High-dose almonertinib in treatment-naïve EGFR-mutated NSCLC with CNS metastases: Efficacy and biomarker analysis.

Abstract

2007 Background: Central nervous system (CNS) metastases is inevitable for epidermal growth factor receptor (EGFR)mutant non-small cell lung cancer (NSCLC). The pre-specified analysis of the FLAURA and other phase III studies has unveiled encouraging results in patients with CNS metastasis. Nevertheless, the availability of limited biomarkers poses a challenge for the early prediction of clinical effects. Methods: We launched a prospective, open-label, single-arm clinical trial across multiple centers (ACHIEVE). Participants, all diagnosed with EGFR-mutated NSCLC with CNS metastases, received first line treatment with high dose Almonertinib through once-daily oral administration, with each dose being 165 mg. The primary endpoints focused on progression free survival (PFS). Concurrently, we gathered baseline and end-of-first-cycle plasma samples, subjecting them to a comprehensive 520 gene-based sequencing analysis. Results: A total of 63 patients were selected and enrolled between Jul 6,2021 and Aug 31,2022. The median follow-up time, until Nov 30,2023, was 538 days. The confirmed Overall Response Rate (ORR) was 88.9% (56/63), while 42.9% (27/63) of patients progressed, with a median PFS of 17.71 months (11.96-NE). Moreover, a notable 88.9% (56/63) of intracranial lesions achieved either a Complete Response (CR) in 21 cases (33.3%) or a Partial Response (PR) in 35 cases (55.6%). To guide and enhance clinical strategy selection, we conducted a comprehensive biomarker evaluation using cell-free DNA (cfDNA) sequencing. Of the 60 baseline plasmas that passed quality control, 81.7% (46/60) were identified as having at least one somatic mutation (ctDNA+). No significant differences were observed between ctDNA+ and ctDNA- groups in terms of ORR (p = 0.33), intracranial ORR (p = 0.499), PFS (p = 0.363, HR = 1.75), and intracranial PFS (p = 0.562, HR = 1.56). Furthermore, we developed a novel algorithm named MedSR (Median Short cfDNA fragment Ratio) based on cfDNA fragment distribution patterns to quantify ctDNA amount. Notably, higher baseline MedSR values (above the median) predicted significantly poorer PFS (p = 0.001, HR = 0.22) and intracranial PFS (p = 0.067, HR = 0.35), demonstrating superior efficacy compared to traditional cfDNA biomarkers like maxAF. On Cycle 2, those achieving ctDNA clearance in C2D1, regardless of their ctDNA status on baseline, exhibited significantly improved PFS (p < 0.001, HR = 4.63) and intracranial PFS (p = 0.001, HR = 5.71). Conclusions: High dose Almonertinib exhibited promising efficacy and maintained tolerable safety as a first-line therapy in EGFR-mutated NSCLC with CNS metastases. The novel MedSR score demonstrated potential value in predicting the efficacy of TKI treatment. Clinical trial information: NCT04808752 .