Toripalimab Plus Sacituzumab Tirumotecan as Neoadjuvant Therapy for Resectable NSCLC

Inclusion Criteria:

• Signed informed consent obtained before any study procedure.
• Age 18 to 75 years, male or female.
• Histologically/cytologically confirmed, treatment-naive, resectable or potentially resectable NSCLC: stage II-IIIA and selected IIIB (T3N2, T4N2) per IASLC/UICC TNM 9th edition.
• Disease staged as cTNM by PET-CT or by neck/chest/abdominal/pelvic CT plus whole-body bone scan and brain MRI.
• Multidisciplinary team including thoracic surgeon judges lesion resectable or potentially resectable.
• At least one measurable target lesion per RECIST 1.1.
• ECOG performance status 0-1.
• Adequate organ function (baseline, no transfusion, rh-EPO, or G-CSF within 2 weeks before first dose): neutrophils ≥1.5 ×10^9/L; platelets ≥100 ×10^9/L; hemoglobin ≥9 g/dL.
• AST, ALT, ALP ≤2.5 × ULN; TBil ≤1.5 × ULN.
• For liver metastases: AST/ALT ≤5 × ULN; TBil ≤2 × ULN.
• For liver or bone metastases: ALP ≤5 × ULN.
• Creatinine clearance (Cockcroft-Gault) ≥60 mL/min.
• INR, APTT, PT ≤1.5 × ULN.
• TSH within normal range; if TSH abnormal but T3 and free T4 normal, eligible.
• Women of childbearing potential must have a negative pregnancy test within 7 days before first dose and use effective contraception during treatment and until 12 months after last dose; men with partners of childbearing potential must use effective contraception during treatment and until 12 months after last dose.

Exclusion Criteria:

• Neuroendocrine histology component in tumor pathology.
• Known EGFR sensitizing mutation or ALK fusion (for non-squamous NSCLC, EGFR/ALK status must be determined).
• Other malignancy within 5 years, except those with clinically negligible metastatic risk and curative treatment intent (e.g., adequately treated carcinoma in situ as per protocol examples).
• Severe or uncontrolled comorbidities, including symptomatic cerebrovascular events or liver disease at Child-Pugh grade ≥A.
• History of allogeneic stem cell transplantation or solid organ transplantation.
• Severe dry eye syndrome, severe meibomian gland dysfunction, severe blepharitis, or corneal disorders that may delay corneal healing.
• History of interstitial lung disease requiring steroids, or active ILD.
• HIV positive or diagnosed AIDS.
• Active tuberculosis.
• Uncontrolled active HBV infection (HBsAg positive with HBV-DNA above local upper limit of normal). HBV-DNA must be <500 IU/mL within 28 days before randomization/inclusion.
• Active HCV infection (HCV antibody positive and HCV RNA positive).
• Known hypersensitivity to toripalimab or sacituzumab tirumotecan (or excipients).
• Live vaccine within 30 days before first dose (except inactivated vaccines allowed where specified by protocol, including local policy).
• Any systemic or local anticancer treatment before first study treatment.
• Use of traditional Chinese medicines with anticancer indication within 7 days before first dose, or need to continue such drugs during study.
• Other investigational drug not discontinued for at least 5 half-lives or 2 months (whichever is longer) before first dose.
• Any known or suspected autoimmune disease or immunodeficiency, except primary hypothyroidism (stable, not requiring hormones, or stable on physiologic hormone replacement) and stable type 1 diabetes mellitus with controlled blood glucose.
• Medical or psychiatric conditions likely to cause premature discontinuation or compromise safety, sampling, or follow-up, including severe social or compliance risks.
• Pregnancy or breastfeeding; unwillingness to use effective contraception as specified.
• Any other condition considered unsuitable by investigator.