild-type tumors when receiving chemotherapy with or without IO with 1L or second-line (2L) treatment17
Most patients had advanced disease at diagnosis
About 25% of patients had documented brain metastasis at the start of 1L treatment.
Those treated with 1L chemotherapy + IO treatment had modest median progression-free survival (PFS) of 5 months and OS of 13-16 months
Those with PD-L1 ≥50% treated with 1L IO had a median PFS of 5 months and median OS of 20-22 months
What does having KRAS G12C–mutant NSCLC mean for your patients?
Patients with KRAS G12C–mutant NSCLC are different from patients with NSCLC with other oncogenic drivers.
KRAS G12C mutation is associated with:
- Current and/or former smoking history
- Higher PD-L1 levels
- Elevated TMB
- Co-mutations
- General sensitivity to IO
Owing to these unique clinical and tumor characteristics, patients with KRAS G12C–mutant NSCLC may not respond to treatment the same as patients with other oncogenic drivers.
Knowing that patients with KRAS G12C–mutant NSCLC need to be approached differently from your patients with other oncogenic drivers, how might this impact the treatment decisions you make?
Explore what underlies the unique characteristics associated with KRAS G12C–mutant NSCLC by continuing to the next section.
1L = first line; 2L = second line; ALK = anaplastic lymphoma kinase; BRAF = B-rapidly accelerated fibrosarcoma; EGFR = epidermal growth factor receptor; HER2 = human epidermal growth factor receptor 2; IO = immunotherapy; KEAP1 = Kelch-like ECH-associated protein 1; KRAS = Kirsten rat sarcoma; LRP1B = low-density lipoprotein receptor-related protein 1B; MET = mesenchymal-epithelial transition; NRG1 = neuregulin 1; NSCLC = non-small cell lung cancer; NTRK = neurotrophic tyrosine receptor kinase; OS = overall survival; PD-L1 = programmed death-ligand 1; PFS = progression-free survival; RET = rearranged during transfection; ROS1 = ROS proto-oncogene 1; SMARCA4 = SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4; STK11 = serine/threonine kinase 11; TMB = tumor mutational burden; TME = tumor microenvironment; TP53 = tumor protein p53.
References
- Chevallier M, et al. Oncogenic driver mutations in non-small cell lung cancer: past, present and future. World J Clin Oncol. 2021;12(4):217-237.
- ACS. What is lung cancer? Last revised January 29, 2024. Accessed August 17, 2025. https://www.cancer.org/cancer/types/lung-cancer/about/what-is.html
- Acker F, et al. KRAS mutations in squamous cell carcinomas of the lung. Front Oncol. 2021;11:788084.
- Lee JK, et al. Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors. NPJ Precis Oncol. 2022;6(1):91.
- Salem ME, et al. Landscape of KRAS G12C, associated genomic alterations, and interrelation with immuno-oncology biomarkers in KRAS-mutated cancers. JCO Precis Oncol. 2022;6:e2100245.
- Wang X, et al. Association between smoking history and tumor mutation burden in advanced non-small cell lung cancer. Cancer Res. 2021;81(9):2566-2573.
- Xu M, et al. Unveiling the role of KRAS in tumor immune microenvironment. Biomed & Pharmacother. 2024;171:116058.
- Alsaed B, et al. Shaping the battlefield: EGFR and KRAS tumor mutations' role on the immune microenvironment and immunotherapy responses in lung cancer. Cancer Metastasis Rev. 2025;44(3):56.
- He Q, et al. First-line treatments for KRAS-mutant non-small cell lung cancer: current state and future perspectives. Cancer Biol Ther. 2025;26(1):2441499.
- Cheema PK, et al. Canadian Consensus Recommendations on the Management of KRAS G12C-Mutated NSCLC. Curr Oncol. 2023;30(7):6473-6496.
- Wu L, et al. Pan-cancer analysis to character the clinicopathological and genomic features of KRAS-mutated patients in China. J Cancer Res Clin Oncol. 2025;151(2):94.
- Judd J, et al. Characterization of KRAS mutation subtypes in non-small cell lung cancer. Mol Cancer Ther. 2021;20(12):2577-2584.
- Negrao MV, et al. Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer. J Immunother Cancer. 2021;9(8):e002891.
- Ghazali N, et al. Immunotherapy in advanced, KRAS G12C-mutant non-small-cell lung cancer: current strategies and future directions. Ther Adv Med Oncol. 2025;17:17588359251323985.
- Hendriks LE, et al. Non-oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(4):358-376.
- Sheffield K, et al. Real-world outcomes with IO and chemo-IO demonstrate unmet need for 1L KRAS G12C-mutant advanced NSCLC in the US. Presented at: IASCL 2025 World Conference on Lung Cancer (WCLC); September 6-9, 2025; Barcelona, Spain. Poster 1615.
- Julian C, et al. Overall survival in patients with advanced non-small cell lung cancer with KRAS G12C mutation with or without STK11 and/or KEAP1 mutations in a real-world setting. BMC Cancer. 2023;23(1):352.
- Dudnik E, et al. BRAF Mutant Lung Cancer: Programmed Death Ligand 1 Expression, Tumor Mutational Burden, Microsatellite Instability Status, and Response to Immune Check-Point Inhibitors. J Thorac Oncol. 2018;13(8):1128-1137.
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