A Phase II Study of Ivonescimab Combined with Cadonilimab and Chemotherapy in Extensive-stage Small Cell Lung Cancer

Inclusion Criteria:

• Written informed consent must be obtained before implementing any trial-relatedprocedures;

• Aged 18-80 years;

• Expected survival of more than 3 months;

• histologically or cytologically confirmed ES-SCLC according to the American VeteransCancer Association VALG staging system；

• Arm 1: subjects who have not received previous systemic therapy for extensive-stageSCLC; Or patients who had received definitive chemoradiotherapy for limited-stagesmall cell lung cancer but had disease progression > 6 months later;Arm 2：ES-SCLCpatients who progressed after only one PD-1/PD-L1 combination chemotherapy and hadresponse to previous treatment (PFS ≥ 3 months), no more than two systemicchemotherapy regimens were used；

• The investigator confirms the presence of at least one measurable lesion accordingto RECIST 1.1 criteria;

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;

• Adequate hematologic function, defined as absolute neutrophil count (ANC) >= 1.5x 10^9/L, platelet count >= 100 x 10^9/L, hemoglobin >= 90 g/L (withouttransfusion history within 7 days);

• Adequate liver function, defined as total bilirubin level <= 1.5 times the upperlimit of normal (ULN) and aspartate aminotransferase (AST) and alanineaminotransferase (ALT) levels <= 2.5 times ULN in all patients, or <= 5 timesULN in patients with liver metastases;

• Adequate renal function, defined as serum creatinine <= 1.5 times ULN;

• Adequate coagulation function, defined as international normalized ratio (INR) orprothrombin time (PT) <= 1.5 times ULN; for subjects receiving anticoagulanttherapy, INR/PT should be within the range planned by the anticoagulant;

• Women of childbearing potential must have a negative pregnancy test within 7 daysbefore starting treatment, and must use reliable contraceptive measures (such asintrauterine device, contraceptive pills, and condoms) during the trial and for 30days after the end of the trial; male subjects of reproductive potential must usecondoms for contraception during the trial and for 30 days after the end of thetrial;

• Willingness to comply with regular follow-up visits and trial requirements.

• Participants were required to provide 10 or more unstained FFPE pathological slides (preferably newly obtained tumor tissue) archived or freshly obtained within 3months prior to the first dose of medication. Tumor lesions used for fresh-tissuebiopsy should not be used as RECIST v1.1 target lesions unless they are the onlymeasurable lesion. The collection of archived tumor-tissue samples beyond 3 monthsof age was permitted, with the consent of the medical monitor, if no samples wereavailable within 3 months of age and biopsy, as judged by the investigator, mightincrease the risk to the subject. If more than 10 slides were not available, some orall of the slides could be waived with investigator approval；

• Participants were required to provide approximately 10 unstained FFPE tumor tissueslides for efficacy biomarker exploration. If it cannot be provided, it can beexempted after approval from the investigator and will not affect the Participantsparticipation in this study；

Exclusion Criteria:

• Currently participating in interventional clinical research treatment;

• For Arm 1: a) Prior immunotherapy, including immune checkpoint inhibitors (e.g.,anti-PD-1 /L1 antibody, anti-CTLA-4 antibody, anti-TIGIT antibody, anti-LAG-3antibody, etc.), immune checkpoint agonists (e.g. ICOS, CD40, CD137, GITR, OX40antibody, etc.), immune cell therapy, and any treatment targeting the tumor immunemechanism; b) previous systemic anti-angiogenic therapy, including but not limitedto bevacizumab small molecule TKI, etc. For Arm 2: a) PD-1/L1 inhibitor crossover therapy: after the failure of PD-1/L1 inhibitorcombined with chemotherapy, the chemotherapy regimen was changed and the originalPD-1/L1 inhibitor was given again. b) Prior immunotherapy other than PD-1/L1inhibitors, including immune checkpoint inhibitors (e.g., anti-TIGIT antibody,anti-LAG-3 antibody, etc., anti-CTLA-4 monoclonal antibody), immune checkpointagonists (e.g. ICOS, CD40, CD137, GITR, OX40 antibody, etc.), immune cell therapy,and any treatment targeting the mechanism of tumor immune action. c) previoustreatment with a taxol chemotherapeutic agent. d) previous systemic anti-angiogenictherapy, including but not limited to bevacizumab, small molecule TKI, etc.

• Imaging during the screening period showed that the tumor was surrounded byimportant blood vessels or had obvious necrosis or cavities, and the investigatorjudged that the entry of the study would cause bleeding risk.

• active autoimmune disease requiring systemic treatment within the past 2 years (e.g., with disease-modifying medications, corticosteroids, immunosuppressants).Replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroidreplacement for adrenal or pituitary insufficiency) is not considered a systemictreatment.

• history of noninfectious pneumonia/interstitial lung disease requiring systemicglucocorticoid treatment or current noninfectious pneumonia.

• History of brain stem, meningeal metastasis, spinal cord metastasis orcompression.presence of active central nervous system (CNS) metastases; Participantswho had previously been treated for brain metastases (e.g., surgery, radiotherapy)were allowed if they were clinically stable for at least two weeks after treatment (calculated from the time of the first administration of the study drug) and ifcorticosteroids were discontinued 7 days before the administration of the studydrug. Participants with untreated, asymptomatic brain metastases (i.e., noneurologic symptoms, no need for corticosteroids, no brain metastases measuring >1.5 cm in the greatest dimension, and no substantial premetastatic edema) wereeligible for enrollment

• presence of current uncontrolled coexisting medical conditions, including but notlimited to decompensated cirrhosis, nephrotic syndrome, uncontrolled metabolicdisorder, severe active peptic ulcer disease, or gastritis, or mental illness/socialcondition that would limit compliance with study requirements or affect theparticipant's ability to provide written informed consent;

• previous history of myocarditis, cardiomyopathy, and malignant arrhythmia. Thepresence of unstable angina, myocardial infarction, congestive heart failure (NewYork Heart Association functional class 2 or higher), or vascular disease (e.g.,aortic aneurysm at risk for rupture) that required hospitalization within 12 monthsbefore the first dose of the study drug or other cardiac impairment (e.g.,uncontrolled arrhythmias, myocardial ischemia) that could affect the safetyevaluation of the study drug; The patient had a history of esophagogastric varices,severe ulcers, unhealed wounds, gastrointestinal perforation, abdominal fistula,gastrointestinal obstruction, intra-abdominal abscess, or acute gastrointestinalbleeding within 6 months before the first dose of medication. Any arterialthromboembolic event, venous thromboembolic event of NCI CTCAE version 5.0 orhigher, transient ischemic attack, cerebrovascular accident, hypertensive crisis, orhypertensive encephalopathy occurred 6 months before the first dose. An acuteexacerbation of chronic obstructive pulmonary disease occurred within 1 month beforethe first dose, except for infusion-related thrombosis that had occurred for morethan 4 weeks.

• history of severe bleeding tendency or coagulopathy; Clinically significant bleedingsymptoms within 1 month before the first dose of medication, including but notlimited to gastrointestinal bleeding, hemoptysis (defined as coughing up or coughingup ≥1 teaspoon of blood or small blood clot or only coughing up blood withoutsputum, and those with blood in sputum were allowed), nasal bleeding (excludingepistaxis and retraction of nasal bleeding); Continuous antiplatelet oranticoagulant therapy had been administered within 10 days before the first dose.

• lack of resolution of toxicity from prior antineoplastic therapy, defined as failureto return to NCI CTCAE version 5.0 grade 0 or 1 or levels specified in theinclusion/exclusion criteria, with the exception of alopecia. Subjects withirreversible toxicity that was not expected to worsen with study drug administration (e.g., hearing loss) may be enrolled after consultation with the medical monitor.Subjects with long-term radiation-induced toxicity that, in the judgment of theinvestigator, did not recover from, may be included in the study.

• serious infection within 4 weeks before the first dose, including but not limited tocoexisting conditions requiring hospitalization, sepsis, or severe pneumonia; Activeinfection (excluding antiviral therapy for hepatitis B or hepatitis C) that hadreceived systemic anti-infective therapy within 2 weeks before the first dose.

• history of immunodeficiency; HIV antibody positive; Long-term use of systemiccorticosteroids or other immunosuppressive agents is ongoing.

• Subjects with known active pulmonary tuberculosis should be excluded by clinicalexamination (e.g., sputum test, chest X-ray, etc.); Known active syphilis infection.

• history of allogeneic organ transplantation and allogeneic hematopoietic stem celltransplantation.

• presence of pleural effusion, pericardial effusion, or ascites with clinicalsymptoms or requiring repeated drainage.

• subjects with active hepatitis B (HBsag-positive and HBV-DNA > 500 copies /ml orhigher than the lower limit of detection); Subjects with active hepatitis C (HCVantibody-positive).

• had a major surgical procedure or major trauma within 30 days before or within 30days after the first dose (at the discretion of the investigator); Minor localprocedures (excluding peripherally inserted central catheters and intravenous-accessports) had been performed within 3 days before the first dose.

• received live attenuated influenza vaccine within 30 days before the first dose orplan to receive live attenuated influenza vaccine during the study and cannotreceive live attenuated influenza vaccine within 90 days after treatment after thelast dose of the study drug.

• known allergy to any component of any study drug; A history of severehypersensitivity reactions to other monoclonal antibodies was known.

• known history of mental illness, substance abuse, alcohol or drug abuse.

• pregnant or lactating women.

• The presence of any past or current medical conditions, treatments, or laboratoryabnormalities that may confound the results of the study, preclude fullparticipation in the study, or participation in the study may not be in the bestinterest of the subject