The Impact of Co-Alterations on Outcomes after Local Therapy for Patients with KRAS-Mutant Lung Adenocarcinoma Brain Metastases

Abstract

Brain metastases are common in NSCLC with up to 25% of patients having brain metastases (BMs) at the time of diagnosis and 30% developing BMs during their disease course. KRAS is an oncogenic driver in approximately 25% of lung adenocarcinomas. Genomic alterations co-occurring with KRAS are associated with distinct biological landscapes which may influence prognosis. Herein, we sought to identify correlations between genomic profiles, intracranial progression free survival (iPFS), and overall survival (OS). We retrospectively reviewed 156 patients with KRAS-mutant lung adenocarcinoma BM who underwent SRS for their BMs at MSKCC from 2010-2022. Each patient had at least one tumor sample profiled with MSK-IMPACT, a custom FDA-cleared next-generation sequencing. Mutations, copy number alterations, and fusions were filtered for driver alterations using OncoKB. Survival outcomes were calculated from date of MRI indicating metastatic brain disease. Of the 156 patients, 80 patients presented with BMs at diagnosis whereas 76 developed BMs during their disease course, with a median 2 lines of therapy prior to BM diagnosis. The most common KRAS mutation was G12C (n = 64; 41%), G12V (n = 26, 17%), G12D (n = 17; 11%), and G12A (n = 11; 7%). The most frequently co-altered genes were TP53 (n = 71, 46%), STK11 (n = 51, 33%), CDKN2A (n = 27, 17%), KEAP1 (n = 17, 11%), and SMARCA4 (n = 10, 6%). The presence of a KEAP1 co-occurring alteration was associated with inferior iPFS (HR 1.95, 95% CI 1.05 - 3.59, p = 0.035) and the presence of SMARCA4 was also associated with inferior iPFS (HR 2.28, 95% CI 1.05 - 4.95, p = 0.038). The presence of an STK11 mutation was associated with worse OS (HR 1.57, 95% 1.01 - 2.43, p = 0.045). In a multi-variate clinico-genomic model, KEAP1 and STK11 co-occurring alterations remained significantly associated with iPFS. Patients with KEAP1-altered tumors had an increased incidence of intracranial regional progression. The 24-month cumulative incidence of regional progression amongst KEAP1-altered tumors was 57% (95% CI, 29%-77%) compared with 37% (95% CI, 29%-46%) among KEAP1-wildtype tumors (P = 0.041). Patients with CDKN2A-altered tumors had an increased incidence of leptomeningeal disease (LMD) as a form of intracranial progression. The 24-month cumulative incidence of LMD amongst CDKN2A-altered tumors was 11% (95% CI, 2.7%-27%) compared with 4.1% (95% CI, 1.5%-8.8%) among CDKN2A-wildtype tumors (P = 0.023). In our cohort of molecularly profiled KRAS-mutant lung adenocarcinoma BM patients treated with SRS, we found that co-occurring KEAP1 and STK11 were significantly associated with worse iPFS. We also observed that CDKN2A co-altered tumors had an increased incidence of LMD. These findings have implications for future efforts to personalize brain metastasis management based on comprehensive genomic profiling.