Non-Small Cell Lung Cancer
Conditions
Keywords
NSCLC, EGFR mutation, circulating tumor DNA (ctDNA), minimal residual disease (MRD), aumolertinib, adjuvant therapy
Brief summary
Despite complete (R0) resection, patients with EGFR-mutant stage IIA-IIIB non-small cell lung cancer (NSCLC) still face a substantial risk of postoperative recurrence. Although adjuvant EGFR tyrosine kinase inhibitors have improved disease-free survival, conventional fixed-duration adjuvant therapy is applied uniformly to all patients and does not distinguish those who genuinely require treatment from those who could be safely spared. Circulating tumor DNA (ctDNA) profiling enables minimal residual disease (MRD) detection that is both earlier and more accurate than imaging, and has therefore emerged as a promising tool for individualizing postoperative adjuvant therapy. This prospective, real-world, interventional study will enroll 50 patients with resected (R0), EGFR 19del or L858R mutant, stage IIA-IIIB non-squamous NSCLC. For three years after surgery, adjuvant treatment is dynamically guided by serial MRD testing performed 3-10 days and 4 weeks (±7 days) after surgery and every 3-6 months thereafter. Patients with a positive MRD result at either of the first two time points receive aumolertinib-based adjuvant therapy, with the regimen determined by the mutations detected in blood: aumolertinib monotherapy (110 mg once daily) when only the EGFR mutation is detected, or aumolertinib combined with chemotherapy (pemetrexed plus carboplatin for four cycles, followed by pemetrexed maintenance) when co-mutations are detected. Patients whose MRD remains negative undergo observation with regular ctDNA monitoring; if MRD turns positive or imaging progression occurs, aumolertinib-based adjuvant therapy is initiated according to the same rules. Treatment is discontinued once MRD becomes undetectable; patients with persistently negative MRD over three years receive no aumolertinib. After three years, subsequent treatment is at the investigator's discretion. The primary endpoint is the 2-year disease-free survival (DFS) rate, defined as the proportion of patients remaining free from recurrence or death for at least 24 months after surgery. Secondary endpoints include the 2-, 3-, and 5-year overall survival rates, 3-year total treatment cost, incremental cost-effectiveness ratio, rate of timely postoperative recurrence diagnosis, and cumulative duration of aumolertinib treatment; exploratory analyses will assess the association between ctDNA/MRD molecular features and clinical efficacy. This study aims to establish a dynamic MRD-guided precision adjuvant strategy that avoids overtreatment while improving outcomes in resected EGFR-mutant NSCLC.
Interventions
DRUGAumolertinib
110 mg orally once daily, for up to 3 years as adjuvant therapy. The dose may be reduced to 55 mg once daily based on adverse events.
DRUGPemetrexed
500 mg/m² by intravenous infusion on day 1 of each 21-day cycle for four cycles, followed by pemetrexed maintenance. Administered in combination with aumolertinib to patients whose blood MRD shows co-mutations.
DRUGCarboplatin
AUC 5 by intravenous infusion on day 1 of each 21-day cycle for four cycles. Administered in combination with aumolertinib and pemetrexed to patients whose blood MRD shows co-mutations.
Sponsors
Peking University People's Hospital
Jiangsu Hansoh Pharmaceutical Group Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provision of written informed consent before any study-related examination, sampling, or analysis. 2. Age ≥18 years. 3. Histologically confirmed primary non-squamous non-small cell lung cancer after surgery, stage IIA-IIIB (8th edition AJCC), with complete (R0) resection. 4. EGFR exon 19 deletion and/or exon 21 L858R mutation detected by histological or cytological testing. 5. Complete recovery from surgery at the time of initiating aumolertinib-containing adjuvant therapy; the interval between surgery and initiation of aumolertinib-containing adjuvant therapy must not exceed 10 weeks; complete postoperative wound healing; and recovery from all toxicities of prior therapy greater than CTCAE grade 1 at the start of study treatment, except for alopecia and grade 2 platinum-related neuropathy. 6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 7. Adequate bone marrow and organ function: absolute neutrophil count (ANC) ≥1.5×10⁹/L; platelet count ≥100×10⁹/L; hemoglobin \>9 g/dL; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN; total bilirubin ≤1.5×ULN; serum creatinine ≤1.5×ULN with creatinine clearance (Cockcroft-Gault formula) ≥60 mL/min. 8. Adequate coagulation function: international normalized ratio (INR) or prothrombin time (PT) ≤1.5×ULN, i.e., PT ≤19.5 seconds or INR ≤1.8. 9. Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days before the first dose of study drug. Women not of childbearing potential are defined as postmenopausal for at least 1 year, or surgically sterilized, or having undergone hysterectomy. 10. If there is a risk of conception, all participants (male or female) must use highly effective contraception throughout the treatment period and for 120 days after the last dose of study drug.
Exclusion criteria
1. Receipt of any of the following: radiotherapy (preoperative, postoperative, or planned) for the current lung cancer; preoperative (neoadjuvant) platinum-based or other chemotherapy; any prior antitumor therapy other than standard platinum-based doublet adjuvant chemotherapy, including investigational therapy; prior neoadjuvant or adjuvant EGFR-TKI therapy; major surgery within 4 weeks before the first dose of study drug; or current use (or inability to discontinue at least 3 weeks before the first dose) of drugs or herbal supplements known to be strong CYP3A4 inducers. Chinese herbal medicines used solely for conditioning or nourishment do not affect enrollment. 2. Segmentectomy or wedge resection, or failure to perform lymph node dissection. 3. Prior interstitial lung disease, drug-induced interstitial disease, or any clinically evident active interstitial lung disease; or idiopathic pulmonary fibrosis detected on baseline CT. 4. Diagnosis of another malignancy within 2 years before the first dose (except radically treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or radically resected carcinoma in situ with ≥5 years of continuous monitoring without recurrence). 5. Any unstable systemic disease, including: active infection; autoimmune disease requiring drug treatment or plasmapheresis; uncontrolled hypertension (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure ≥100 mmHg); unstable angina or angina of new onset within the last 3 months; myocardial infarction (within 6 months before enrollment) or ongoing warfarin anticoagulation after cardiac stent implantation; uncontrolled asthma, chronic obstructive pulmonary disease (COPD), or pulmonary hypertension; renal insufficiency requiring dialysis; insufficient organ reserve; type 1 diabetes mellitus, or type 2 diabetes mellitus complicated by renal or cardiovascular disease or diabetic foot, or a history of ketoacidosis, lactic acidosis, hyperosmolar hyperglycemic state, or random blood glucose ≥11.1 mmol/L; and cardiac findings meeting any of the following: mean resting corrected QT interval (QTc) \>470 msec from 3 ECGs (using QTcF), any clinically important abnormality of cardiac rhythm, conduction, or morphology on resting ECG (such as complete left bundle branch block, third-degree or second-degree atrioventricular block), or any factor increasing the risk of QTc prolongation or arrhythmia (such as heart failure ≥ New York Heart Association class II, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, unexplained sudden death in a first-degree relative under 40 years of age, or any concomitant medication known to prolong the QT interval). 6. NSCLC with large cell neuroendocrine carcinoma or sarcomatoid carcinoma histology. 7. Known allergy or hypersensitivity to aumolertinib, to compounds of similar structure, or to any of its excipients. 8. Mixed small cell lung cancer. 9. Pregnant or breastfeeding women. 10. Uncontrolled nausea and vomiting, chronic gastrointestinal disease, inability to swallow the drug product, or prior major bowel resection that may affect adequate absorption of aumolertinib. 11. Any condition that, in the investigator's judgment, makes the patient unsuitable for enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 2-year disease-free survival (DFS) rate | 24 months after surgery | DFS is defined as the time from the date of surgery to the first occurrence of disease recurrence (local/regional recurrence or distant metastasis) or death from any cause, whichever occurs first. The 2-year DFS rate is the proportion of patients remaining free from recurrence or death for at least 24 months after surgery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 2-year overall survival (OS) rate | 24 months after surgery | OS is defined as the time from the date of surgery to death from any cause. OS rate at 2 years after surgery will be estimated using the Kaplan-Meier method. |
| 3-year overall survival (OS) rate | 36 months after surgery | OS is defined as the time from the date of surgery to death from any cause. OS rate at 3 years after surgery will be estimated using the Kaplan-Meier method. |
| 5-year overall survival (OS) rate | 60 months after surgery | OS is defined as the time from the date of surgery to death from any cause. OS rate at 5 years after surgery will be estimated using the Kaplan-Meier method. |
| 3-year total treatment cost | 3 years after surgery | Total direct treatment costs incurred during the 3 years following surgery, including the costs of adjuvant therapy, MRD testing, and follow-up examinations. |
| Incremental cost-effectiveness ratio (ICER) | 3 years after surgery | The incremental cost per unit of effectiveness (e.g., cost per disease-free year gained) of MRD-guided aumolertinib-based adjuvant therapy relative to conventional adjuvant approaches. |
| Rate of timely postoperative recurrence diagnosis | Through the follow-up period, up to 5 years after surgery | The proportion of disease recurrences that are diagnosed in a timely manner during postoperative follow-up, as enabled by serial MRD monitoring (i.e., earlier than or concurrent with radiological evidence of progression). |
| Cumulative duration of aumolertinib treatment | Up to 3 years after surgery | The cumulative duration of aumolertinib administration during the 3-year postoperative period. |
| Incidence and severity of adverse events (AEs) | From the first dose through 30 days after the last dose of study treatment | AEs will be graded according to NCI-CTCAE version 5.0 and summarized by incidence and severity, including serious adverse events (SAEs) and laboratory abnormalities. |
Countries
China
Contacts
CONTACTKezhong Chen
Outcome results
None listed