Front Immunol. 2026 Jul 10;17:1848431. doi: 10.3389/fimmu.2026.1848431. eCollection 2026.
ABSTRACT
BACKGROUND: Despite the proven efficacy of KRAS G12C inhibitors (KRAS G12Ci) in solid tumors, evidence from direct comparisons with standard of care is scarce, and no analysis has investigated the potential immunological basis for differential responses.
METHODS: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov for randomized controlled trials (RCTs) involving solid tumors patients who had received KRAS G12Ci were retrieved from inception to March 28, 2026. Individual participant data on progression-free survival (PFS) and overall survival (OS) were extracted from the published Kaplan-Meier survival curves. When available, subgroup data by programmed death ligand 1 (PD-L1) expression were extracted to explore immune-related correlates of treatment response.
RESULTS: A total of 4 articles with 3 RCTs and 949 participants were selected. In 1-stage reconstructed individual patient data meta-analyses, PFS was better in the KRAS G12Ci group (HR, 0.62; 95% CI, 0.53-0.74; P < 0.001). However, no statistical difference in OS was observed (HR, 0.93; 95% CI, 0.74-1.16; P = 0.495). The results were confirmed by 2-stage meta-analyses which additionally exhibited an objective response rate (ORR) of 3.60 (95% CI; 2.01-6.46; P < 0.001; I2 = 39.7%). Regarding PD-L1 expression, PFS benefits were observed in patients with expression levels <1% (HR, 0.56; 95% CI: 0.38-0.83; P = 0.004) and 1%-49% (HR, 0.58; 95% CI: 0.43-0.78; P < 0.001). KRAS G12Ci demonstrated a better safety profile, apart from diarrhea and rash.
CONCLUSIONS: A similar OS, but better PFS and ORR with a superior safety profile were observed in patients receiving KRAS G12Ci, suggesting that KRAS G12Ci may be more suitable for later-line therapy. Older patients, those without liver metastases, or those with PD-L1<50% may be the target population. These subgroup observations are hypothesis-generating and require prospective validation.
SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251146769.
PMID:42500683 | PMC:PMC13396023 | DOI:10.3389/fimmu.2026.1848431
