2498 - Impact of KEAP1/NFE2L2 Mutations on Local Recurrence in Patients Receiving Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases

M. S. Chen¹, D. J. Carpenter², J. X. Leng¹, J. J. Qazi¹, Z. Wan³, D. Niedzwiecki³, L. R. Alder⁴, J. Clarke⁴, J. P. Kirkpatrick^1,5, S. R. Floyd¹, Z. J. Reitman¹, and T. C. Mullikin¹; ¹Department of Radiation Oncology, Duke University Medical Center, Durham, NC, ²Wellstar Paulding Hospital, Hiram, GA, ³Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, ⁴Department of Medical Oncology, Duke University Medical Center, Durham, NC, ⁵Department of Neurosurgery, Duke University Medical Center, Durham, NC

Purpose/Objective(s): The Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-like 2 (NFE2L2) pathway is important for cellular processing of reactive oxygen species that contribute to indirect cell killing from radiotherapy. KEAP1/NFE2L2 mutations have been shown to be promising molecular markers of clinical radioresistance in localized non-small cell lung cancer (NSCLC). However, it is unknown if these mutations similarly impact the response of brain metastases to radiation therapy. In this study, we tested whether KEAP1/NFE2L2 mutations associate with outcomes in patients with brain metastases from NSCLC undergoing stereotactic radiosurgery (SRS). The objective of this study is to determine the impact of KEAP1/NFE2L2 mutations on overall and intracranial progression free survival (OS, ICP), radionecrosis (RN), and intracranial local control (LC) in this population receiving SRS. We hypothesize that KEAP1/NFE2L2 mutations are associated with decreased local control. Materials/

Methods: Patients undergoing SRS for brain metastases secondary to NSCLC at a single institution were retrospectively identified. A subset of these patients also underwent molecular profiling with next generation sequencing (NGS). Kaplan-Meier survival analyses were calculated based on KEAP1/NFE2L2 mutation status using the log-rank test. Comparisons were performed for mutation versus no mutation, and also by mutational variant (pathogenic variant (PV); variant of unknown significance (VUS)).
Results: 541 patients with brain metastases from NSCLC who received SRS were included in the study. Of these, 269 underwent molecular profiling. KEAP1 variants were identified in 24.5% of patients. At 12 months, among patients with mutations, LC was 87.8% (95% CI, 74.2-96.1%), compared to 90.6% (84.4-94.4%) in patients without mutations. No significant difference was observed up to 24 months. The incidence of RN was similar between patients harboring KEAP1/NFE2L2 mutations and those without (9.3 + 4.5% and 6.7 + 2.1% at 12 months, respectively). There was no significant difference in median OS between patients with mutations (12.5 months; 95% CI, 9.5-21.7 months) compared to those without (14.9 months; 95% CI, 11.7-20.5 months). Similarly, there was no significant difference in median ICP between patients with mutations (5.1 months; 95% CI, 3.3-9.5 months) compared to those without (7.2 months; 95% CI, 5.7-9.5 months). Analyses by variant subtype also showed no significant differences.
Conclusion: While numeric differences were noted, KEAP1/NFE2L2 mutation status did not demonstrate a statistically significant difference in LC, RN, OC, and ICP after SRS for brain metastases from NSCLC in this cohort. Interestingly KEAP1/NFE2L2 PV and VUS diverged when analyzed separately for PFS, LC, and RN. Further analyses combining domain mapping of variants and co-mutated genes in larger patient cohorts may further clarify this observation and these data.