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.

Study Overview

• Status: Not yet recruiting
• Conditions: NSCLC
• Intervention / Treatment: Drug: Adebrelimab; Drug: Trastuzumab rezetecan

• Study Type: Interventional
• Enrollment (Estimated): 37
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Meng Wang Meng Wang; Phone Number: 18622221623; Email: 18622221623@pm.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Experimental: Adebrelimab + Trastuzumab rezetecan Induction Therapy

Drug: Adebrelimab; 1200mg intravenous infusion on Day 1 of every 21-day cycle for 3-4 induction cycles; consolidation therapy after local treatment as physician discretion. Infusion duration 30-60 minutes.; Drug: Trastuzumab rezetecan; 3.2mg/kg intravenous infusion on Day 1 of every 21-day cycle for 3-4 induction cycles; fixed dose 408mg if body weight ≥85kg. First infusion over 90 mins, subsequent cycles 60 mins if well tolerated.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Proportion of participants achieving Complete Response (CR) or Partial Response (PR) after 3-4 cycles induction therapy, assessed per RECIST v1.1 by investigators	End of Cycle 3/Cycle 4 induction (each cycle 21 days). Surgery-eligible patients assess tumor 6-8 weeks after Cycle3 last dose; others evaluate at Cycle4 end, ±7-day imaging window.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Surgical Conversion Rate	Percentage of subjects receiving R0 radical pulmonary resection after MDT re-evaluation post induction	Within 6 to 8 weeks after the last induction study drug infusion (42-56 days post final induction dose)
Major Pathological Response (MPR) Rate	Proportion of surgical patients with ≤10% viable tumor cells in resected primary tumor specimen (central blinded pathology review)	Within 4 weeks after curative lung resection (pathology report completion window)
Event-Free Survival (EFS)	Time from first study drug dose to disease progression, local recurrence, distant metastasis, or death from any cause	Up to 36 months after the first dose of study treatment (3-year full survival follow-up)
Overall Survival (OS)	OS defined as time from first dose to all-cause death; survival rate calculated at fixed time points	12 months, 18 months, 24 months, and 36 months after the first dose of study treatment
Safety Profile (Treatment-Related Adverse Events)	Incidence and grade of all adverse events, ≥3 grade AEs, serious adverse events (SAE), immune-related AEs, interstitial lung disease graded per NCI CTCAE v6.0	From the date of signed informed consent through 30 days after the last study treatment infusion; long-term safety follow-up continues up to 36 months post first dose for delayed irAEs.

Collaborators and Investigators

• Sponsor: Tianjin Medical University Cancer Institute and Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): August 20, 2026
• Primary Completion (Estimated): August 30, 2027
• Study Completion (Estimated): August 30, 2029

Study Registration Dates

• First Submitted: August 6, 2026
• First Submitted That Met QC Criteria: August 19, 2026
• First Posted (Actual): August 21, 2026

Study Record Updates

• Last Update Posted (Actual): August 21, 2026
• Last Update Submitted That Met QC Criteria: August 19, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: NSCLC-HER2-II-001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No