A Prospective Phase II Clinical Trial Evaluating the Efficacy and Safety of Adebrelimab in Combination With Trastuzumab Rezetecan for Patients With Stage III Unresectable HER2-Positive NSCLC

A Prospective Phase II Clinical Trial Evaluating the Efficacy and Safety of Adebrelimab in Combination With Trastuzumab Rezetecan for Patients With Stage III Unresectable HER2-Positive NSCLC

This is a single-arm, open-label, multicenter phase II investigator-initiated trial. The study aims to explore the efficacy and safety of Adebrelimab plus Trastuzumab rezetecan induction therapy in patients with stage III unresectable HER2-altered non-small cell lung cancer (NSCLC). Eligible patients receive 3-4 cycles Q3W induction combination therapy. After induction, patients will receive radical surgery or concurrent chemoradiotherapy via MDT evaluation, followed by consolidation therapy and long-term survival follow-up. The primary endpoint is objective response rate (ORR) assessed per RECIST v1.1. Secondary endpoints include surgical conversion rate, major pathological response (MPR), event-free survival (EFS), overall survival (OS), and safety profiles.

Inclusion Criteria:

• Aged 18-75 years, male or female.

• Histologically or cytologically confirmed stage III unresectable NSCLC per AJCC 9th edition, judged unresectable by institutional MDT team.

• Confirmed HER2 alteration: HER2 mutation/amplification detected by tissue NGS, or HER2 protein overexpression (IHC 2+ or 3+).

• No prior systemic anti-tumor therapy for NSCLC; prior anti-tumor Chinese herbal medicine allowed if ≥2 weeks washout before first dose.

• At least 1 measurable target lesion per RECIST v1.1.

• ECOG performance status 0 or 1.

• Able to provide tumor tissue specimen (archival ≤6 months or newly biopsied non-irradiated lesion).

• FEV1 >1.0 L and FEV1% predicted >40% within past 3 months.

• Adequate organ function within 7 days before first dose (no blood product/G-CSF support within 14 days):

  • Hematology: WBC ≥3.0×10⁹/L, ANC ≥1.5×10⁹/L, PLT ≥100×10⁹/L, Hb ≥90g/L
  • Liver: AST/ALT ≤2.5×ULN (≤5×ULN for liver metastasis), TBIL ≤1.5×ULN
  • Renal: Serum Cr ≤1.5×ULN or CrCl ≥50 mL/min
  • Cardiac: LVEF ≥50% by echocardiogram

• Fertile male/female participants must use effective contraception during treatment and 6 months after last dose; female participants non-lactating, negative serum HCG within 14 days pre-first dose.

• Voluntarily sign written informed consent, good compliance for follow-up.

Exclusion Criteria:

• Mixed small cell/large cell neuroendocrine/sarcomatoid NSCLC histology.
• Concurrent other actionable driver gene alterations (EGFR, ALK, MET, BRAF, RET etc.) besides HER2.
• Past or concurrent other malignant tumor (except fully resected cancer ≥5 years without active treatment).
• Prior thoracic radiotherapy.
• Major surgery within 28 days or minor invasive surgery within 7 days before first dose.
• HIV infection, active hepatitis B/C, organ transplant history, congenital/acquired immunodeficiency.
• Systemic immune modulators (thymosin, interferon, IL-2) within 4 weeks pre-enrollment.
• Uncontrolled severe cardiovascular disease, unstable angina or intervention-required ventricular arrhythmia within 1 month.
• Confirmed or suspected interstitial lung disease, severe baseline pulmonary dysfunction interfering with lung toxicity monitoring.
• Active uncontrolled ≥2 grade infection within 2 weeks before enrollment.
• Active tuberculosis under treatment.
• Known hypersensitivity to any component of study drugs or other monoclonal antibodies/fusion proteins.
• Any condition judged by investigator to compromise participant safety or trial compliance.