High-Dose Aumolertinib Shows Survival and Safety Profile in EGFR-Variant NSCLC

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High-dose aumolertinib demonstrated a progression-free survival (PFS) benefit and a manageable safety profile in patients with untreated EGFR-variant non–small cell lung cancer (NSCLC) and brain metastases, according to findings from the prospective, single-arm phase 2 ACHIEVE trial (NCT04808752), published in JAMA Oncology.¹

At a median follow-up of 28.8 months (95% CI, 27.0-29.8), 65.1% of patients (41 of 63) experienced PFS events in the full analysis set (n = 63). Hu Li, MD, and colleagues reported a 12-month PFS rate of 62.1% (95% CI, 48.7-73.0) with a median PFS of 20.5 months (95% CI, 12.0-26.9). Systemic objective response rate (ORR) was 82.5% (95% CI, 78.4-95.4) for the full analysis set, and the intracranial ORR was 82.5% (95% CI, 70.9-90.9). Twenty-one intracranial complete response (CR) events were observed.

In the CNS evaluable-for-response set (n = 49), the systemic ORR was 87.8% (95% CI, 75.2-95.4) and the intracranial ORR was 85.7% (95% CI, 72.8-94.1) per RECIST 1.1, with 11 intracranial CR events (22.4%) observed. The intracranial PFS at 12 months was 76.8% (95% CI, 63.2-85.9), and the median intracranial and overall survival was not reached.

Li, et al, wrote that “the results of this nonrandomized clinical trial suggest the potential of high-dose aumolertinib as first-line treatment for this population.”

Treatment-related AEs (TRAEs) of any grade were reported in 58 of 63 patients (92.1%),with grade 3 or higher TRAEs occurring in 20 patients (31.7%). The most common TRAEs were increased blood creatine phosphokinase (68.3%), increased aspartate aminotransferase (49.2%), increased alanine aminotransferase (24 [38.1%]), and increased blood lactate dehydrogenase (27.0%). Grade 3 or higher TRAEs included increased blood creatine phosphokinase (27.0%) and increased alanine aminotransferase. TRAEs led to dose reduction of aumolertinib in 7 patients (11.1%).

A total of 75 patients with untreated EFGR-variant metastatic NSCLC were screened and 63 were enrolled in the trial. Sixty-three patients received aumolertinib and were included in the full analysis set and 49 patients with 1 or more brain lesions were included in the central nervous system evaluable-for-response set.

Eligible patients received aumolertinib, 165 mg, orally once daily in each 28-day cycle until disease progression, unacceptable toxic effects, withdrawal of consent, or death. Brain magnetic resonance imaging and body computed tomography scans were performed at baseline and every 8 weeks.

The primary end point was 12-month PFS rate and secondary end points were intracranial PFS, systemic ORR, and intracranial ORR.

Of the 63 patients, the median age was 60 years (range, 47-76), and the majority (61.9%) were female. Thirty-three (52.4%) had EGFR exon 19 deletion and 30 (47.6%) had exon 21 L858R variant. Twenty-nine patients (46.0%) harbored TP53 variants. Regarding CNS involvement, 21 (33.3%) patients had lesions in the brain and double that (66.7%) had simultaneous extracranial metastases. A total of 12 (19.0%) patients had symptomatic brain metastases at baseline.

The investigators noted limitations to the study including its single-arm design without a control group, the lack of independent central review for tumor response analysis, and the enrollment of only Chinese patients. They concluded that the agent “deserves further validation in a randomized clinical trial.”

REFERENCE:

Li H, Chen K, Gong L, et al. High-dose aumolertinib for untreated EGFR-variant non-small cell lung cancer with brain metastases: The ACHIEVE phase 2 nonrandomized clinical trial. JAMA Oncol. Published online June 26, 2025. doi:10.1001/jamaoncol.2025.1779