Background Immunotherapy combined with chemotherapy is the standard first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) with KRAS mutations. However, the efficacy of this treatment in patients with different KRAS mutation subtypes remains unclear.

Methods This study retrospectively collected data from patients diagnosed with KRAS mutations through pathological examination and next-generation sequencing (NGS) testing between June 1, 2017 and November 1, 2024 at Zhejiang Cancer Hospital and Nanjing University Affiliated Jinling Hospital of Medical School. The analysis focused on NSCLC patients who received first-line immune combination chemotherapy. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Objective response rate (ORR) and disease control rate (DCR) were used to assess treatment efficacy.

Results Among the 129 KRAS-mutant NSCLC patients who received first-line immunotherapy combined with chemotherapy, 26 had the KRAS G12D mutation and 103 had non-G12D KRAS mutations. The median PFS for all patients was 8.1 months 95% confidence interval (CI) 5.5~10.7, and the median OS was 19.4 months (95% CI 8.8~30.0). The ORR and DCR for the entire cohort were 35.7% and 84.5%, respectively. Patients with KRAS G12D mutations had significantly shorter PFS compared to those with non-G12D mutations (5.6 mos vs. 10.0 mos, P = 0.044). The OS of patients with KRAS G12D mutations was also shorter than that of non-G12D patients (15.6 mos vs. 31.7 mos, P = 0.029). Among patients with non-G12D KRAS mutations, no survival differences were observed across different mutation subtypes.

Conclusion KRAS G12D mutation in NSCLC is associated with poorer efficacy and worse prognosis in patients treated with first-line immunotherapy combined with chemotherapy compared to other KRAS mutations.