High-Dose Aumolertinib for Untreated EGFR-Variant Non–Small Cell Lung Cancer With Brain Metastases

Importance Central nervous system (CNS) metastases remain a significant challenge in the management of EGFR -variant non–small cell lung cancer (NSCLC). Objective To evaluate the activity and safety of high-dose aumolertinib in patients with untreated EGFR -variant NSCLC and brain metastases. Design, Setting, and Participants This was a phase 2 nonrandomized clinical trial conducted at 10 centers in China. Patients with untreated EGFR -variant metastatic NSCLC and brain metastases were enrolled between July 6, 2021, and August 31, 2022. The data cutoff date was October 10, 2024. Interventions Patients received aumolertinib, 165 mg, orally once daily until disease progression or unacceptable toxic effects. Main Outcomes and Measures The primary end point was 12-month progression-free survival (PFS) rate assessed by investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1. Results A total of 63 patients (39 female [61.9%]; median age, 60 [range, 47-76] years) were enrolled (full analysis set), and 49 had at least 1 measurable brain lesion (CNS evaluable-for-response set). Median follow-up duration was 28.8 months (95% CI, 27.0-29.8). In the full analysis set, the 12-month PFS rate was 62.1% (95% CI, 48.7-73.0), the median PFS was 20.5 months (95% CI, 12.0-26.9), the 12-month intracranial PFS rate was 76.8% (95% CI, 63.2-85.9), and the median intracranial PFS and overall survival were not reached. Systemic and intracranial objective response rates per RECIST 1.1 were 56 of 63 (88.9% [95% CI, 78.4-95.4]) and 52 of 63 (82.5% [95% CI, 70.9-90.9]) in the full analysis set and 43 of 49 (87.8% [95% CI, 75.2-95.4]) and 42 of 49 (85.7% [95% CI, 72.8-94.1]) in the CNS evaluable-for-response set, respectively. The most common grade 3 or 4 treatment-related adverse event was increased blood creatine phosphokinase (17 participants [27.0%]). No treatment-related deaths occurred. EGFR variant clearance in plasma circulating tumor DNA at day 1 of cycle 2 was independently associated with longer PFS (hazard ratio, 0.14 [95% CI, 0.04-0.47]; P = .001). Conclusions and Relevance The findings of this nonrandomized clinical trial suggest that high-dose aumolertinib is associated with long-term survival benefit in patients with untreated EGFR -variant NSCLC and brain metastases, with a manageable safety profile. Trial Registration ClinicalTrials.gov Identifier: NCT04808752