Characteristics and clinical outcomes of US veterans with advanced non–small cell lung cancer (NSCLC) by KRAS subtype: A National Veterans Health Administration analysis.
Authors: Clare E. Anderson, Micaela R Scobie, Katherine I. Zhou, Mark Maddox, Michael J. Kelley, Chenyu Lin
Journal: Journal of Clinical Oncology (2024)

8581 Background: KRAS mutations have historically carried a poor prognosis in NSCLC. The most common variant, G12C, had similar survival compared to non-G12C variants. However, new KRAS G12C inhibitors have since been approved. This national VHA study evaluates the outcomes of KRAS-mutated advanced NSCLC by KRAS subtype in the era of KRAS G12C inhibitors. Methods: Patients with unresectable or metastatic NSCLC and a KRAS mutation detected between 2021-2022 were identified from the VA National Precision Oncology Program database. Analysis utilized Fisher’s exact test, logistic regression, and Cox regression. Results: 841 patients across 107 VA medical centers met search criteria. The median age was 73, and 95% were male. 21% were non-Hispanic black, 70% non-Hispanic white, and 2.5% Hispanic. 4% were never smokers. The most common KRAS mutations were G12C (35%), G12V (18%), G12D (13%), G12A (6%), Q61H (4%), and G13D (4%). The most common co-mutations to KRAS were TP53 (54%), STK11 (28%), KEAP1 (16%), and BRAF (3%). KEAP1 mutations more frequently co-occurred with KRAS Q61H (p=0.048), while BRAF mutations were more commonly seen with KRAS G13D (p=0.02) and G13C (p=0.01). In univariable analysis of overall survival (OS), KRAS G12C had a favorable OS compared to all non-G12C variants (HR 0.77, 95% CI 0.64-0.93, p=0.006). Specifically, KRAS G12D (HR 1.35, CI 1.03-1.76, p=0.03) and G12V (HR 1.42, CI 1.10-1.81, p=0.006) had significantly worse OS compared to G12C. Higher PDL1 TPS (HR 0.997, CI 0.995-0.999, p=0.02) and higher TMB (HR 0.96, CI 0.95-0.98, p&lt;0.0001) had better OS, while older age (HR 1.02, CI 1.01-1.03, p=0.004) and co-mutations in KEAP1 (HR 1.60, CI 1.28-1.97, p&lt;0.0001) and STK11 (HR 1.57, CI 1.31-1.88, p&lt;0.0001) had worse OS. Social deprivation index (SDI, calculated by zip code), race/ethnicity, rural residence, and other co-mutations did not affect survival. In multivariable Cox regression, age (HR 1.02, CI 1.003-1.03), KRAS G12C (HR 0.74, CI 0.58-0.93), TMB (HR 0.97, CI 0.95-0.98), and STK11 (HR 1.62, CI 1.23-2.12) retained their association, while KEAP1 and PDL1 were no longer significant. Use of sotorasib had a borderline association with improved survival in univariable analysis (HR 0.74, CI 0.52-1.02). After adjusting for sotorasib in the multivariable model, the association of G12C with OS was no longer significant. In KRAS G12C NSCLC receiving at least 2 lines of therapy (n=90), the likelihood of receiving sotorasib did not differ by age, SDI, gender, race/ethnicity, or rural vs. urban residence. Only a history of economic instability (by ICD10 code) was associated with a lower likelihood of getting sotorasib (OR 0.22, 95% CI 0.03-0.91). Conclusions: In this cohort, KRAS G12C appears to confer a favorable prognosis compared to non-G12C variants, which may be explained in part by the adoption of sotorasib.