Intracranial disease control and survival among patients with KRAS-mutant lung adenocarcinoma and brain metastases treated with SRS.

Abstract

Background: Precision medicine according to molecularly defined subgroups offers great potential to improve outcomes for patients with metastatic lung adenocarcinoma. This study describes clinical outcomes and the impact of co-occurring genetic alterations on outcomes following SRS among patients with KRAS-mutant lung adenocarcinoma.

Methods: 195 patients with KRAS-mutant lung adenocarcinoma were treated with SRS for BM between 2014 and 2018 with follow-up until 2022 or death. Co-primary outcomes were median overall survival (OS) and intracranial progression-free (iPFS) survival; univariable and multivariable Cox regression models and Kaplan-Meier survival analysis was utilized.

Results: Median follow-up from date of BM diagnosis was 11 months. Median OS and iPFS for the cohort was 27.7 months (95% CI 19.7 - 36.8) and 22.1 months (95% CI 16.8-48.9), respectively. Lesion-level local control (LC) at 12 and 24 months was 89.9% and 87.5%, respectively. In a multivariable cox-regression model, inferior OS was associated with co-alterations in KEAP1 and STK11 (HR 1.94, 95% CI 1.04 - 3.62, q =0.087), progressive (HR 3.41, CI 1.38 - 8.39, q = 0.087) and mixed response (HR 3.52, CI 1.2 - 10.3, q =0.092) extracranial disease, and 6 or more BMs at time of diagnosis (HR 2.58, CI 1.22 - 6.63, q =0.087). Positive PD-L1 status was associated with improved OS (HR 0.57, 95% CI 0.37 - 0.87 p = 0.01). Inferior iPFS was associated with chemotherapy prior to SRS (HR 2.69, 95% CI 1.42 - 5.09, q = 0.04) and age greater than 65 (HR 2.21, 95% CI 1.25 - 3.93, q = 0.055). KRAS G12C was not associated with differences in iPFS, OS, or type of intracranial progression event following SRS.

Conclusions: Co-alteration of KRAS and KEAP1/STK11 was associated with inferior OS, but not iPFS. Similar outcomes were found in patients harboring KRAS G12C and non-G12C mutant NSCLC BM. Further understanding of molecularly characterized subgroups will be critical in driving personalized radiotherapy for patients with lung cancer brain metastases.