Abstract 1809P
Background
Activating mutations in KRAS are the most common driver mutations in metastatic non-small cell lung cancer (mNSCLC). KRAS-mutant NSCLCs are heterogeneous in their biology and the response of the various KRAS alleles to immune checkpoint inhibitors (ICI) remains unclear. We sought to investigate differential outcomes to ICI among KRAS subtypes.
Methods
Patients with KRAS mt mNSCLC receiving ICI at two institutions from 2013-2021 were included. Outcomes studied were overall response rate (ORR) and median progression-free survival (mPFS). Patients with KRAS G12C mutations were compared to non-G12C.
Results
We identified 123 patients, 42 (37%) KRAS G12C and 73 (63%) non-G12C. The G12C group were older (median 67 vs 65; p=0.05) and had a greater proportion of PD-L1 high (>50%) expression (63 vs 39%, p=0.02). There were no differences in other characteristics including smoking history: (86% vs 76%; p=0.2). Most patients received ICI monotherapy (81% vs 73%). ORR was significantly higher in G12C vs. non-G12C (49% vs 25%, p=0.031). In a multivariate logistic regression, G12C (OR 2.7, p=0.04), PD-L1≥50% (OR 4.6, p=0.002), TP53 (OR 3.0, p=0.02), but not smoking (p=0.4), were independent predictors of response. mPFS was longer in the G12C vs. non-G12C group (11.7m vs. 3.8m, p=0.1). In a multivariate analysis adjusting for smoking, TP53 and line of treatment, G12C (HR 0.6, p=0.05) and PD-L1≥50% (HR 0.5, p=0.01) remained predictive of PFS. Further subdivision by KRAS subtype and PD-L1 status (Table) revealed that patients in the G12C group with high PD-L1 expression had significant benefit from ICI over other subtypes: ORR 65%, mPFS 23.5m. Table: 1809P
mPFS by KRAS subtype and PD-L1 expression
| Group | ORR | mPFS (months, univariate HR, p-value) |
| G12C, PD-L1 high (n=24) | 65% | 23.5 (0.2, p<0.001) |
| G12C, PD-L1 low (n=14) | 21% | 4.7 (0.7, p=0.3) |
| Transversion mutation, PD-L1 high (n=23) (G12R, G12V, G12A) | 43% | 4.9 (0.4, p=0.02) |
| Transversion mutation, PD-L1 low (n=25) (G12D, G12S) | 16% | 4.0 (0.7, p=0.3) |
| Transition mutation (n=20) | 20% | 2.6 (ref) |
Conclusions
KRAS G12C mutated tumors had higher ORR and PFS than non-G12C mutations to ICI. Further research is required to understand the molecular mechanisms by which KRAS subtype modulates the immune microenvironment and response to ICI.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.