Real-World outcomes of Non-Small cell lung cancer patients harbouring KRAS G12C and KRAS G12D mutations

Background: KRAS G12D and G12C mutations have distinct biological traits influencing treatment response. This study examines real-world demographics, clinical characteristics, and first-line treatment outcomes in metastatic non-small-cell lung cancer (NSCLC) patients with these mutations. Methods: This retrospective, multi-institution observational study used data from the AURORA database. Patients aged 18 years or older, diagnosed with metastatic KRAS G12D or G12C NSCLC between January 1, 2010, and April 30, 2024, were included. Descriptive statistics compared patient characteristics, and time-to-event outcomes were assessed using Cox proportional hazards regression. Results: A total of 298 (216 KRAS G12C and 82 KRAS G12D) patients were included. The KRAS G12D group had a higher proportion of never smokers (15 % vs. 1 %, p < 0.01) and PD-L1 < 1 % (36 % vs. 21 %, p = 0.06). No significant differences were observed in overall survival (OS) (HR 1.09, 95 % CI 0.80–1.48, p = 0.60) or real-world progression-free survival (rwPFS) (HR 1.21, 95 % CI 0.92–1.59, p = 0.18) between mutation groups. In KRAS G12C, monotherapy immunotherapy (HR 0.61, 95 % CI 0.39–0.97, p = 0.04) and chemo-immunotherapy (HR 0.59, 95 % CI 0.37–0.94, p = 0.03) improved OS compared to chemotherapy. For KRAS G12D, 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) improved OS compared to chemotherapy alone. Conclusion: KRAS G12C and G12D mutations demonstrate distinct clinical characteristics and treatment responses, with poorer immunotherapy outcomes in KRAS G12D patients. Prospective studies are needed to validate these findings.