KRAS G12C inhibitors in KRASG12C-mutated solid tumors: an immunologically informed systematic review and reconstructed individual patient data meta-analysis
In brief
KRAS G12C inhibitors lengthen progression-free survival by about 40%
In a meta-analysis of 949 patients from three trials, KRAS G12C inhibitors reduced the risk of disease progression by roughly 38%, while overall survival was unchanged. Objective response rates more than tripled and side effects were milder except for diarrhea and rash. The benefit appeared strongest in older patients, those without liver metastases, or with low PD-L1 expression, but these subgroup signals need prospective confirmation.
- Journal
- Frontiers in immunology (Q1)
- Published
- 10 July 2026
- Study design
- Systematic review / meta-analysis of RCTs
- Evidence level
- Level 1, High (CEBM 1a)
- Authors
- Yici Yan, Leyi Zheng, Hongfei Wang, Leitao Sun, Xing Xu
- PMID
- 42500683
- DOI
- 10.3389/fimmu.2026.1848431
Why clinicians should know about it
- Picked for Public Health, Environmental and Occupational Health (paper of the day, 26 July 2026).
- Picked for Oncology and Radiation Oncology (top studies of the week, 26 July 2026): KRAS G12C inhibitors meta‑analysis in solid tumours
- Picked for Immunology and Allergy (top studies of the week, 26 July 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.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.