Efficacy and Safety of Sacituzumab Tirumotecan (SKB264) in Combination With Toripalimab in Patients With Initially Unresectable Stage III NSCLC

Efficacy and Safety of Sacituzumab Tirumotecan (SKB264) in Combination With Toripalimab in Patients With Initially Unresectable Stage III Non-small Cell Lung Cancer (NSCLC): a Phase II Study

This study is a phase 2 open-label, single-center clinical study to evaluate the efficacy and safety SKB264 in combination with toripalimab in patients with unresectable stage III non-small cell lung cancer

This study is a phase 2 open-label, single-center clinical study to evaluate the efficacy and safety SKB264 in combination with toripalimab in patients with unresectable stage III non-small cell lung cancer. The study includes a screening period (up to 28 days after the subject signs the informed consent form until before the first dose), a treatment period (including an induction treatment period, a local treatment period (surgery or radical radiotherapy), and a consolidation treatment period), and a follow-up period (including two parts of safety follow-up and survival follow-up). Approximately 50 patients with initially unresectable stage III non-small cell lung cancer patients, without EGFR/ALK/ROS-1-sensitive mutations, without chest radiotherapy and systemic anti-tumor therapy, were enrolled

Inclusion Criteria:

1. Patients who voluntarily participate in this clinical study, understand the study procedures and are able to sign the informed consent form in writing;
2. Men or women aged 18-70 years (inclusive) at the time of signing the informed consent form.
3. ECOG PS score of 0 or 1.
4. Histologically or cytologically confirmed stage III non-small cell lung cancer that cannot be surgically treated as determined by the investigator. Disease staging should be based on the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) NSCLC staging system, 8th edition.
5. Ability to provide tumor tissue specimens, either archived within 6 months prior to the first dose of study drug or freshly obtained. See the laboratory manual for specific requirements.
6. Pulmonary function of at least FEV1 > 1.0 L and FEV1% > 40% within 3 months.
7. Patients must have measurable target lesions examined by CT or MRI per RECIST v1.1 criteria. Tumor imaging assessments are performed within 28 days prior to the first dose.
8. Adequate hematologic and vital organ functions, as defined by the following laboratory findings, which need to be completed within 14 days prior to the first study treatment:

(1). Hematology (no hematopoietic stimulating factor drugs or blood transfusion within 14 days before the first study treatment): absolute neutrophil count (ANC) ≥ 1.5 × 109/L, absolute lymphocyte count (LC) ≥ 0.5 × 109/L; platelet count (PLT) ≥ 100 × 109/L, hemoglobin (Hb) ≥ 90 g/L (2). Liver function: aspartate transferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN; ; serum total bilirubin (TBIL) ≤ 1.5 x ULN (total bilirubin ≤ 3.0 mg/dL in patients with confirmed Gilbert syndrome); albumin (ALB) ≥ 3 g/dL; (3). Renal function: creatinine clearance rate (CrCl) ≥ 45 mL/minute (by Cockcroft-Gault formula); (4). Coagulation: international normalized ratio (INR) ≤ 1.5, activated partial thromboplastin time (APTT) ≤ 1.5 x ULN; (5). Cardiac color ultrasound: left ventricular ejection fraction (LVEF) ≥ 50% 9.Female patients of childbearing potential must have a negative pregnancy test (serum or urine) within 72 hours prior to receiving the study drug. Reliable contraception, such as intrauterine devices, oral contraceptives, or condoms, must be used during the trial and for 90 days following the final dose. Male participants with partners of childbearing potential must use condoms during the trial and for 30 days following the study's conclusion.

Exclusion Criteria:

1. Histologically or cytologically confirmed mixed small cell and non-small cell lung cancer, large cell neuroendocrine carcinoma, or sarcomatoid carcinoma.
2. Patients with EGFR gene mutations or ALK/ROS1 gene rearrangements.
3. Prior systemic anti-tumor therapy for NSCLC (including investigational agents in clinical trials) or prior thoracic radiotherapy.
4. History of other malignancies within 3 years prior to the first dose, except for those cured by local therapy (e.g., basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the cervix, etc.).
5. Presence of any of the following cardiovascular or cerebrovascular diseases or risk factors: (1) Myocardial infarction, unstable angina, acute or persistent myocardial ischemia, New York Heart Association (NYHA) Class III or IV heart failure, symptomatic or poorly controlled severe arrhythmia, cerebrovascular accident, transient ischemic attack, or other serious cardiovascular or cerebrovascular events occurring within 6 months prior to the first dose; (2) History of myocardial diseases, including myocarditis, primary cardiomyopathy, or specific cardiomyopathy; (3) Any deep vein thrombosis (DVT) within 3 months prior to the first dose (enrollment is permitted if DVT has been stabilized with low molecular weight heparin or equivalent therapy for ≥2 weeks), peripheral arterial thromboembolic events, pulmonary embolism, or other serious thromboembolic events; (4) Presence of aortic aneurysm, aortic dissection, or other major vascular diseases that are potentially life-threatening or requiring surgical intervention within 6 months prior to the first dose
6. Uncontrolled systemic diseases as judged by the investigator, including but not limited to: (1) Poorly controlled diabetes mellitus (fasting blood glucose ≥10 mmol/L on two consecutive measurements); (2) Poorly controlled hypertension (systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg).
7. History of (non-infectious) interstitial lung disease (ILD) or non-infectious pneumonitis requiring steroid therapy; current ILD or non-infectious pneumonitis; or suspected ILD or non-infectious pneumonitis at screening that cannot be excluded by imaging.
8. Clinically significant pulmonary impairment caused by pulmonary comorbidities, including but not limited to any underlying pulmonary conditions (e.g., pulmonary embolism within 3 months prior to the first dose, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, etc.) or any autoimmune, connective tissue, or inflammatory diseases potentially involving the lungs (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc.).
9. Active chronic inflammatory bowel disease, gastrointestinal obstruction, severe ulceration, gastrointestinal perforation, intra-abdominal abscess, or acute gastrointestinal hemorrhage.
10. Active autoimmune diseases requiring systemic therapy within the past 2 years (including but not limited to autoimmune hepatitis, uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism, etc.); systemic therapy is defined as disease-modifying agents, immunosuppressants, or systemic corticosteroids (>10 mg/day prednisone or equivalent). Note: Hormone replacement therapies, such as thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency, are not considered systemic therapies. Patients who have received systemic corticosteroid therapy at a dose of >10 mg/day prednisone or equivalent, or other immunosuppressive medications within 2 weeks prior to the first dose are excluded.
11. Known active pulmonary tuberculosis (TB). Subjects with suspected active TB must undergo clinical evaluation to rule out the diagnosis.
12. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
13. Active hepatitis B [hepatitis B surface antigen (HBsAg) positive with HBV-DNA ≥500 IU/mL or above the lower limit of detection (whichever is higher)] or active hepatitis C [hepatitis C antibody positive with HCV-RNA above the lower limit of detection]. Note: HBsAg-positive subjects are required to receive anti-HBV antiviral therapy throughout the study treatment period.
14. Known positive human immunodeficiency virus (HIV) test result or history of acquired immunodeficiency syndrome (AIDS); known active syphilis infection.
15. Known hypersensitivity to disitamab vedotin, toripalimab, platinum-based agents, pemetrexed, paclitaxel, docetaxel, or any of their excipients (including polysorbate-20); known history of severe hypersensitivity reactions to other monoclonal antibodies.
16. Major surgical procedure within 4 weeks prior to the first dose, or anticipated need for major surgery during the study period.
17. Serious infection within 4 weeks prior to the first dose, including but not limited to infections with complications requiring hospitalization, sepsis, or severe pneumonia; active infection requiring systemic anti-infective therapy within 2 weeks prior to the first dose.
18. Receipt of non-specific immunomodulatory therapy (including but not limited to interferon, IL-2) or approved traditional Chinese medicine preparations with anti-tumor indications within 2 weeks prior to the first dose.
19. Administration of a live vaccine within 30 days prior to the first dose, or planned live vaccination during the study period.
20. Rapid disease deterioration observed during the screening period prior to the first dose, such as significant decline in performance status.
21. Pregnant or breastfeeding women.
22. Presence of local or systemic diseases attributable to non-malignant causes, or conditions secondary to the tumor, that may confer significant medical risk and/or uncertainty in survival assessment, such as leukemoid reaction or cachexia.
23. Documented severe dry eye syndrome, severe meibomian gland disease and/or blepharitis, or history of corneal disease that impairs delayed corneal healing.
24. Any condition that, in the opinion of the investigator, may interfere with the evaluation of the investigational drug, compromise patient safety, or confound the interpretation of study results; or any other condition deemed by the investigator to render the subject unsuitable for participation in this study.