Phase III Clinical Study of HB0025 Combined With Chemotherapy Versus Pembrolizumab Combined With Chemotherapy for the First-Line Treatment of Advanced Squamous Non-Small Cell Lung Cancer

12\. Female and male subjects of childbearing potential must agree to use effective contraceptive measures from the screening period until 90 days after the last dose of study treatment. Discussion with the investigator is required to determine whether contraception can be discontinued after this period. Female subjects must not be breastfeeding. Female subjects of childbearing potential must have a negative serum pregnancy test result within 7 days before randomization.

1. Histologically confirmed presence of any small cell carcinoma, neuroendocrine carcinoma, or sarcoma components \[mixed-type NSCLC (e.g., adenosquamous carcinoma) is permitted for enrollment\].

2. Known presence of driver gene alterations with approved first-line therapeutic options, such as sensitive EGFR mutations, ALK fusion, ROS1 fusion, BRAF V600 mutation, NTRK fusion, MET exon 14 skipping mutation, or RET fusion.

3. History of a second primary malignancy within 3 years before Randomization (enrollment is permitted for other malignancies cured by local treatment, e.g., carcinoma in situ of the cervix, localized cutaneous squamous cell carcinoma, basal cell carcinoma, ductal carcinoma in situ of the breast, \< T1 urothelial carcinoma, and papillary microcarcinoma of the thyroid).

4. Symptomatic central nervous system (CNS) metastasis; or diameter of brain metastases ≤ 1.5 cm, or receipt of CNS radiotherapy within 2 weeks before randomization; or anticipated need for CNS radiotherapy during the first treatment cycle after randomization. Subjects with asymptomatic CNS metastasis or symptomatically stable CNS metastasis (≥ 2 weeks before randomization) are permitted for enrollment only if all the following criteria are met:

* No increase in lesion size or new lesions after treatment; ② No history of intracranial hemorrhage;

* Discontinuation of corticosteroid therapy \> 3 days before randomization;

* Diameter of brain metastases \< 1.5 cm.

5. Prior receipt of immunotherapy, including immune checkpoint inhibitors (e.g., anti-PD-1/L1/L2, anti-CTLA-4 agents), immune checkpoint agonists (e.g., ICOS, CD40, GITR, OX40, CD137 agents), or cellular immunotherapy, or any treatment targeting the tumor immune mechanism. Additionally, for subjects who received PD-(L)1 inhibitors in the neoadjuvant/adjuvant setting or as consolidation therapy after definitive chemoradiotherapy, enrollment may be permitted (with sponsor approval) if disease progression occurs \> 12 months after the last dose of prior treatment.

6. Prior receipt of systemic anti-angiogenic therapy, including but not limited to bevacizumab and its biosimilars, Endostar, small-molecule TKIs, and ramucirumab.

7. Prior antineoplastic treatment or concomitant medication use (washout period calculated from the end of the last treatment):

1. Concurrent enrollment in another clinical trial, unless it is an observational, non-interventional clinical trial or the follow-up phase of an interventional clinical trial (defined as an interval of ≥ 4 weeks between the last dose of the previous study drug and randomization in this study);

2. Receipt of chest radiotherapy with \> 30 Gy within 180 days before randomization; non-chest radiotherapy with \> 30 Gy within 4 weeks before randomization; local palliative radiotherapy with ≤ 30 Gy for non-target lesions within 2 weeks before randomization;

3. Use of Chinese herbal medicines (with antineoplastic indications) within 1 week before randomization; receipt of non-specific immunomodulatory therapy (e.g., interleukin, interferon, thymosin, tumor necrosis factor, excluding IL-11 for thrombocytopenia treatment) within 2 weeks before randomization;

4. Need for systemic use of corticosteroids (≥ 10 mg/day prednisone or equivalent) or other immunomodulators within 2 weeks before randomization \[short-term use (≤ 7 days) for prophylaxis (e.g., contrast agent allergy) or treatment of non-autoimmune diseases (e.g., delayed hypersensitivity reaction to allergens), or topical use (e.g., intraocular, intra-articular, intranasal, or inhaled administration) is permitted\].

5. Subjects who are currently using preventive or full-dose anticoagulants or antiplatelet drugs for therapeutic purposes and have not reached a stable state before randomization will not be enrolled. According to the medical standards of the enrolling institution, as long as the INR, PT and APTT of the subjects are within the therapeutic range and they have used or are currently using anticoagulants or antiplatelet drugs, they can be enrolled.

8\. Major surgery or severe trauma within 4 weeks before the first dose of study treatment; inadequate recovery from prior surgery (as judged by the investigator); anticipated need for major surgery during the study; minor local surgery (e.g., needle biopsy, endoscopy, interventional procedure/examination, excluding vascular access establishment) within 7 days before randomization; presence of incompletely healed surgical incisions or wounds.

9\. Active autoimmune disease requiring systemic treatment (e.g., treatment with immunomodulators or corticosteroids) within 2 years before randomization, except for replacement therapy (e.g., thyroid hormone, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency).

10\. Presence of any of the following infections:

1. Severe infection (including but not limited to comorbidities requiring hospitalization, sepsis, or severe pneumonia) within 4 weeks before the first dose of study treatment; active infection requiring systemic anti-infective treatment (with antibiotics for ≥ 7 days) within 2 weeks before randomization;

2. Known active tuberculosis (TB) (subjects with suspected active TB must undergo clinical examination to rule out the diagnosis);

3. Known active syphilis infection;

4. Has a known history of HIV;

5. Active hepatitis B or hepatitis C; asymptomatic hepatitis B virus (HBV) carriers (HBV DNA ≤ 200 IU/ml or ≤ 1000 copies/ml or below the lower limit of detection, whichever is applicable) or subjects with clinically cured hepatitis C (HCV RNA below the lower limit of detection) are permitted for enrollment.

Note: Anti-HBV treatment is required for HBsAg-positive subjects during the study treatment period.

11\. Known hypersensitivity to protein drugs, recombinant proteins, components of HB0025, and/or components of chemotherapy drugs (pemetrexed and carboplatin/cisplatin).

12\. Uncontrolled arterial hypertension despite standard treatment (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg).

13\. Those with a history of non-infectious pneumonia requiring systemic corticosteroid treatment in the past, or currently having interstitial lung disease, pneumoconiosis, drug/radiation-related pneumonia that requires treatment, or those with severe functional impairment indicated by pulmonary function tests.

14\. Presence of any of the following severe comorbidities:

1. Clinically significant bleeding (including but not limited to hemoptysis \[defined as coughing up or expectorating ≥ 1 teaspoon (approximately 5 ml) of fresh blood or small blood clots, or hemoptysis without sputum; subjects with blood-tinged sputum or transient hemoptysis related to diagnostic bronchoscopy or lung biopsy are permitted\], gastrointestinal bleeding, nasal bleeding \[subjects with bloody nasal discharge are permitted\]) within 4 weeks before the first dose of study treatment; any arterial thrombosis or embolism event, or significant vascular disease (e.g., aortic aneurysm, aortic dissection) within 180 days before the first dose of study treatment; history of deep vein thrombosis within 90 days before the first dose of study treatment;

2. Imaging findings at screening showing: Tumor invasion of large blood vessels (e.g., central pulmonary artery, central pulmonary vein, aorta, brachiocephalic artery, common carotid artery, subclavian artery, superior vena cava); tumor invasion of vital organs (e.g., heart, trachea, esophagus, main bronchus); or imaging evidence of risk for esophagotracheal fistula or esophagopleural fistula; tumor encasement of large blood vessels with vascular stenosis; or pulmonary lesions with obvious necrosis/cavitation (as judged by the investigator to pose a bleeding risk if enrolled);

3. History of persistent bleeding disorders or coagulation disorders (past or current);

4. Clinically significant (e.g., active) cardiovascular or cerebrovascular disease within 180 days before the first dose of study treatment, including but not limited to unstable angina requiring hospitalization, myocardial infarction, myocarditis, cardiomyopathy, New York Heart Association (NYHA) Class ≥ II congestive heart failure, poorly controlled severe arrhythmia, transient ischemic attack (TIA), cerebrovascular accident (CVA), or vascular disease (e.g., aortic aneurysm at risk of rupture); or other cardiac impairment that may affect the safety evaluation of study drugs (e.g., poorly controlled arrhythmia, myocardial ischemia); Fridericia-corrected QT interval (QTcF) \> 480 ms at screening, or history of congenital long QT syndrome or family history of the syndrome;

5. History of conditions potentially causing gastrointestinal bleeding or perforation (e.g., gastrointestinal obstruction, acute Crohn's disease, ulcerative colitis, esophagogastric varices, gastrointestinal perforation, unhealed wound, intra-abdominal abscess, or acute gastrointestinal bleeding) within 180 days before the first dose of study treatment; subjects with chronic Crohn's disease or ulcerative colitis (excluding those who have undergone total colectomy and proctectomy) are excluded, even if in remission;

6. History of gastrointestinal fistula or genitourinary fistula (past or current) that remains unhealed after surgical treatment;

7. Hydronephrosis unrelieved by nephrostomy or ureteral stenting, or infected hydronephrosis/hydroureter;

8. Current presence of third-space fluid collections (e.g., pleural effusion, pericardial effusion, abdominal/pelvic effusion) requiring repeated puncture/drainage for local management; or receipt of local drainage within 2 weeks before the first dose of study treatment;

9. Acute exacerbation of chronic obstructive pulmonary disease within 30 days before the first dose of study treatment;

10. Current presence of uncontrolled comorbidities, including but not limited to decompensated liver cirrhosis, nephrotic syndrome, uncontrolled metabolic disorders, severe active peptic ulcer disease or gastritis (enrollment decision requires joint discussion between the investigator and the sponsor).

15\. Pregnant or lactating women, or those planning to breastfeed during the study period.

16\. There is a known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.

17\. Live virus vaccine or attenuated live vaccine was received within 30 days before randomization, or vaccination was planned during the study period (Note: Inactivated vaccine is allowed).

18\. It is known that there is a history of mental illness, alcoholism, drug abuse or substance abuse.

19\. There have been or are currently uncontrolled metabolic disorders, local or systemic diseases not caused by tumors, secondary diseases or symptoms of tumors, abnormal laboratory tests or any treatments that may lead to higher medical risks and/or confuse research results, interfere with the subjects' participation in the entire study, or participation in the study may not be in the best interests of the subjects.

20\. Subjects who, as assessed by the researchers, are not suitable to participate in the trial for other reasons.

What this study is about