Intracranial Disease Control and Survival among Patients with KRAS-mutant Lung Adenocarcinoma and Brain Metastases Treated with Stereotactic Radiosurgery

Abstract

Purpose

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 stereotactic radiosurgery (SRS) among patients with Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant lung adenocarcinoma.

Methods and Materials

A total of 195 patients with KRAS-mutant lung adenocarcinoma were treated with SRS for brain metastases (BMs) between 2014 and 2018 with follow-up until 2022 or death. Coprimary outcomes were median overall survival (OS) and intracranial progression-free survival (iPFS); univariable and multivariable Cox regression models and Kaplan-Meier survival analysis were used.

Results

Median follow-up from the date of BM diagnosis was 11 months. Median OS and iPFS for the cohort were 27.7 months (95% CI, 19.7-36.8) and 22.1 months (95% CI, 16.8-48.9), respectively. Lesion-level local control at 12 and 24 months was 89.9% and 87.5%, respectively. In a multivariable Cox regression model, inferior OS was associated with coalterations in KEAP1 and STK11 (hazard ratio [HR], 1.94; 95% CI, 1.04-3.62; q = 0.087), progressive (HR, 3.41; 95% CI, 1.38-8.39; q = 0.087), and mixed response (HR, 3.52; 95% CI, 1.2-10.3; q = 0.092) extracranial disease, and 6 or more BMs at time of diagnosis (HR, 2.58; 95% CI, 1.22-6.63; q = 0.087). Positive programmed death ligand 1 status was associated with improved OS (HR, 0.57; 95% CI, 0.37-0.87; P = .01). Inferior iPFS was associated with chemotherapy before SRS (HR, 2.69; 95% CI, 1.42-5.09; q = 0.04) and age >65 years (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

Coalteration 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 non-small cell lung cancer BMs. Further understanding of molecularly characterized subgroups will be critical in driving personalized radiation therapy for patients with lung cancer BMs.