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

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)

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.

Study Overview

• Status: Recruiting
• Conditions: Lung Cancer, Non-small Cell; Circulating Tumor DNA; EGFR Gene Mutation; EGFR-TKI Resistant Mutation; Primary Resistance
• Intervention / Treatment: Other: Genomic profiles detection; Other: circulating tumor DNA detection

• Study Type: Observational
• Enrollment (Estimated): 210

Contacts and Locations

Study Locations

• China
  • Hunan
    • Changsha, Hunan, China, 410011
      • Recruiting
      • Department of Oncology, The Second Xiangya Hospital, Central South University
      • Contact: Fang Wu, MD, PhD; Phone Number: +86 13574858332; Email: wufang4461@csu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Stage IIIB-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.

Description

Inclusion Criteria:

1. Age >18 years;
2. Histological or cytopathological diagnosed NSCLC;
3. 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;
4. At least one measurable lesion can be evaluated according to the Response Evaluation Criteria In Solid Tumours v1.1 (RECIST1.1) criteria;
5. Positive EGFR mutation confirmed by tissue or cytology (pleural fluid, cerebrospinal fluid, etc.);
6. Use of third-generation EGFR-TKIs approved by the NMPA for NSCLC as first-line therapy;
7. 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;
8. Agree to participate in this study and sign an informed consent form.

Exclusion Criteria:

1. Patients who cannot understand the content of the experiment and cannot cooperate, and those who refuse to sign the informed consent form;
2. Pregnant and lactating women;
3. Other malignant neoplastic diseases within 3 years;
4. Patients who have undergone other clinical drug trials;
5. Received systemic anti-tumor therapy within 2 years;

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
EGFR-positive lung patients recieving 3rd generation EGFR-TKIs as first-line therapy; 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; The Paraffin-embedded tumor tissue at diagnosis is collected and assessed by Next- generation gene sequencing; Other: circulating tumor DNA detection; The Plasma at diagnosis and at 1-month treatment are collected and assessed by Next-generation gene sequencing

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The correlation between tumor microenvironment signature and efficacy of 3rd EGFR-TKIs	The baseline paraffin-embedded tissue is collected and assessed by multiplex immunohistochemistry, including T lymphocytes, B lymphocytes, NK lymphocytes, macrophagocyte, and DC cells. And explore the association between tumor microenvironment signature and primary resistance and the efficacy of 3rd EGFR-TKIs during the enrolled observation process.	3 years

Collaborators and Investigators

• Sponsor: Second Xiangya Hospital of Central South University
• Collaborators: The First Affiliated Hospital of Nanchang University; Xiangya Hospital of Central South University; Fudan University; West China Hospital; Tongji Hospital; Hunan Cancer Hospital; Second Affiliated Hospital, School of Medicine, Zhejiang University; The Third Xiangya Hospital of Central South University; Shanghai Chest Hospital; China-Japan Friendship Hospital; Hunan Provincial People's Hospital; ZhuZhou Central Hospital; First People's Hospital of Chenzhou; Wuhan Union Hospital, China; Renmin Hospital of Wuhan University; The First Affiliated Hospital of University of South China; The First Affiliated Hospital of Xiamen University; First Affiliated Hospital of Guangxi Medical University; People's Hospital of Zhangjiajie; Loudi Central Hospital; Xiangtan Central Hospital; Yueyang Central Hospital; Yongzhou Central Hospital; Shaoyang Central Hospital; Yiyang Central Hospital; Changsha Central Hospital; The first people's hospital of Guiyang; The First People's Hospital of Changde; Zhuzhou Second Hospital; First Hospital of Changsha; Hengyang Central Hospital; Huaihua first people's Hospital; The First People's Hospital of Xiangtan; University of South China Affiliated Nanhua Hospital; Xiangxi Autonomous Prefecture People's Hospital; Second People's Hospital Of Huaihua; Hunan Academy of Traditional Chinese Medicine Affiliated Hospital; The Third Hospital of Changsha; Xiangya Changde Hospital; Changsha County first People's Hospital; Hunan Provincial Straight Hospital of Traditional Chinese Medicine; Liuyang Hospital of traditional Chinese Medicine; Second People's Hospital of Hunan; First Affiliated Hospital of Kunming Medical University; Guiyang Public Health Treatment Center; The Affiliated Bethune Hospital of Shanxi Medical University; The First Affiliated Hospital of Hunan University of Chinese Medicine

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2021
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: October 25, 2022
• First Submitted That Met QC Criteria: October 25, 2022
• First Posted (Actual): October 28, 2022

Study Record Updates

• Last Update Posted (Actual): August 2, 2023
• Last Update Submitted That Met QC Criteria: July 31, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: XYEYY20220928

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No