KRAS G12C Mutation Predicts Improved Survival in NSCLC Patients Receiving Immunotherapy: Insights from a Real-World Cohort

Background: KRAS mutations are among the most common oncogenic drivers in non-small cell lung cancer (NSCLC), with KRAS G12C emerging as a therapeutically targetable subtype. However, the prognostic relevance of KRAS G12C compared with non-G12C mutations in patients receiving immune checkpoint inhibitors (ICIs) remains unclear. Methods: We retrospectively analyzed 80 NSCLC patients treated with ICIs between January 2020 and July 2024; data were censored on 3 July 2025. The cohort included 32 KRAS-mutant (20 G12C, 12 non-G12C) and 48 KRAS wild-type patients. Clinicopathological features, treatment details, and survival outcomes were collected. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method, with group comparisons made using the log-rank test. Univariate and multivariate Cox regression analyses were conducted to identify independent prognostic factors. Results: Among 80 NSCLC patients treated with ICIs, the median OS and PFS were 14.3 and 8.2 months, respectively. Survival outcomes were comparable between KRAS-mutant and wild-type patients. Within the KRAS-mutant subgroup (n = 32), baseline characteristics were generally balanced between G12C (n = 20) and non-G12C (n = 12) cases, with non-significant trends toward higher metastatic burden and PD-L1 ≥ 50% in the G12C group. Median OS was significantly longer in G12C patients than in non-G12C patients (20.7 vs. 6.4 months; p = 0.021), whereas PFS did not differ significantly (10.2 vs. 3.7 months; p = 0.181). In multivariate analysis, non-G12C mutation independently predicted increased mortality risk (HR 3.35, 95% CI 1.26–8.89; p = 0.015). For PFS, recurrent disease status was associated with improved outcomes in univariate analysis (HR 0.30, 95% CI 0.09–0.94; p = 0.040), but no independent predictors were identified in multivariate modeling. Conclusions: In NSCLC patients treated with ICIs, the KRAS G12C mutation was associated with significantly improved OS compared with other KRAS subtypes, independent of clinicopathological characteristics. These findings suggest distinct biological behavior of KRAS variants in immunotherapy response and warrant further prospective validation.