Trastuzumab Rezetecan(SHR-A1811) Combined With Ivonescimab (AK112) in Locally Advanced or Metastatic Non-small Cell Lung Cancer Harboring HER2 Gene Abnormalities

Evaluation of the Efficacy and Safety of Trastuzumab Rezetecan(SHR-A1811) Combined With Ivonescimab (AK112) in Locally Advanced or Metastatic Non-small Cell Lung Cancer With HER2 Gene Abnormalities in a Phase II Clinical Trial

This is a phase II trial in patients with locally advanced or metastatic non-small cell lung cancer harboring HER2 gene abnormalities （amplification or overexpression）with a performance status of 0 to1 who are planned to receive first-line treatment or who have falied the first-line treatment

This is a Phase II study aimed at evaluating the efficacy and safety of Trastuzumab Rezetecan (SHR-A1811) combined with ivonescimab (AK112) in the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with HER2 gene abnormalities (amplification or overexpression). The study was divided into two cohorts: Cohort 1 included patients with HER2 amplification or overexpression who had failed first-line treatment; Cohort 2 included patients with HER2 amplification or overexpression who were diagnosed for the first time and had PD-L1 expression ≥ 1%. All eligible patients received intravenous administration of SHR-A1811 at 4.8 mg/kg combined with AK112 at 20 mg/kg, once every 3 weeks. The primary endpoint was the progression-free survival (PFS) evaluated by the investigators according to RECIST v1.1; secondary endpoints included duration of response (DOR), objective response rate (ORR), overall survival (OS), and safety indicators (adverse events, serious adverse events, etc.).

Inclusion Criteria:

- 1. The subjects voluntarily participated in this study and signed the informed consent form, showing good compliance; 2. Age: 18 - 75 years old (at the time of signing the informed consent form); 3. ECOG PS score: 0 - 1 point; 4. Expected survival period: more than 3 months; 5. According to the International Association for the Study of Lung Cancer and the 8th edition of the American Joint Committee on Cancer's Lung Cancer TNM staging system, patients with locally advanced (stage IIIB/III C), metastatic or recurrent (stage IV) NSCLC that cannot be treated surgically and cannot receive radical concurrent radiotherapy and chemotherapy, and whose cancer is confirmed by cytology or histology, are eligible for this study. (Note: Mixed tumors will be classified according to the main cell type; if there is a small cell component, the subject does not meet the inclusion criteria); 6. Cohort 1: Previous first-line treatment failed, and HER2 amplification or overexpression (2+ or 3+) is required; Cohort 2: Patients who received no systematic treatment at the initial diagnosis, with HER2 amplification or overexpression (2+ or 3+), and with PD-L1 ≥ 1%; 7. At least one measurable lesion must be present according to the RECIST 1.1 standard. Lesions that have received radiotherapy cannot be regarded as target lesions unless there is a clear progression after radiotherapy; 8. Patients must have adequate organ and bone marrow functions, defined as follows:

1. Absolute neutrophil count ≥ 1,500/mcL
2. Platelet count > 90,000/mcL 19
3. Hemoglobin ≥ 9 g/dL (allow for blood transfusion)
4. Creatinine ≤ 1.5 × ULN
5. Total bilirubin ≤ 1.5 mg/dL or ≤ 26 μmol/L
6. If there is liver metastasis, AST (SGOT) / ALT (SGPT) ≤ 5 × ULN; if there is no liver metastasis, ≤ 2.5 × ULN
7. Albumin ≥ 2.5 g/dL 9. Both the reproductive-aged women and their male partners must agree to take adequate contraceptive measures (hormonal or barrier methods; abstinence) before entering the study, during the study, and within 90 days after completing the study (hormonal or barrier methods; abstinence). If a woman becomes pregnant during the study or suspects she is pregnant, she should immediately inform the attending physician.

Note: Reproductive-aged women are any women who meet the following criteria (regardless of sexual orientation, whether they have undergone tubal ligation or chosen to remain single):

1. No hysterectomy or bilateral oophorectomy;
2. No natural menopause for at least 12 consecutive months (i.e., any time during the previous 12 months there was menstruation).

Exclusion Criteria:

• 1. Have previously received treatment with anti-HER2 drugs, including large molecule antibodies, TKIs, ADCs, etc.; 2. Have a history of interstitial lung disease, radiation pneumonitis, or immune-related pneumonitis after using steroids, or have active non-infectious pneumonia with interstitial lung changes during the screening period, active pulmonary tuberculosis, pneumoconiosis, or having ≥2 grade other types of pneumonia, or severe impairment of lung function (FEV1 or DLCO or DLCO/VA as a percentage of the predicted value is less than 40%) confirmed by lung function tests, etc.; 3. Have experienced arterial/deep vein thrombosis events within 6 months before treatment, such as cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism, etc.; 4. Have ≥2 grade myocardial ischemia or myocardial infarction, arrhythmias (including QTcF ≥ 450ms (male), QTcF ≥ 470ms (female), and ≥2 grade congestive heart failure (New York Heart Association (NYHA) classification), left ventricular ejection fraction (LVEF) < 50%; angina pectoris requiring anti-myocardial ischemia drugs; clinically significant heart valve disease); 5. Have active autoimmune diseases or autoimmune disease history, including but not limited to Crohn's disease, ulcerative colitis, autoimmune hepatitis/enteritis/vasculitis/renalitis, etc., except for the following situations: ① Controllable type I diabetes; ② Hypothyroidism controlled by hormone replacement therapy; ③ Skin diseases that do not require systemic treatment (such as vitiligo, psoriasis); ④ Other diseases that are expected not to recur (such as asthma that has been cured in childhood); 6. Need systemic or local use of immunosuppressants to achieve the purpose of immunosuppression and still need to continue using them within 2 weeks before randomization; 7. Have pleural effusion (thoracic cavity, abdominal cavity or pericardial cavity) with repeated drainage to relieve clinical symptoms (judged by the investigator), or have received pleural effusion drainage for therapeutic purposes within 2 weeks before treatment; 8. Have symptomatic or progressive CNS metastasis or cancerous meningitis, with diffuse dissemination; Have a history of brain metastasis and if the subject is clinically stable, can be considered for inclusion.