A Phase II Clinical Study to Evaluate HLX43 in Subjects With Advanced Non-small Cell Lung Cancer (NSCLC)

Inclusion Criteria:

• Have a full understanding of the study content, process, and possible adversereactions before the study, and sign the informed consent form (ICF); voluntarilyparticipate in the study; be able to complete the study as per protocolrequirements;

• Aged ≥ 18 years at the time of signing the ICF, male or female;

• Histologically or cytologically confirmed, locally advanced (stage IIIB/IIIC) ormetastatic (stage IV) NSCLC not suitable for radical treatment (complete surgicalresection, concurrent/sequential radio-chemotherapy) according to the Union forInternational Cancer Control and the American Joint Committee on Cancer (AJCC) TNMstaging system (8th edition), and should meet the following criteria: 1)Subjectswithout actionable genomic alterations (AGAs):

Prior standard treatment failure, including at least PD-(L)1 and platinum-based chemotherapy; 2) Subjects with AGAs: Prior standard treatment failure, including at least targeted therapy for driver gene alterations (patients with EGFR mutations must be previously treated with EGFR inhibitors) and platinum-based chemotherapy;

• At least one measurable lesion as per RECIST 1.1 within 4 weeks prior torandomization;

• Subjects who agree to provide archived tumor tissue specimens that meets the testingrequirements (either from the most recent surgery or biopsy, preferably within 2years) or agree to undergo a biopsy to collect tumor tissue for PD-L1 expressiontesting;

• The following conditions must be met in terms of the time of the firstadministration of the investigational product: at least 3 weeks (or 5 half-lives ofthe drug, whichever is shorter) from the previous major surgery, medical devicetreatment, locoregional radiotherapy (except for palliative radiotherapy for bonelesions), cytotoxic chemotherapy, immunotherapy, or biological product therapy; atleast 2 weeks from the previous hormone therapy or small molecular targeted therapy;at least 1 week from the administration of the traditional Chinese medicine foranti-cancer indications or minor surgery; and recovery of treatment-induced AEs toGrade ≤ 1 (CTCAE v5.0, except for Grade 2 peripheral neurotoxicity and alopecia);

• ECOG PS score of 0-1 within 1 week prior to randomization;

• Life expectancy > 3 months;

• Adequate organ functions as confirmed by laboratory tests within 1 week prior torandomization (no blood transfusions or treatment with granulocytecolony-stimulating factor is allowed within 14 days prior to the first dose)

• Male and female subjects with child-bearing potential must agree to use at least onehighly effective contraception method during the study and within at least 6 monthsafter the last dose of the investigational product; female subjects of childbearingage must be negative for pregnancy test within 7 days prior to enrollment.

Exclusion Criteria:

• Histologically or cytologically confirmed tumor containing components of small celllung cancer, neuroendocrine carcinoma, or sarcomatoid carcinoma;

• Prior treatment with any medication targeting topoisomerase I, includingchemotherapy or ADCs;

• Imaging examination during the screening period shows the following evidence: a.Imaging evidence of tumor invasion of large blood vessels, tumor invasion of vitalorgans, or risk of esophagobronchial fistula ; b. Imaging evidence of tumorencasement of large blood vessels with vascular stenosis, or cavitation or necrosisin a lung lesion, with a risk of hemorrhage if participating in the study asassessed by the investigator;

• Radical radiation therapy within 3 months prior to the first dose;

• History of any second malignancy within 2 years prior to randomization, except forearly-stage malignancies (carcinoma in situ or stage I tumors) that have receivedradical treatment, such as non-melanoma skin cancer, cervical carcinoma in situ,localized prostate cancer, ductal carcinoma in situ of the breast, and papillarythyroid carcinoma;

• Occurrence of Grade ≥ 3 immune-related adverse events (irAEs) during priorimmunotherapy;

• Presence of uncontrollable pleural effusion, pericardial effusion, or ascitesrequiring repeated drainage;

• Presence of spinal cord compression or clinically active metastases to centralnervous system (referring to untreated or symptomatic metastases, or metastasesrequiring corticosteroids or anticonvulsants to control associated symptoms),carcinomatous meningitis. Subjects who have previously received treatment for brainmetastases (such as whole brain radiotherapy or stereotactic brain radiotherapy) maybe eligible, provided that they are clinically stable for at least 4 weeks with noimaging evidence of brain metastasis progression;

• Subjects with current or prior history of clinically significant pulmonaryimpairment due to pulmonary comorbidities, including but not limited to anyunderlying lung disease (e.g., pulmonary embolism within 3 months prior to the firstdose, severe asthma, severe chronic obstructive pulmonary disease, restrictive lungdisease, interstitial pneumonia, pneumoconiosis, drug-related pneumonitis, andpleural effusion within 3 months prior to the first dose), any autoimmune,connective tissue, or inflammatory disease that may involve the lungs (i.e.,rheumatoid arthritis, Sjogren's syndrome, sarcoidosis), prior pneumonectomy that mayinterfere with the detection and management of suspected drug-related pulmonarytoxicity, or history of with radiation pneumonitis within 6 months;

• Patients with any poorly-controlled cardiovascular and cerebrovascular clinicalsymptoms or diseases, including but not limited to: (1) NYHA Class II or greaterheart failure or left ventricular ejection fraction (LVEF) < 50%; (2) unstableangina pectoris; (3) myocardial infarction or cerebrovascular accident within 6months (except lacunar infarction, slight cerebral ischemia, or transient ischemicattack); (4) poorly controlled arrhythmia (including QTc intervals ≥ 470 ms) (QTcintervals are calculated by Fridericia's formula); (5) poorly-controlledhypertension (systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg after active treatment);

• Patients with active systemic infectious diseases requiring intravenous antibioticswithin 2 weeks prior to randomization;

• Patients who have used moderate or potent CYP2D6 or CYP3A inhibitors or inducerswithin 2 weeks prior to randomization;

• Patients who have received systemic corticosteroids (prednisone > 10 mg/d orequivalent dose of similar drug) or other immunosuppressants within 2 weeks prior torandomization; Except: patients treated with topical, ocular, intra-articular,intranasal, and inhaled corticosteroids; short-term prophylactic use ofcorticosteroids for contrast agents, etc.;

• Patients with known active or suspected autoimmune diseases. Patients withautoimmune-related hypothyroidism and receiving thyroid hormone replacement therapyand those with type 1 diabetes mellitus controlled with insulin therapy are eligibleto be enrolled;

• Patients who have received live vaccine or live attenuated vaccine within 4 weeksprior to randomization;

• Patients who are known to have anaphylaxis to macromolecular proteinpreparations/monoclonal antibodies or are allergic to any component in theformulation of the investigational product;

• Patients with active tuberculosis;

• Patients with a history of immunodeficiency, including human immunodeficiency virus (HIV)-positive or other acquired or congenital immunodeficiencies, or history oforgan transplantation;

• Patients with active HBV or HCV infection or HBV/HCV co-infection;

• Pregnant or lactating women;

• Patients who are not suitable for participating in this clinical study due to anyclinical or laboratory abnormalities or other reasons as assessed by theinvestigator.