Exploring the Mechanism of Primary Resistance to Third-generation EGFR-TKIs as First-line Treatment in EGFR-positive Advanced NSCLC (PRECISE Study)

Study Overview
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Brief Summary
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Lung cancer is currently the world's largest malignant tumor for cancer-related deaths with non-small cell lung cancer (NSCLC) accounting for 80%-85%. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), especially the 3rd-generation EGFR-TKIs have demonstrated strong antitumor effects in EGFR-positive patients. However, approximately 20% of EGFR-positive were primarily resistant to 3rd generation EGFR-TKIs, i.e., clinical non-response or disease progression in the short term. This study aimed to clarify the molecular indicators that predict the benefits of 3-rd EGFR-TKIs as first-line therapy in NSCLCpatients with EGFR-positive. Further, to clarify their primary drug resistance mechanisms, which is of great significance for the treatment and clinical decision-making of NSCLC disease.

Official Title
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A Multicenter Clinical Study to Explore the Mechanism of Primary Resistance to Third-generation EGFR-TKIs as First-line Treatment in EGFR-positive Advanced NSCLC (PRECISE Study)

Conditions
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Lung Cancer, Non-small Cell, EGFR Gene Mutation, EGFR-TKI Resistant Mutation, Primary Resistance, Circulating Tumor DNA

Intervention / Treatment
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* Other: Genomic profiles detection
* Other: circulating tumor DNA detection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years; Histological or cytopathological diagnosed NSCLC; According to the American Joint Committee on Cancer (AJCC) eighth edition of the Lung Cancer Staging Manual, the clinical stage is unresectable IIIB-IV or recurrence and metastasis after surgery; At least one measurable lesion can be evaluated according to the Response Evaluation Criteria In Solid Tumours v1.1 (RECIST1.1) criteria; Positive EGFR mutation confirmed by tissue or cytology (pleural fluid, cerebrospinal fluid, etc.); Use of third-generation EGFR-TKIs approved by the NMPA for NSCLC as first-line therapy; Cooperate with the provision of clinicopathological data, imaging data, sample collection, and follow-up required for the research process, and agree to use the test data for subsequent research and product development; Agree to participate in this study and sign an informed consent form. Exclusion Criteria: Patients who cannot understand the content of the experiment and cannot cooperate, and those who refuse to sign the informed consent form; Pregnant and lactating women; Other malignant neoplastic diseases within 3 years; Patients who have undergone other clinical drug trials; Received systemic anti-tumor therapy within 2 years;

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| EGFR-positive lung patients recieving 3rd generation EGFR-TKIs as first-line therapy<br>Stage III-IV EGFR-positive lung patients receiving 3rd generation EGFR-TKIs (Osimertinib 80mg/Qd or Almonertinib 110mg/Qd or Furmonertinib 80mg/Qd) as first-line therapy. | Other: Genomic profiles detection<br>* The Paraffin-embedded tumor tissue at diagnosis is collected and assessed by Next- generation gene sequencing<br>Other: circulating tumor DNA detection<br>* The Plasma at diagnosis and at 1-month treatment are collected and assessed by Next-generation gene sequencing<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | The proportion of patients with a complete response or partial response to treatment according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) | 2 years | 
| Progression-free survival (PFS) | Time from the beginning of treatment to the first disease progression (PD) in patients with advanced NSCLC | 3 years | 
| Differences in genomic profiles of tumor tissues and ctDNA clearance of third-generation EGFR-TKIs sensitive and primary drug-resistant NSCLC. | The patients who don't achieve partial response or progress within 6 months are defined as the primary resistant group. The genomic profiles and ctDNA clearance detected by Next-generation gene sequencing will be compared between the primary drug-resistant group and sensitive-drug group. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Overall survival (OS) is defined as the duration from the beginning of first-line immunotherapy until death due to any cause. Subjects who are still alive at the end of the study observation period will be censored at the time of last known vital status | 5 years | 
| Disease Control Rate (DCR) | The proportion of patients with a complete response or partial response or stable desease to treatment according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) | 3 years |