Befotertinib Plus Chemotherapy With an MRD-guided Adaptive Strategy for Treatment Escalation and Response Optimization in EGFR-mutated NSCLC Patients

Befotertinib Plus Chemotherapy With an MRD-guided Adaptive Strategy for Treatment Escalation and Response Optimization in EGFR-mutated NSCLC Patients

This is a multicenter, phase II exploratory clinical trial in untreated patients with EGFR-mutant non-small cell lung cancer (stages IIIB-IV) .All participants will receive oral befotertinib monotherapy for 3 weeks first, then serial minimal residual disease (MRD/MRD) testing is performed to adjust subsequent treatment. Patients with positive MRD will receive 4 cycles of pemetrexed plus platinum chemotherapy; patients with negative MRD will continue single-agent befotertinib. After induction, maintenance therapy will be given according to follow-up MRD results. The primary goal is to evaluate progression-free survival guided by dynamic MRD monitoring, and secondary endpoints include objective response rate, disease control rate, safety and MRD clearance rate.

Inclusion Criteria:

1. Histologically or cytologically confirmed stage IIIB-IV non-small cell lung cancer (NSCLC).

2. Age ≥18 years, any gender.

3. Confirmed EGFR exon 19 deletion or exon 21 (L858R) substitution mutation by central laboratory or site-validated testing assay.

4. No prior systemic anti-tumor therapy.

5. ECOG performance status 0-2.

6. Expected survival ≥12 weeks.

7. Able to swallow oral study medication.

8. At least one measurable lesion per RECIST 1.1 criteria.

9. Adequate organ function as defined below:

   1. Absolute neutrophil count ≥1.5 × 10^9/L;
   2. Platelet count ≥100 × 10^9/L;
   3. Hemoglobin ≥9 g/dL (transfusion allowed);
   4. Total bilirubin ≤1.5 × ULN;
   5. ALT/AST ≤2.5 × ULN (≤5 × ULN if liver metastasis);
   6. Serum creatinine ≤1.5 × ULN, or creatinine clearance ≥45 mL/min by Cockcroft-Gault formula if creatinine >1.5 × ULN.

10. Fertile men and women agree to effective contraception during study treatment and for specified time after last dose.

Exclusion Criteria:

1. Receiving other systemic anti-tumor therapy, or plan to combine other systemic anti-cancer agents during study.
2. Participated in another investigational drug trial within 4 weeks prior to first study drug; major surgery within 4 weeks; unhealed wound, active ulcer or fracture; radiotherapy within 2 weeks without recovery.
3. Severe cardiovascular disease: QTcF ≥450 ms or clinically significant ECG abnormality; uncontrolled hypertension (SBP>160 mmHg or DBP>100 mmHg); congestive heart failure, cardiomyopathy, arrhythmia requiring intervention, unstable angina, myocardial infarction, stroke or TIA within 6 months prior to treatment.
4. Uncontrolled active infection including active HBV, HCV, HIV, active syphilis infection judged by investigator. Stable infection without safety risk is permitted.
5. History of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroids, or active interstitial lung disease.
6. Active hemorrhage, clinically significant hemoptysis, high thromboembolic risk or prior severe thromboembolic events unsuitable for study treatment.
7. Renal dysfunction with creatinine clearance <45 mL/min; prior intolerable toxicity to pemetrexed; severe hypersensitivity to pemetrexed or its excipients.
8. Positive serum pregnancy test within 7 days before treatment, pregnant or breastfeeding women; fertile subjects refusing contraception during study and 3 months after last dose.
9. Known severe hypersensitivity to befotertinib, cisplatin, carboplatin or their excipients.
10. Any other medical, metabolic, physical or lab abnormality that may compromise subject safety or interfere with study results per investigator judgment.