Trastuzumab Rezetecan and Adebrelimab, Alone or in Combination, After Chemoradiotherapy for HER2-Altered Unresectable Stage III Lung Cancer

A Randomized, Open-label, Multicenter, Phase II Study of Trastuzumab Rezetecan With Adebrelimab, Trastuzumab Rezetecan Alone and Adebrelimab Alone as Consolidation Therapy in Patients With Unresectable Stage III Non-Small Cell Lung Cancer Harboring HER2 Alterations Without Progression After Definitive Chemoradiotherapy

A randomized phase II study to assess the efficacy and safety of Trastuzumab Rezetecan and/or Adebrelimab as consolidation therapy following chemoradiotherapy in patients with unresectable stage III HER2-altered NSCLC.

Study Overview

• Status: Not yet recruiting
• Conditions: Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: Trastuzumab Rezetecan (SHR-A1811) + Adebrelimab; Drug: Trastuzumab Rezetecan (SHR-A1811); Drug: Adebrelimab

Detailed Description

This is a randomized, open-label, multi-center phase II study evaluating the efficacy and safety of consolidation therapy with Trastuzumab Rezetecan combined with Adebrelimab versus Trastuzumab Rezetecan monotherapy versus Adebrelimab monotherapy in patients with unresectable stage III NSCLC harboring HER2 alterations (mutation or overexpression) who have not progressed after definitive concurrent or sequential chemoradiotherapy. Eligible patients will be randomized in a 1:1:1 ratio to receive either combination therapy, SHR-A1811 alone, or Adebrelimab alone for up to 12 months. The primary endpoint is progression-free survival (PFS) per RECIST v1.1.

• Study Type: Interventional
• Enrollment (Estimated): 105
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ming Chen, MD; Phone Number: +86 020-87345647; Email: chenming@sysucc.org.cn
• Study Contact Backup: Name: Chenfei Wu, MD; Phone Number: +86 020-87345647; Email: wucf@sysucc.org.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥18 years.
2. ECOG performance status 0-1.
3. Histologically or cytologically confirmed Non-Small Cell Lung Cancer (NSCLC).
4. Radiologically confirmed unresectable Stage III NSCLC per AJCC 9th edition.
5. Pathologically confirmed HER2 mutation or HER2 overexpression (IHC 2+ or 3+).
6. Life expectancy ≥3 months.
7. Completed at least two cycles of platinum-based chemotherapy (concurrent or sequential) with definitive radiotherapy. Consolidation chemotherapy after radiotherapy is not permitted; chemotherapy with or without immunotherapy before concurrent chemoradiotherapy is permitted.
8. Total radiotherapy dose 60 Gy ± 10% (54-66 Gy) using IMRT (preferred) or 3D-CRT, with acceptable dosimetric constraints.
9. Adequate organ and bone marrow function.
10. Negative pregnancy test for women of childbearing potential within 7 days prior to first dose. Willing to use effective contraception during the study and for 180 days after the last dose.
11. Signed informed consent form (ICF).

Exclusion Criteria:

1. Known EGFR-activating mutations or ALK fusions.
2. Presence of other driver gene mutations with approved targeted therapies available.
3. Mixed SCLC and NSCLC, large cell neuroendocrine carcinoma, or sarcomatoid carcinoma.
4. Prior treatment with HER2-targeted ADCs or HER2 TKIs.
5. Malignant pleural effusion, pericardial effusion, or ascites.
6. Participation in another clinical trial within 4 weeks or 5 half-lives prior to first dose.
7. Systemic immunosuppressive therapy within 2 weeks prior to first dose.
8. Known HIV infection.
9. Active hepatitis B (HBsAg positive with detectable HBV-DNA and ALT > ULN) or active hepatitis C.
10. Active autoimmune disease requiring systemic treatment.
11. Other malignancies within 5 years, except adequately treated cervical carcinoma in situ, basal/squamous cell skin carcinoma, localized prostate cancer, or ductal carcinoma in situ.
12. Active or history of Grade ≥2 radiation pneumonitis per RTOG/EORTC, or symptomatic interstitial lung disease. Participants with grade 2 radiation pneumonitis that resolves to grade 1 or lower within 14 days without systemic glucocorticoid treatment may undergo screening if the investigator considers there to be no risk of recurrence.
13. Significant cardiovascular disease.
14. Severe infection within 4 weeks prior to first dose.
15. Prior or planned allogeneic bone marrow or solid organ transplantation.
16. Live attenuated vaccine within 28 days prior to first dose or planned during study. Pregnancy or breastfeeding.
17. Known hypersensitivity to Adebrelimab, Trastuzumab Rezetecan, or any excipients.
18. Known history of psychotropic substance abuse, alcohol abuse, or illicit drug use.
19. Any condition that might impair the subject's ability to comply with study requirements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A (Combination Therapy); Drug: Trastuzumab Rezetecan + Adebrelimab	Drug: Trastuzumab Rezetecan (SHR-A1811) + Adebrelimab; Trastuzumab Rezetecan (4.8mg/kg, iv, d1, Q3W) and Adebrelimab (1200mg, iv, d1, Q3W). Treatment will continue for up to 12 months or until disease progression, unacceptable toxicity, or other criteria for treatment discontinuation are met.
Experimental: Arm B (Targeted Monotherapy); Drug: Trastuzumab Rezetecan	Drug: Trastuzumab Rezetecan (SHR-A1811); Trastuzumab Rezetecan (4.8mg/kg, iv, d1, Q3W). Treatment will continue for up to 12 months or until disease progression, unacceptable toxicity, or other criteria for treatment discontinuation are met.
Experimental: Arm C (Immunotherapy Monotherapy); Drug: Adebrelimab	Drug: Adebrelimab; Adebrelimab (1200mg, iv, d1, Q3W). Treatment will continue for up to 12 months or until disease progression, unacceptable toxicity, or other criteria for treatment discontinuation are met.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	Defined as the time from randomization to disease progression or death from any cause, whichever occurs first.	Assessed up to approximately 36 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Defined as the time from randomization to death from any cause.	Assessed up to approximately 60 months.
Objective Response Rate (ORR)	Defined as the proportion of participants whose best overall response (BOR) is complete response (CR) or partial response (PR), as assessed according to RECIST v1.1.	Assessed up to approximately 36 months.
Duration of Response (DoR)	Defined as the time from the first documented response (CR or PR) to the first documented disease progression (PD) or death from any cause, whichever occurs first.	Assessed up to approximately 36 months.
Disease Control Rate (DCR)	Defined as the proportion of participants who achieve complete response (CR), partial response (PR), or stable disease (SD) following treatment, as assessed according to RECIST v1.1.	Assessed up to approximately 36 months.
Time to Death or Distant Metastasis (TTDM)	Defined as the time from randomization to the first occurrence of distant metastasis or death from any cause.	Assessed up to approximately 36 months.
Progression-Free Survival Rate at 6 Months	Kaplan-Meier estimate of the percentage of participants alive without disease progression at 6 months after randomization.	6 months after randomization.
Progression-Free Survival Rate at 12 Months	Kaplan-Meier estimate of the percentage of participants alive without disease progression at 12 months after randomization.	12 months after randomization.
Overall Survival Rate at 12 Months	Kaplan-Meier estimate of the percentage of participants alive at 12 months after randomization.	12 months after randomization.
Overall Survival Rate at 24 Months	Kaplan-Meier estimate of the percentage of participants alive at 24 months after randomization.	24 months after randomization.
Incidence of Adverse Events (AEs)	AEs graded by CTCAE version 6.0	Assessed up to approximately 36 months.

Other Outcome Measures

Outcome Measure	Time Frame
Patients reported disease-related symptoms and HRQoL by the EORTC QLQ-C30 questionnaires	Assessed up to approximately 36 months.
Patients reported disease-related symptoms and HRQoL by the EORTC QLQ-LC13 questionnaires	Assessed up to approximately 36 months.

Collaborators and Investigators

• Sponsor: Ming Chen

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2031

Study Registration Dates

• First Submitted: September 13, 2026
• First Submitted That Met QC Criteria: September 17, 2026
• First Posted (Actual): September 23, 2026

Study Record Updates

• Last Update Posted (Actual): September 23, 2026
• Last Update Submitted That Met QC Criteria: September 17, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: MA-NSCLC-II-064

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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