The following is a summary of “Real-World Outcomes Of Non-Small Cell Lung Cancer Patients Harbouring Kras G12c And Kras G12d Mutations,” published in the March 2025 issue of Lung Cancer by Shahnam et al.

KRAS G12D and G12C mutations exhibit distinct biological and clinical characteristics that influence treatment response in patients with metastatic non-small-cell lung cancer (NSCLC). Understanding these differences is essential for optimizing therapeutic strategies. This study aimed to evaluate real-world demographics, clinical profiles, and first-line treatment outcomes in patients with NSCLC harboring KRAS G12D or G12C mutations. A retrospective, multi-institutional observational study was conducted using data from the AURORA database, including patients aged 18 years or older diagnosed with metastatic NSCLC with either KRAS G12D or G12C mutations between January 1, 2010, and April 30, 2024. Descriptive statistical analyses were performed to compare baseline patient characteristics, while time-to-event outcomes were analyzed using Cox proportional hazards regression models. 

A total of 298 patients were included in the study, comprising 216 with KRAS G12C and 82 with KRAS G12D. Compared to KRAS G12C, the KRAS G12D cohort had a significantly higher proportion of never-smokers (15% vs. 1%, p < 0.01) and a greater percentage of patients with low PD-L1 expression (<1%) (36% vs. 21%, p = 0.06). Despite these clinical differences, no statistically significant difference was observed in OS ([HR] 1.09, 95% [CI] 0.80–1.48, p = 0.60) or real-world progression-free survival (HR 1.21, 95% CI 0.92–1.59, p = 0.18) between the two mutation subtypes. However, treatment responses varied significantly. In patients with KRAS G12C, monotherapy with immune checkpoint inhibitors (HR 0.61, 95% CI 0.39–0.97, p = 0.04) and chemo-immunotherapy combinations (HR 0.59, 95% CI 0.37–0.94, p = 0.03) significantly improved OS compared to chemotherapy alone. Conversely, in KRAS G12D patients, neither immunotherapy (HR 0.74, 95% CI 0.29–1.89, p = 0.53) nor chemo-immunotherapy (HR 0.73, 95% CI 0.34–1.57, p = 0.42) conferred a survival benefit over chemotherapy. 

These findings suggest that KRAS G12D and G12C mutations represent distinct molecular subgroups with differential therapeutic responsiveness, particularly regarding immunotherapy efficacy. Given the poor response to immunotherapy in patients with KRAS G12D, alternative treatment strategies should be explored. Prospective studies are warranted to validate these observations and further elucidate the molecular mechanisms underlying these differential treatment responses, ultimately guiding precision medicine approaches for patients with NSCLC with KRAS mutations.

Source: lungcancerjournal.info/article/S0169-5002(25)00042-X/abstract