Clinical Value and Optimal Timing of Cranial Local Therapy among EGFR-Mutant Non-small-cell Lung Cancer with Brain Metastases in the Era of Osimertinib

Abstract

Despite the potent central nervous system (CNS) efficacy of osimertinib confirmed in a number of preclinical and clinical studies, little is known about the clinical value and optimal timing of cranial local therapies (LTs) among EGFR-mutant NSCLC patients with brain metastases (BMs) treated with osimertinib. We retrospectively screened the cases with EGFR-mutant advanced NSCLC and baseline BM at two academic medical centers from May 2015 to November 2019. Patients who received osimertinib for treatment-naïve advanced disease or acquired T790M mutation were included. The patients were divided into two groups based on whether cranial LTs, which included whole brain radiotherapy (WBRT), stereotactic radiotherapy (SRT) or surgical resection were administered before progression to osimertinib. A total of 186 patients were included, among whom osimertinib were used in 65 (34.9%) patients as first-line therapy and 121 (65.1%) for acquired T790M mutation. Forty-nine patients received additional cranial LT, with WBRT administered in 33 (67.3%), SRT in 12 (24.5%) and surgical resection in 4 (8.2%). Compared with osimertinib alone, the overall survival (OS) was not prolonged when additional cranial LTs were administered, either in first-line osimertinib users (24.9 months vs not reached; HR 1.30; p = 0.583) or pretreated patients (28.4 vs 21.1 months; HR 0.64; p = 0.145). In subgroup analyses, cranial LT was found to significantly improve OS for patients with ds-GPA scoring 2 to 4 (40.1 vs 22.2 months; HR 0.36; p = 0.014), and those with ≤3 BM lesions (40.1 vs 22.2 months; HR 0.19; p = 0.004). Pattern of cranial failure analyses indicated that 59.7% patients had oligo-residual BMs (no more than 3 BMs and the maximum of which not exceed 3cm) when the maximum response to osimertinib was achieved. Initial intracranial failure was predominantly (73.7%) limited to the site of residual lesions at maximal response. Patients without LTs were more likely to develop multiple-progressive BMs, even in the baseline oligo-metastatic state (less than three BMs), with the rate of 31.2% compared to 0.0% in LT group. Cranial LTs improve OS among subgroups of patients with osimertinib treated EGFR-mutant NSCLC and baseline BM, including those with ds-GPA scoring 2 to 4 and fewer BMs (≤3). Consolidation cranial LTs at the maximal response to osimertinib may be preferred, which need to be further validated.