A Prospective Study of Firmonertinib as First-line Adaptive Therapy Guided by Dynamic ctDNA (MRD) Changes in Locally Advanced or Metastatic EGFR-mutated Non-small Cell Lung Cancer

Inclusion Criteria:

• Sign a written informed consent before implementing any trial-related procedures;
• At least 18 years of age;
• Have histologically or cytologically confirmed non-squamous non-small cell lung cancer.
• Confirmed presence of EGFR-sensitive mutation-positive by tumor histology, cytology, hematology, or pleural effusion supernatant;
• ECOG score of 0-1;
• According to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1), there must be at least one measurable lesion on imaging. Lesions located within the previous radiation field that have proven progression can be considered measurable;
• Life expectancy >3 months at Day 1;
• Patients newly diagnosed with locally advanced (IIIB-IIIC), metastatic, or recurrent (stage IV) lung cancer according to the 9th edition of the TNM classification by the International Association for the Study of Lung Cancer and the American Joint Committee on Cancer; not suitable for treatment with surgery or radiotherapy;
• Confirmed presence of EGFR mutation-positive by tumor histology, cytology, or hematology;
• Not previously treated with anti-angiogenic drugs/chemotherapy;
• Brain metastasis patients are allowed to be enrolled, as long as they meet the following conditions:

• Sufficient organ function, and the subjects must meet the following laboratory criteria:

  1. Absolute neutrophil count (ANC) ≥1.5x10^9/L without the use of granulocyte colony-stimulating factor in the past 14 days;
  2. Platelets ≥100×10^9/L without blood transfusion in the past 14 days;
  3. Hemoglobin >9g/dL without blood transfusion or erythropoietin use in the past 14 days;
  4. Total bilirubin ≤1.5×upper limit of normal (ULN);
  5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN (subjects with liver metastasis are allowed to have ALT or AST ≤5×ULN);
  6. Serum creatinine ≤1.5×ULN and creatinine clearance rate (calculated using the Cockcroft-Gault formula) ≥60 ml/min;
  7. Good coagulation function, defined as international normalized ratio (INR) or prothrombin time (PT) ≤1.5×ULN;
  8. Normal thyroid function, defined as thyroid-stimulating hormone (TSH) within the normal range. If the baseline TSH exceeds the normal range, subjects with total T3 (or FT3) and FT4 within the normal range may also be enrolled;
  9. myocardial enzyme profile within the normal range (subjects with simple laboratory abnormalities that the investigator comprehensively judges to have no clinical significance are also allowed to be enrolled);
• For female subjects of childbearing age, urine or serum pregnancy tests must be conducted within 3 days before the first dose of study drug (on Day 1 of Cycle 1) and the results must be negative. If the urine pregnancy test result cannot be confirmed as negative, a blood pregnancy test is required. Non-childbearing age females are defined as those who have been postmenopausal for at least 1 year, or have undergone surgical sterilization or hysterectomy;
• If there is a risk of pregnancy, all subjects (regardless of gender) must use contraception with an annual failure rate of less than 1% throughout the treatment period until 120 days after the last dose of study drug (or 180 days after the last dose of study drug).

Exclusion Criteria:

• The pathology is small cell lung cancer (SCLC), including lung cancer with a mixture of SCLC and non-small cell lung cancer (NSCLC);

• The patient has received the following treatments:

  1. received systemic anti-tumor therapy within 3 weeks before treatment, such as chemotherapy, targeted therapy, immunotherapy (including Chinese herbal medicine therapy with anti-tumor indications), etc.;
  2. received any investigational drug therapy within 4 weeks before treatment;
  3. received high-dose immunosuppressive drugs (systemic glucocorticoids exceeding 10mg/day of prednisone or its equivalent dose) within 4 weeks before treatment;
  4. received attenuated live vaccines within 4 weeks before treatment (or plans to receive attenuated live vaccines during the study period);
  5. underwent major surgery (such as thoracotomy, thoracotomy, or Kaifu surgery) within 4 weeks before treatment, or has unhealed surgical wounds, ulcers, or fractures.
• Subjects with clinically uncontrollable pleural/peritoneal effusion (not requiring drainage of effusion or showing no significant increase in effusion after 3 days of cessation of drainage) may be enrolled;
• Subjects with a history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonia requiring steroid treatment, or any evidence of clinically active ILD;
• Subjects who have received chest radiotherapy exceeding 30 Gy within 6 months prior to treatment or palliative radiotherapy of 30 Gy or less within 7 days prior to treatment (palliative radiotherapy for bone or intracranial lesions is allowed);
• Subjects who have experienced active autoimmune diseases requiring systemic treatment (such as the use of disease-modifying drugs, corticosteroids, or immunosuppressants) within 2 years prior to the first dose. Alternative therapies (such as thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency) are not considered systemic treatment;
• Known allogeneic organ transplantation (excluding corneal transplantation) or allogeneic hematopoietic stem cell transplantation;
• Subjects who have not fully recovered from toxicity and/or complications caused by any intervention prior to the start of treatment (i.e., grade ≤1 or baseline, excluding fatigue or alopecia);
• Known history of human immunodeficiency virus (HIV) infection (i.e., HIV 1/2 antibody positive);
• Untreated active hepatitis B (defined as HBsAg positive with HBV-DNA copy number greater than the upper limit of normal in the laboratory department of the research center); Note: Subjects with hepatitis B who meet the following criteria may also be enrolled: 1) HBV viral load <1000 copies/ml (200 IU/ml) prior to the first dose, and subjects should receive anti-HBV treatment throughout the study drug treatment period to avoid viral reactivation; 2) For subjects with anti-HBc (+), HBsAg (-), anti-HBs (-), and HBV viral load (-), prophylactic anti-HBV treatment is not required, but close monitoring for viral reactivation is necessary.
• Subjects with active HCV infection (HCV antibody positive and HCV-RNA level above the detection limit);
• Subjects who have received a live vaccine within 30 days prior to the first dose (Cycle 1, Day 1); Note: Inactivated virus vaccine for seasonal influenza administered via injection is allowed within 30 days prior to the first dose; however, attenuated live influenza vaccine administered intranasally is not allowed.
• Pregnant or lactating women;

• Subjects with any severe or uncontrollable systemic diseases, such as:

  1. significant and symptomatically severe abnormalities in rhythm, conduction, or morphology on resting electrocardiogram, such as complete left bundle branch block, second-degree or higher heart block, ventricular arrhythmias, or atrial fibrillation;
  2. unstable angina, congestive heart failure, chronic heart failure with New York Heart Association (NYHA) classification of ≥ 2;
  3. myocardial infarction within 6 months prior to enrollment;
  4. poorly controlled blood pressure (systolic blood pressure >140 mmHg, diastolic blood pressure >90 mmHg);
  5. history of non-infectious pneumonia requiring glucocorticoid treatment within 1 year prior to the first dose, or current clinically active interstitial lung disease;
  6. active tuberculosis;
  7. active or uncontrollable infections requiring systemic treatment;
  8. clinically active diverticulitis, abdominal abscess, or gastrointestinal obstruction;
  9. liver diseases such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis;
  10. poorly controlled diabetes (fasting blood glucose (FBG) >10 mmol/L);
  11. urine routine test indicating proteinuria ≥++ and confirmed 24-hour urine protein quantitation >1.0 g;
  12. subjects with mental disorders and unable to cooperate with treatment; subjects with medical history or disease evidence, treatment, or laboratory test values that may interfere with trial results, hinder the subject's full participation in the study, or other situations deemed unsuitable for enrollment by the investigator; subjects deemed by the investigator to have other potential risks and are not suitable to participate in this study