Postoperative EGFR-TKI Therapy for High-Risk Synchronous Resectable Contralateral Pulmonary Nodules in Patients With EGFR-Mutant Non-Small Cell Lung Cancer（ARMOR2501）

1. Background Lung cancer is the most prevalent and deadliest malignancy worldwide. It is estimated that 0.2%-20% of lung cancer patients have synchronous multiple primary lung cancer (sMPLC) at the time of diagnosis, with most lesions appearing as multiple bilateral ground-glass opacities (GGOs) on imaging1。In clinical practice, the surgical resection strategy for sMPLC depends on factors such as the number, anatomical location, and size of the lesions, while also considering the patient's age and lung function. This approach is often influenced by the surgeon's subjective judgment.2 For unilateral sMPLC, complete eradication can be achieved through a single surgery. However, for bilateral sMPLC, simultaneous bilateral surgery carries a high risk of perioperative complications, especially for elderly patients or those with poor lung function, making it difficult to tolerate.3Conversely, staged surgery exposes patients to the trauma of a second operation and additional perioperative and anesthesia-related risks.4-6If the contralateral lesion left untreated after initial surgery is malignant, the patient faces a high risk of disease progression. Therefore, effective postoperative treatment is necessary to prevent recurrence or progression while minimizing the trauma and financial burden associated with a second surgery.7However, there is currently no established standard therapy for residual contralateral operable lesions after initial surgery.

The epidermal growth factor receptor (EGFR) is a protein tyrosine kinase receptor located on chromosome 7p13-q22, spanning 200 kb and composed of 28 exons encoding 1,186 amino acids. The glycoprotein has a molecular weight of approximately 170 kDa and is widely distributed in all tissue cells except mature skeletal muscle cells, mesodermal tissues, and hematopoietic tissues. The EGFR family consists of four structurally similar receptor molecules: ErbB1 (EGFR), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4), all of which belong to the receptor tyrosine kinase (RTK) family. They contain an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain, with the intracellular region being highly homologous to the erbB oncogene product.

Aberrant EGFR activation mechanisms include receptor amplification, ligand overexpression, activating mutations, and the loss of negative regulatory pathways, with EGFR mutation activation being the primary driver of tumor cell abnormal biological behavior. Anti-tumor agents targeting EGFR include small-molecule EGFR kinase inhibitors and anti-EGFR antibodies. Small-molecule EGFR tyrosine kinase inhibitors (TKIs) competitively bind to the ATP-binding site within the EGFR kinase domain, inhibiting kinase activity and blocking signal transduction pathways related to cancer cell proliferation and metastasis.

In sMPLC, a high proportion of patients harbor EGFR mutations.8,9 According to the National Comprehensive Cancer Network (NCCN) guidelines, adjuvant therapy with EGFR-TKIs is recommended for patients with EGFR-mutant IB-IIIA non-small cell lung cancer (NSCLC). 10However, the efficacy of EGFR-TKIs for residual contralateral operable lesions following surgical resection of an EGFR-mutant tumor remains unclear. A retrospective study showed that in EGFR-mutant sMPLC patients, EGFR-TKI therapy led to a reduction in the diameter of some residual GGOs, with an objective response rate of approximately 15%.7 However, this retrospective study did not specify the location, size, or nature of the residual GGOs, nor did it confirm whether they received standardized anti-inflammatory treatment. In a small-scale exploratory study conducted by our research team on early-stage sMPLC patients with bilateral operable lesions, the largest lesion was subjected to genetic testing following complete surgical resection of one lung. If EGFR L858R or exon 19 deletion mutations were detected, the patients received EGFR-TKI therapy for three months, followed by chest CT re-evaluation. A total of 12 patients were included in the analysis, of whom 3 exhibited significant regression of contralateral operable lesions, yielding a response rate of 25%.

Based on previous literature and our preliminary research findings, we propose a prospective study enrolling early-stage sMPLC patients with bilateral operable lesions. After surgical resection of one side and confirmation of EGFR mutation positivity, third-generation EGFR-TKI therapy will be administered for residual contralateral operable lesions. This study aims to validate the efficacy and safety of EGFR-TKI treatment for EGFR-mutant sMPLC residual lesions, providing a foundation for future postoperative adjuvant treatment strategies in bilateral sMPLC patients. 2. Objective 2.1 Primary To explore the secondary surgery rate within one year after three months of EGFR-TKI treatment for contralateral residual lesions in patients with bilateral sMPLC with EGFR mutations who have undergone unilateral surgery.