A Phase II Study of Aumolertinib Combined With Phased Chemotherapy for Treatment-Naïve EGFR L858R-Mutated Lung Adenocarcinoma (ACCEL Trial)
Background: While third-generation EGFR tyrosine kinase inhibitors (TKI) like aumolertinib have significantly improved outcomes for patients with advanced lung adenocarcinoma, those harboring the L858R mutation still experience inferior prognosis compared to those with exon 19 deletions. Recent evidence suggests that combining TKIs with chemotherapy improves progression-free survival (PFS), but universal application of this combination exposes all patients to cytotoxic toxicity, even those who might thrive on TKI monotherapy alone. Circulating cell-free DNA (cfDNA) and minimal residual disease monitoring offer a dynamic window to identify which patients truly require treatment intensification.
Objectives: The primary objective is to evaluate the predictive value of early molecular response by determining the association between the change in EGFR mutant allele fraction in cfDNA after a 6-week aumolertinib lead-in induction phase (T1) and a 4-cycle combination chemotherapy (T2) with clinical PFS. Secondary objectives include assessing overall response rates (ORR), disease control rate (DCR), safety, and the dynamics of EGFR mutant allele fraction and circulating immune cell profiles. Study
Design: This is a prospective, single-arm, multicenter, phase II clinical trial enrolling 50 evaluable patients. The study utilizes a three-phase treatment framework: * Induction Phase: Aumolertinib monotherapy (110 mg/day) once daily for 6 weeks. * Consolidation Phase: Combination of aumolertinib (110 mg/day) once daily with pemetrexed (500 mg/m²) and carboplatin (AUC 5) once every three weeks for 4 cycles. * Maintenance Phase: Aumolertinib monotherapy once daily until disease progression. Endpoints: The primary efficacy endpoint is Progression-Free Survival (PFS). Molecular efficacy will be measured via the Molecular Clearance Rate (MCR) and Molecular Response Rate (MRR) at baseline (T0), post-induction (T1), and post-chemotherapy (T2). Safety will be graded according to CTCAE v5.0. Conclusion and Significance: This trial aims to establish a molecularly driven framework for personalized lung cancer management, seeking to maximize efficacy for high-risk patients while providing the foundation to spare molecular responders from unnecessary chemotherapy in the future. The results will serve as the base for the design of future confirmatory phase III trials.
• Individuals must be at least 18 years of age at the time of signing the informed consent form.
• Participants must demonstrate the ability to understand the study procedures and provide written informed consent before any trial-specific activities begin.
• A confirmed diagnosis of lung adenocarcinoma (LUAD) via histological or cytological examination is required. The disease must be in an advanced or metastatic stage (stage IIIB, IIIC, or IV by AJCC TNM staging system 9th edition) that is not suitable for curative-intent surgery or radiation therapy.
• Documentation of an EGFR L858R mutation is mandatory. This status can be confirmed using tumor tissue or plasma-based molecular testing.
• Participants must not have received prior systemic therapy for advanced or metastatic LUAD. Previous adjuvant or neoadjuvant treatments are allowed if they were completed at least 12 months before the first dose of the study medication.
• An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 is required. The estimated life expectancy of the participant must be at least three months.
• Participants must have at least one measurable lesion that has not been previously irradiated, as defined by RECIST 1.1 criteria.
• Adequate physiological function must be demonstrated within 14 days before the start of treatment, including:
• Bone Marrow: Absolute neutrophil count ≥ 1.5 x 10\^9/L, platelet count ≥ 100 x 10\^9/L, and hemoglobin ≥ 9.0 g/dL.
• Hepatic: Total bilirubin ≤ 1.5 x upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present.
• Renal: Serum creatinine ≤ 1.5 x ULN or a calculated creatinine clearance ≥ 45 mL/min.
• Reproductive Safety: Participants of childbearing potential must agree to use highly effective contraception throughout the study and for a specified period after the final dose of the investigational products