A Study of MRG002 in the Treatment of Patients With HER2-mutated Unresectable/Metastatic Non-small Cell Lung Cancer (NSCLC).

The objective of this study is to assess the safety, efficacy, pharmacokinetics, and immunogenicity of MRG002 in patients with HER2-mutated unresectable or metastatic non-small-cell lung cancer (NSCLC).

The trial consists of two stages: efficacy exploration and efficacy verification.

At the first stage, at most 30 patients will be enrolled for each of the two cohorts as defined by HER2 mutation sites. If ≥8 patients achieved objective response, the second stage will be continued; otherwise the trial will be terminated. Approximately 40 patients will be enrolled in the second stage.

Eligibility Criteria:
Inclusion Criteria:

1. Understands and provides written informed consent and willing to follow the requirements specified in protocol.
2. Aged 18 to 75 (including 18 and 75), both genders;
3. Life expectancy ≥ 3 months;
4. Advanced NSCLC patients with HER2 mutation in tumor tissue/blood confirmed by NGS/PCR methods. If no prior test results, a tumor tissue specimen from the most recent archival or biopsy (if archival tissue is not available or sufficient) should be provided.
5. Histologically and/or cytologically confirmed unresectable locally advanced or NSCLC with histological subtype of either non-squamous cell carcinoma or squamous cell carcinoma, and patients have at least one measurable lesion as defined by RECIST v1.1.
6. Patients who have failed at least one prior line of Stand of Care (SOC) therapy. Those who refuse or cannot tolerate chemotherapy can also be enrolled.
7. The score of ECOG for performance status is 0 or 1 with no deterioration within 2 weeks prior to the first dose of the study drug.
8. Radiographic evidence of tumor progression during or after the most recent therapy confirmed by investigator.
9. Organ functions must meet the basic requirements.
10. A negative serum or urine pregnancy test within 72 hours of receiving the first dose of study treatment. A serum pregnancy test is required if the urine pregnancy test is positive or cannot be confirmed negative. Women who are pregnant or breast feeding should be excluded.
11. Adequate contraception for women of childbearing potential is defined as hormonal birth control or an intrauterine device and willingness to use 2 methods of contraception or be surgically sterile, or abstain from hetero sexual activity for the course of the study through 120 days after receiving the last dose of study medications.
12. Male patients must be willing to use a latex condom during any sexual contact with females of childbearing potential during and for 120 days after the last infusion of MRG002, even after having undergone a successful vasectomy.

Exclusion Criteria:

1. Prior treatment with HER2-targeted ADC or HER2 targeted antibody.
2. Histologically/cytologically confirmed small-cell lung cancer (SCLC) and mixed type of lung cancer with SCLC histopathology.
3. Received systemic cytotoxic chemotherapy, small molecule targeted drugs within 3 weeks before the first dose of the study drug; received anti-tumor biological therapy, immunotherapy or major surgery within 4 weeks before first dose of the study drug. Use of any other type of anti-cancer therapy is prohibited throughout the study.
4. Known active CNS metastases and/or carcinomatous meningitis.
5. Presence of severe cardiac dysfunction within 6 months of enrollment.
6. Pulmonary embolism or deep venous thrombosis within 3 months prior to the first dose of the study drug.
7. Known history of malignancy except if the patient has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.
8. Uncontrolled or poorly controlled hypertension. Patients with active bleeding, history of coagulation disorder, or on Coumarin anticoagulant.
9. Known allergic reactions to any component or excipient of MRG002, or known allergic reaction to other prior anti-HER2 (including investigational) or to other monoclonal antibodies ≥ Grade 3.
10. Known active infection, including hepatitis B, hepatitis C. Presence of other significant liver disease.
11. Concurrent, serious, uncontrolled infection or known infection with human immunodeficiency virus (HIV), or have a diagnosed acquired immunodeficiency syndrome (AIDS); or an uncontrolled autoimmune diseases; or previously undergone allogeneic tissue/organ transplantation, stem cell or bone marrow transplantation, or has previously received a solid organ transplantation.
12. Active uncontrolled bacterial, viral, fungal, rickettsial, or parasitic infection and has not received systemic antibiotics within 14 days unless treated and resolved prior to study treatment.
13. Received a live-viral vaccination within 30 days prior to the first dose of the study drug. Seasonal influenza or approved COVID-19 vaccines that do not contain live virus are allowed.
14. History of moderate to severe dyspnea at rest due to advanced cancer or their complications, severe primary lung disease, current need for continuous oxygen therapy, or any history of interstitial lung disease or pneumonia that required oral or intravenous glucocorticoids to assist with management.
15. Patients who are receiving immunologically based therapy for any reason.
16. History or current active or chronic autoimmune disease, or glomerulonephritis that has required systemic therapy in the past 2 years or who are receiving systemic therapy for an autoimmune or inflammatory disease.
17. Has a clinically significant cardiac condition.
18. Uncontrolled pleural effusion, pericardial effusion, or recurrent ascites requiring ≥ 1 drainage per month.
19. Use of strong CYP3A4 inhibitors or inducers with MRG002 is prohibited due to increased risk of adverse reactions or potential adverse reduction in potential efficacy.
20. Any other disease or clinically significant abnormality in laboratory parameters, or serious medical or psychiatric illnesses/conditions, substance abuse disorder including alcoholism, which in the judgment of the Investigator might compromise the safety of the patient, integrity of the study, interfere with the patient participation in the study, or confound or compromise the study objectives and their interpretability.