Randomized Phase II Study of Amivantamab Plus Lazertinib Versus Afatinib in Patients with Uncommon/compound EGFR-mutated Non-Small Cell Lung Cancer (WJOG17323L: AGEHA Study).

TPS8676 Background: While EGFR tyrosine kinase inhibitors (TKIs) such as afatinib are standard treatments for patients with advanced non-small cell lung cancer (NSCLC) harboring uncommon or compound EGFR mutations (excluding exon 20 insertions and T790M), the duration of response is often limited, with a median progression-free survival (PFS) of approximately 8 to 10 months. Amivantamab is an EGFR mesenchymal–epithelial transition factor (MET) bispecific antibody with immune cell–directing activity that has multiple mechanisms of action as defined in preclinical models. For common EGFR mutated NSCLC, combination therapy with lazertinib has been approved in several countries based on its superiority in Phase III trial. Although a phase I study of amivantamab plus lazertinib combination therapy showed promising efficacy with a median PFS of 19.5 months in treatment-naïve patients with uncommon or compound EGFR mutations, this was a small-scale non-comparative study where efficacy was not the primary endpoint. The AGEHA study (WJOG17323L) is designed to prospectively evaluate whether amivantamab + lazertinib provides superior efficacy and acceptable safety compared to afatinib in patients with treatment-naïve, uncommon or compound EGFR mutated NSCLC. Methods: This multicenter, randomized, open-label, phase II trial is conducted by the West Japan Oncology Group (WJOG). Eligible patients are randomized in a 1:1 ratio to receive either combination therapy with amivantamab plus lazertinib in Arm A, or afatinib monotherapy in Arm B. The primary objective is to compare PFS between the two treatment arms. Secondary objectives include safety, overall response rate, and overall survival. Additionally, mandatory blood samples are collected at baseline and at the time of disease progression for comprehensive biomarker analysis using the Guardant Health platform to identify molecular predictors of response and resistance mechanisms, including approximately 740 gene alterations and methylation abnormalities. The target sample size is 70 patients (35 per arm). This study is designed with a one-sided alpha of 0.1 and a power of 80% to detect the superiority of amivantamab plus lazertinib over afatinib monotherapy. The primary analysis will compare PFS using a stratified log-rank test, and hazard ratios will be estimated using a Cox proportional hazards model. Key Eligibility Criteria: Patients must be histologically confirmed advanced or recurrent non-squamous NSCLC harboring uncommon or compound EGFR mutations, excluding exon 20 insertions and T790M. Participants must be treatment-naïve for advanced disease with an ECOG performance status of 0–1. Patient enrollment began in January 2026, with a recruitment period of two years and a total study duration of five years. Clinical trial information: jRCTs031250560 .