Non-small cell lung cancer (NSCLC) harboring EGFR mutations and brain metastases (BM) is historically associated with poor outcomes and a limited treatment landscape. Additionally, current subgroup data focused on osimertinib for managing BM is lacking.
Researchers, led by Yuankai Shi, MD, PhD, conducted the ESAONA trial to determine whether first-line asandeutertinib can control disease progression to the brain more effectively than osimertinib. They found that asandeutertinib demonstrated promising efficacy and a manageable safety profile in patients with EGFR-mutated NSCLC with BM.
Dr. Shi said the novel third-generation EGFR-TKI candidate may significantly reduce toxic metabolites of osimertinib via deuteration technology, blocking key metabolic sites.
The ESAONA trial is the first pivotal study to demonstrate that asandeutertinib provides significant improvements in intracranial objective response rate (iORR) and intracranial progression-free survival (iPFS) versus osimertinib as a first-line treatment for EGFR-mutant NSCLC with BM.
Interim analysis data from the trial were presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.
Study Design
The randomized, open-label, phase II study evaluated 224 eligible patients with advanced NSCLC and measurable intracranial lesions who were treatment naïve. Patients were randomly assigned in a 1:1 ratio to receive either 160 mg of asandeutertinib daily (n = 111) or 80 mg of osimertinib daily (n = 113).
The primary endpoints were iORR and iPFS assessed by blinded independent central review (BICR). Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety.
An interim analysis was conducted upon reaching 220 intracranial evaluable patients. A second interim analysis was performed after 238 iPFS events, representing 70% of the planned total events.
The study implemented a multiple-testing procedure to control for multiplicity. Formal iPFS testing was conducted only if iORR achieved statistical significance. Additionally, testing of key secondary endpoints was conducted only after both primary endpoints met statistical success.
Safety Profile
Dr. Shi said the side effects were generally manageable for patients treated with asandeutertinib. The incidence of treatment-related adverse events (TRAEs) was comparable between the two cohorts (99.1% with asandeutertinib vs. 95.6% with osimertinib).
While the incidence of grade 3 or higher TRAEs was higher in the asandeutertinib group (43.2% vs. 15.9%)—largely driven by increased blood creatine phosphokinase and decreased white blood cell and neutrophil counts—Dr. Shi said most events were manageable following dose interruption or reduction.
The types of TRAEs were generally similar in both groups. Most TRAEs were grade 1 or 2 in both groups; however, serious TRAEs occurred in 10.8% of patients treated with asandeutertinib compared to 7.1% in the osimertinib cohort.
Only a small proportion of patients treated with asandeutertinib experienced TRAEs that led to permanent discontinuation (3.6%), compared to those treated with osimertinib (3.5%).
Key Findings
The study revealed that asandeutertinib demonstrated higher BICR-assessed iORR compared with osimertinib (95.5% vs. 79.6%; p = 0.0004). This advantage was generally consistent across multiple subgroups.
A particularly superior benefit was observed in patients who were female, under age 65, had no history of smoking, and had an ECOG performance status of 1. Additionally, asandeutertinib maintained this benefit regardless of whether patients had more or fewer than three intracranial lesions or whether they harbored exon 19 deletions or L858R mutations.
Median BICR-assessed iPFS was not reached for patients in the asandeutertinib group, compared with 17.51 months for those receiving osimertinib. Asandeutertinib also demonstrated a statistically significant improvement in ORR at 89.2% compared with 77.9% for osimertinib.
Although the BICR-assessed median PFS was not reached with asandeutertinib, a higher percentage of patients remained progression-free versus those treated with osimertinib:
- At 6 months: 92.55% with asandeutertinib versus 82.83% with osimertinib
- At 12 months: 75.62% with asandeutertinib versus 69.5% with osimertinib
- At 18 months: 59.58% with asandeutertinib versus 40.56% with osimertinib
- At 24 months: 50.17% with asandeutertinib versus 37.67% with osimertinib
Dr. Shi concluded by saying the efficacy and safety results support asandeutertinib as a potentially superior treatment option for patients with advanced EGFR-mutant NSCLC with BM. While the iPFS/PFS and OS data remain immature, these preliminary findings suggest favorable trends toward a more durable treatment benefit with asandeutertinib compared to osimertinib, he said.
Follow-up is ongoing, and several studies in China are currently investigating asandeutertinib both as monotherapy and in combination regimens. Additionally, a conditional New Drug Application for asandeutertinib has been accepted by China’s National Medical Products Administration (NMPA) and granted priority review.
