Toripalimab Plus Sacituzumab Tirumotecan as Neoadjuvant Therapy for Resectable NSCLC

This prospective, multicenter, single-arm Phase II investigator-initiated trial evaluates neoadjuvant sacituzumab tirumotecan (SKB264), a TROP2-directed antibody-drug conjugate, plus the PD-1 antibody toripalimab in treatment-naive adults with resectable or potentially resectable, driver-negative NSCLC. Participants have stage II-IIIA or selected IIIB disease (T3N2 or T4N2). Sacituzumab tirumotecan 5 mg/kg and toripalimab 3 mg/kg are administered intravenously on Day 1 every 2 weeks for up to 6 cycles. Surgery is planned 4-6 weeks after the final neoadjuvant dose when the participant remains operable following multidisciplinary assessment. Tumor response is assessed using RECIST 1.1. Safety is assessed using NCI CTCAE version 5.0, including adverse events, serious adverse events, perioperative complications, and surgery delays or cancellations. The primary endpoint is pathologic complete response, defined as no residual viable tumor cells in the resected primary tumor and all resected lymph nodes. Major pathologic response is defined as residual viable tumor of 10% or less.

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.