This is a Phase 1, open-label study to evaluate the safety and the efficacy of inetetamab in combination with pyrotinib in patients in HER2 mutant or amplified patients with advanced non-small cell lung cancer

This study is a multi-center, opening, dose-escalating phase Ib clinical trial. The aim of the study is to evaluate the safety and efficacy of inetetamab combined with pyrotinib in the treatment of patients in HER2 mutant or amplified patients with advanced non-small cell lung cancer .Primary endpoint of the study is dose-limiting toxicity dosage and safety. Efficacy indicators including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) are as Secondary endpoint. Up to 48 NSCLC patients will be enrolled the treatment will be performed 3+3 dose-escalation phase I design and expanded to phase II study. A treatment cycle lasts 3 weeks,and the combined medication will be continued until the occurrence of toxicity intolerance,disease progression,or death,or patients refuse to continue participating in this clinical study,or the investigators determine that the medication must be terminated.

The recommended initial consistent dose of inetetamab in groups 1-3 are 8 mg/kg, intravenous infusion for more than 90 minutes, and the maintenance dose is 6 mg/kg.

The oral doses of pyrotinib in groups 1-3 were 240 mg, 320 mg, or 400 mg, respectively.

Safety evaluation will be taken according to hematological toxicity, non-hematological toxicity and National Cancer Institute (NCI)-Common Terminology Criteria (CTC) For Adverse Events (AE) V5.0.

Inclusion Criteria:

1. Age over 18;

2. Histologically or cytologically documented metastatic NSCLC, HER2 activation amplification or mutation stage IIIB-IV NSCLC patient;

3. At least 1 measurable lesion according to RECIST 1.1;

4. ECOG score 0 or 1;

5. Life expectancy of at least 3 months;

6. Within one week before admission, blood routine examination was basically normal:

   1. hemoglobin ≥90g/L or ≥5.6mmol/L;
   2. neutrophil count (ANC) ≥ 1.5 × 10 ^ 9 / L;
   3. platelet count (PLT) ≥ 100 × 10 ^ 9 / L;
   4. Liver and kidney function tests were basically normal within one week before enrollment;
   5. total bilirubin (TBIL) ≤ 1.5 × upper limit of normal value (ULN);
   6. alanine aminotransferase (ALT / AST) ≤ 2.5 × ULN (liver metastasis patients ≤ 5xuln);
   7. serum creatinine ≤ 1.5 × ULN;
   8. Partially activated thrombin time(APTT)≤ 1.5 × ULN;

7. For fertile women had negative blood pregnancy tests 7 days before screening;

8. willing to participate and sign the informed consent in person.

Exclusion Criteria:

1. Patients who have received anti-HER2 monoclonal antibody therapy;
2. Have received chemotherapy, biotherapy, targeted therapy, immunotherapy and other anti-tumor therapies within 4 weeks prior to the first use of the study drug including: oral small molecule targeted drugs within 2 weeks prior to the first use of the study drug or within 5 half-lives of known drugs (depending on the time);Radiotherapy was performed within 2 weeks prior to the first administration of the study drug;
3. Have received other clinical study drugs within 4 weeks prior to the first study drug administration;
4. Patients who underwent major surgery within 4 weeks prior to the first dosing of the study drug(except needle biopsy or significant trauma);
5. Those who have been known to have allergic history to the drug components of this regimen;
6. Study drugs that had used a CYP3A4 inhibitor, inducer, or a narrow therapeutic window with a CYP3A4-sensitive substrate ,P-ep strong inducer and inhibitor within 14 days before first administration;
7. The adverse reactions of previous antitumor therapy have not recovered to CTCAE 5.0 grade 1(Hair loss and other toxicities were excluded for which the researchers judged no safety risk);
8. Patients with central nervous system metastasis and clinical symptoms;
9. History of immunodeficiency, including positive HIV test, or suffering from other acquired, congenital immunodeficiency diseases, or history of organ transplantation;
10. Active hepatitis B (HBV virus titer 1000 copies /ml or 200IU/ml);Hepatitis C virus, syphilis infection;
11. Severe heart disease or discomfort, including, but not limited to, the following: complete left bundle branch block or degree atrioventricular block, history of myocardial infarction, angioplasty, coronary artery bridging, patients with prolonged QT/QTc interval at baseline (QTcF men >450 ms, women >480ms), significant ventricular arrhythmias (such as ventricular tachycardia), history of heart failure or systolic dysfunction (LVEF < 50%), cardiac failure, New York College of Cardiology (NYHA) grade II or higher, uncontrolled hypertension (systolic blood pressure > 180 mmHg ), history or current history of cardiomyopathy that the investigator judged to have an impact on the study;
12. Inability to swallow medications orally, or that the investigator determines severely affect gastrointestinal absorption;
13. Other malignant tumors in the past 5 years, excluding cured cervical carcinoma in situ, skin basal cell carcinoma or skin squamous cell carcinoma or in situ cervical cancer and/or breast cancer;
14. Any history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonia requiring steroid treatment, or evidence of clinically active interstitial lung disease;
15. Patients with a history of other serious systemic diseases who were judged by the investigator to be unsuitable for clinical trials;
16. Alcohol or drug dependence;
17. Have a clear history of neurological or mental disorders, including epilepsy or dementia;
18. Pregnant and/or breastfeeding;
19. Any other reason the investigator considers the patient is not suitable to participate in the study.