A Clinical Study to Evaluate the Efficacy and Safety of HLX26 (Anti-LAG-3 Monoclonal Antibody Injection) Combined With Serplulimab and Chemotherapy in Previously Untreated Advanced NSCLC Patients

A Phase II Study to Evaluate the Efficacy, Safety and Tolerability of HLX26 (Anti-LAG-3 Monoclonal Antibody Injection) Combined With Serplulimab (Anti-PD-1 Humanized Monoclonal Antibody Injection) and Chemotherapy in Previously Untreated Advanced Non-small Cell Lung Cancer (NSCLC) Patients

A Phase II Study to Evaluate the Efficacy, Safety and Tolerability of HLX26 (Anti-LAG-3 Monoclonal Antibody Injection) Combined With Serplulimab (Anti-PD-1 Humanized Monoclonal Antibody Injection) and Chemotherapy in Previously Untreated Advanced Non-small Cell Lung Cancer (NSCLC) Patients

This study is a phase II study to evaluate the efficacy, safety and tolerability of HLX26 in combination with Serplulimab and chemotherapy in the treatment of patients with Non-small cell lung cancer.

The trial was divided into period 1 (safety run-in phase) and period 2 (dose expansion phase).

The first phase is an open-label study, patients will receive varying doses (800 mg, 600 mg or lower) of HLX26 combined with a fixed dose (300 mg) of serplulimab and chemotherapy, administered by intravenous infusion every 3 weeks. Observation period of DLT lasts for 3 weeks after the first administration of HLX26. Safety review committee (SRC) will responsible for the safety of combination treatment. After confirmation of the safety, the efficacy of HLX26 combined with Serplulimab and chemotherapy will be evaluated in period 2.

The second phase (dose expansion phase) is a randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of 2 dose levels of HLX26 combined with fixed-dose (300 mg) of serplulimab and chemotherapy in patients with NSCLC. If the tolerability observation of the 600mg dose group is completed in the first phase, the SRC will review the safety data obtained from the study and decide whether to enter into the second phase; if 2 of the 6 subjects in the 600mg dose group in the first phase occur DLT event, we will continue to explore the safe dose of HLX26 and enroll another 3-6 subjects. Once the maximum tolerated dose (MTD) is found, two doses, MTD and MTD-1, will be selected to enter the dose expansion phase. (The SRC will review the safety and tolerability results obtained in the study to determine the MTD, and will select the dose of MTD-1 below the MTD and within the effective dose range). In the second stage, there are 3 groups and 40 people in each group. The interactive network/voice response system (IWRS) is used to randomly assign qualified subjects to the following three groups in a 1:1:1 allocation ratio:

> Group A: HLX26 MTD intravenous infusion + serplulimab 300 mg intravenous infusion, Q3W; chemotherapy

> Group B: HLX26 MTD-1 intravenous infusion + serplulimab 300 mg intravenous infusion, Q3W; chemotherapy

> Group C: placebo + serplulimab 300 mg intravenous infusion, Q3W; chemotherapy

The chemotherapy will be decided by investigator per patients' pathological type. nsqNSCLC patients will receive pemetrexed and carboplatin as chemotherapy and sqNSCLC patients will receive nab-paclitaxel or paclitaxel and carboplatin.

Key Inclusion Criteria:

1. Stage IV (AJCC 8th Edition) non-small cell lung cancer confirmed by histology or cytology.
2. No EGFR sensitive mutation or ALK, ROS1 rearrangement.
3. Have not received systemic treatment for stage IV disease. For patients who have received adjuvant or neoadjuvant treatment, if the adjuvant/neoadjuvant treatment has been completed for at least 6 months, they are allowed to be enrolled.
4. At least one measurable lesion evaluated by the investigator per RECIST v1.1.
5. Subjects must provide qualified tumor tissue samples for the detection of PD-L1 and LAG-3 expression level.
6. Have adequate organ function with expected survival period ≥ 12 weeks and ECOG score of 0 or 1.

Key Exclusion Criteria:

1. Subjects with other histopathological types including small cell lung cancer, neuroendocrine cancer or sarcoma.
2. Have other malignant tumors within 3 years.
3. Pleural effusion, pericardial effusion or ascites that require clinical intervention.
4. Myocardial infarction and poorly controlled arrhythmia occurred within six months before the first administration of the study drug.
5. III - IV cardiac insufficiency per NYHA standard or left ventricular ejection fraction<50%.
6. Patients with active pulmonary tuberculosis.
7. Patients with previous or current interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, or severe pulmonary function impairment that may interfere with the detection and management of suspected drug-related pulmonary toxicity.
8. Patients who have known active autoimmune diseases or suspected auto-immue disease. Patients in stable condition and do not require systemic immunosuppressant therapy are allowed to be enrolled.
9. Require systemic treatment with corticosteroids (> 10 mg/day prednisone or equivalent) or other immunosuppressive agents within 14 days prior to the first dose of the study products or during the study.
10. Patients who have received any T-cell costimulatory agents or immune checkpoint blockade therapy, including but not limited to cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) inhibitors, PD-1 inhibitors, PD-L1 inhibitors.
11. Patients with a history of severe allergy to any monoclonal antibody products.