DURHAM, NC — KRAS mutations have historically carried a poor prognosis in NSCLC, and the most common variant, G12C, had similar suboptimal survival compared to non-G12C variants.
That has changed, however, with the approval of new KRAS G12C inhibitors, according to a study presented at the recent American Society of Clinical Oncology meeting in Chicago.1
A national VHA study evaluated the outcomes of KRAS-mutated advanced NSCLC by KRAS subtype in the era of KRAS G12C inhibitors. To do that, researchers from the Durham, NC, VA Health Care System and Duke University identified patients with unresectable or metastatic NSCLC and a KRAS mutation detected between 2021-2022.
Meeting search criteria were 841 patients across 107 VA medical centers; their median age was 73, and 95% were male. Most, 70%, were non-Hispanic white, with 21% non-Hispanic Black and 2.5% Hispanic. About 4% were never smokers.
Results indicate that 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),” the researchers point out.
They add that, 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,” according to the authors. “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<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<0.0001) and STK11 (HR 1.57, CI 1.31-1.88, p<0.0001) had worse OS.”
Survival was not affected, however, by social deprivation index (SDI, calculated by zip code), race/ethnicity, rural residence, and other co-mutations, according to the report.
On the other hand, age (HR 1.02, CI 1.003-1.03), KRAS G12C (HR 0.74, CI 0.58-0.93), tumor mutational burden (TMB) (HR 0.97, CI 0.95-0.98), and STK11 mutations (HR 1.62, CI 1.23-2.12) retained their association, while Kelch-like ECH-associated protein 1 (KEAP1) and programmed death-ligand 1 (PD-L1) were found to be no longer significant.
“Use of sotorasib had a borderline association with improved survival in univariable analysis (HR 0.74, CI 0.52-1.02),” according to the study. “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).”
The researchers conclude that, 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.”
In 2021, the Food and Drug Administration (FDA) granted accelerated approval to sotorasib, the first KRAS-blocking drug, which is marketed as Lumakras by Amgen.
- Anderson, CE, Scobie MR, Zhou KI, Maddox M, Kelley MJ, Lin C. ” Characteristics and clinical outcomes of US veterans with advanced non–small cell lung cancer (NSCLC) by KRAS subtype: A National Veterans Health Administration analysis. “Presented at 2024 American Society of Clinical Oncology Annual Meeting. Chicago, IL, May 31-June 4, 2024. https://meetings.asco.org/abstracts-presentations/232161
