ctDNA-MRD Based Adjuvant Targeted Therapy for EGFR Positive Stage I Lung Adenocarcinomas

Circulating Tumor DNA (ctDNA)-Minimal Residual Disease (MRD) Based Adjuvant Targeted Therapy in EGFR Mutation-positive Stage I Lung Adenocarcinoma Patients After Complete Surgical Resection

The purpose of this study is to determine the feasibility and effectiveness of ctDNA-MRD based adjuvant furmonertinib therapy in EGFR mutation-positive stage I lung adenocarcinoma patients after complete surgical resection.

Study Overview

• Status: Not yet recruiting
• Conditions: Adenocarcinoma of Lung
• Intervention / Treatment: Drug: Furmonertinib

Detailed Description

Despite surgery provides the best chance for the cure of early-stage lung cancer patients, 20%-40% of stage I non-small cell lung cancer (NSCLC) patients still suffer from disease relapse after R0 resection. One of the important strategies to improve survival is adjuvant therapy.

The adjuvant chemotherapies are reported to improve outcomes of patients with stage II and III lung cancer. However, for stage IA patients, adjuvant chemotherapy is not recommended, while its application in stage IB patients is still controversial. The adjuvant targeted therapy has shown promising effectiveness which can lead to better RFS of EGFR mutation-positive stage IB-IIIA NSCLC patients than chemotherapy in according to several phase III studies. According to the ADAURA study, stage IB NSCLC patients can benefit from the third-generation EGFR-TKI. However, no available study has evaluated the effectiveness of adjuvant targeted therapy in the overall cohort of stage I patients.

Molecular residual disease or minimal residual disease (MRD) refers to residual tumor cells or relative biomarkers that persist in the body after treatment and is below the conventional detection limit. Several studies have confirmed that positive MRD was associated with a poor prognosis. The use of circulating tumor DNA (ctDNA) to reflect MRD at the molecular level can overcome the shortcomings of conventional tests or radiological tests in the detection of recurrence. ctDNA has been proven to detect MRD effectively in stage I-III lung cancer patients and identifying MRD after surgery could facilitate the selection of patients for customized adjuvant therapies.

Thus, the investigators innovatively propose this study to assess the effectiveness of adjuvant targeted therapy (furmonertinib, one third-generation EGFR-TKI) in stage I lung adenocarcinoma patients and explore the role of ctDNA as an MRD monitoring marker in guiding personalized adjuvant therapies.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Fan Yang, MD; Phone Number: +86-010-88326657; Email: yangfan@pkuph.edu.cn

Study Locations

• China
  • Beijing, China, 100044
    • Peking University People's Hospital
    • Contact: Fan Yang, MD; Phone Number: +86-010-88326657; Email: yangfan@pkuph.edu.cn
    • Principal Investigator: Fan Yang, MD
    • Sub-Investigator: Hao Li, MD
    • Sub-Investigator: Heng Zhao, MD
    • Sub-Investigator: Sida Cheng, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Stage I lung adenocarcinoma patients underwent complete surgical resection with negative margins (R0) and harbor sensitizing EGFR mutations (exon 19 and/or exon 21).
2. Positive ctDNA after surgery and prior to adjuvant therapy (4 weeks after surgery).
3. Completely recovered from surgery before adjuvant treatment and showed no signs of tumor recurrence in imaging.
4. Adequate organ function: 1) Hemoglobin ≥ 9.0 g/dL; 2)Absolute neutrophil count (ANC) ≥ 1500 cells/mm3; 3) Platelets ≥ 90,000/mm3; 4) AST, ALT ≤ 2.5 x ULN; 5) Total bilirubin ≤ 1.5 x ULN; 6) Serum creatinine ≤ 1.5x ULN and calculated creatinine clearance ≥ 60ml/min.
5. Age >18 years old.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
7. Females must have a negative pregnancy test within 7 days prior to the start of dosing if of child-bearing potential.
8. Males and females of reproductive potential who are sexually active must agree to use adequate contraception prior to entry, during the process and 8 weeks after drug withdrawal.
9. Written informed consent.
10. Compliance with the protocol.
11. Ability to swallow the formulated product.

Exclusion Criteria:

1. Any type of systemic anticancer therapy for lung adenocarcinomas, including chemotherapy, targeted therapy or immunotherapy.
2. Any prior local radiotherapy for lung adenocarcinomas.
3. Clinical objective evidence (pathology or imaging) to confirm disease recurrence before the start of adjuvant therapy.
4. Allergy to furmonertinib or any ingredients.
5. Past medical history of ILD, drug-induced ILD or any evidence of clinically active ILD; CT scan at baseline revealed the presence of idiopathic pulmonary fibrosis.
6. Any evidence of uncontrolled systemic diseases, including active infection, uncontrolled hypertension, unstable angina, angina within the last 3 months, congestive heart failure (≥ New York Heart Association [NYHA] Grade II), myocardial infarction (6 months before enrollment), severe arrhythmia requiring medical treatment, liver diseases, kidney diseases or metabolic diseases.
7. Known history of human immunodeficiency virus (HIV) infection.
8. Pregnant or lactating women.
9. History of neurological or psychiatric disorders, including epilepsy or dementia.
10. Other judgments by the Investigator that the patient should not participate in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Furmonertinib; ctDNA-MRD positive participants received 3 years of furmonertinib once daily as adjuvant therapy after radical surgery until disease progression or unacceptable toxicity occurs.	Drug: Furmonertinib; Furmonertinib at 80mg dose will be administered orally once daily.; Other Names: AST2818; AST5902

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clearance of ctDNA at 6 months	To estimate the percentage of patients with undetectable ctDNA at 6 months after adjuvant furmonertinib therapy in stage I lung adenocarcinoma patients who underwent R0 resection and have postoperatively detectable ctDNA prior to adjuvant therapy.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse-free survival (RFS)	To estimate RFS in all postoperative ctDNA-positive stage I lung adenocarcinoma patients, who underwent adjuvant furmonertinib therapy; To compare the RFS in postoperative ctDNA(+) patients who received adjuvant furmonertinib with that in postoperative ctDNA(-) patients, and with that in postoperative ctDNA(+) patients who didn't receive any adjuvant therapy, including chemotherapy, radiotherapy, targeted therapy or immunotherapy.	Through study completion, an average of 3 years
Clearance of ctDNA at 12 months	To estimate the percentage of patients with undetectable ctDNA at 12 monthsafter adjuvant furmonertinib therapy in stage I lung adenocarcinoma patients who underwent R0 resection and have postoperatively detectable ctDNA prior to adjuvant therapy.	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events	All patients who have received at least one dose furmonertinib will be regarded as the effective population for the safety analysis. Adverse events will be reported and graded in accordance with the NCI common adverse event terminology standard CTCAE version 5.0.	Through study completion, an average of 3 years
Genomic changes of ctDNA	To dynamically evaluate the ctDNA profiles by next-generation sequencing and illustrate the genomic changes of ctDNA at baseline, during treatment, and at disease relapse.	0, 3, 6, 12, 18, 24, 30, 36 months
Relationship between radiomics features and ctDNA status	To evaluate if the radiomics signatures on preoperative CT scans can be a prediction tool for the postoperative ctDNA-MRD status.	pre-surgery and 3 days after the surgery
Relationship between radiomics features and clinical outcome	To evaluate if the radiomics signatures on preoperative CT scans can be a prediction tool for relapse-free survival of stage I lung adenocarcinoma patients with R0 resection.	pre-surgery and through study completion (an average of 3 years)

Collaborators and Investigators

• Sponsor: Peking University People's Hospital
• Collaborators: Guangzhou Burning Rock Medical Examination Institute Co., Ltd.; Beijing CSCO-Allist Cancer Research Foundation; Shanghai Allist Pharmaceutical Technology Co., Ltd.
• Investigators: Study Director: Fan Yang, MD, Peking University People's Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): October 1, 2021
• Primary Completion (Anticipated): March 1, 2023
• Study Completion (Anticipated): September 1, 2024

Study Registration Dates

• First Submitted: September 9, 2021
• First Submitted That Met QC Criteria: October 3, 2021
• First Posted (Actual): October 15, 2021

Study Record Updates

• Last Update Posted (Actual): October 15, 2021
• Last Update Submitted That Met QC Criteria: October 3, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: EGFR; minimal residual disease; lung adenocarcinoma; circulating tumor DNA; furmonertinib
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Adenocarcinoma; Adenocarcinoma of Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Aflutinib
• Other Study ID Numbers: Y-2021 AST/zd-0105

Drug and device information, study documents

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