214eTiP A prospective, multicenter phase II study of ctDNA-guided Individualized therapy with aumolertinib ± chemotherapy in advanced L858R EGFR+ NSCLC

Background:The third-generation EGFR-TKI aumolertinib has shown significant efficacy and favorable safety in NSCLC patients with EGFR-sensitive mutations.Despite the high response rates to third-generation EGFR-TKIs, patients with the exon 21 L858R mutation typically have a poorer prognosis compared to those with exon 19 deletions, based on tumor biology and previous clinical data, warranting exploration of intensified individualized treatment strategies.Trial design: This study plans to recruit 47 advanced NSCLC patients with EGFR L858R mutation and ctDNA positive.Patients will receive induction therapy with aumolertinib (110 mg once daily) combined with platinum-based chemotherapy (pemetrexed plus cisplatinum or carboplatin) for 4 to 6 cycles.After induction therapy, ctDNA will be re-evaluated.Patients achieving ctDNA clearance will transition to aumolertinib monotherapy, while those with ctDNA persistent positive will continue with aumolertinib plus oral vinorelbine 40mg three times weekly (Monday-Wednesday-Friday). Treatment continues until disease progression or unacceptable toxicity.The primary endpoint is Progression-free survival (PFS).This study incorporates two key innovations.First, the initial TKI-chemotherapy combination therapy aims to maximal tumor cytoreduction.Subsequent ctDNA assessment then guides maintenance therapy, Patients with persistently positive ctDNA continue an intensified yet manageable oral regimen designed to suppress emerging resistance, while those with ctDNA negativity de-escalate to reduce treatment burden.EGFR L858R mutation and positive ctDNA are critical clinical indicators of poor prognosis.By ctDNA dynamic monitoring as a potential prognostic biomarker, this study aims to address two clinical questions, the necessity of initial intensive therapy for high-risk patients and the feasibility of transitioning to metronomic chemotherapy regimen during maintenance to balance efficacy and tolerability, and how to dynamically adjust treatment strategies (intensification or de-escalation) based on ctDNA status to achieve precision therapy.