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

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.