Non-Small Cell Lung Cancer
Conditions
Brief summary
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.
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.
Interventions
DRUGTrastuzumab 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.
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.
DRUGAdebrelimab
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.
Sponsors
Ming Chen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Patients will be randomized in a 1:1:1 ratio to three parallel arms: Arm A (Trastuzumab Rezetecan + Adebrelimab), Arm B (Trastuzumab Rezetecan monotherapy), and Arm C (Adebrelimab monotherapy).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Assessed up to approximately 36 months. | Defined as the time from randomization to disease progression or death from any cause, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Assessed up to approximately 60 months. | Defined as the time from randomization to death from any cause. |
| Objective Response Rate (ORR) | Assessed up to approximately 36 months. | 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. |
| Duration of Response (DoR) | Assessed up to approximately 36 months. | 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. |
| Disease Control Rate (DCR) | Assessed up to approximately 36 months. | 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. |
| Time to Death or Distant Metastasis (TTDM) | Assessed up to approximately 36 months. | Defined as the time from randomization to the first occurrence of distant metastasis or death from any cause. |
| Progression-Free Survival Rate at 6 Months | 6 months after randomization. | Kaplan-Meier estimate of the percentage of participants alive without disease progression at 6 months after randomization. |
| Progression-Free Survival Rate at 12 Months | 12 months after randomization. | Kaplan-Meier estimate of the percentage of participants alive without disease progression at 12 months after randomization. |
| Overall Survival Rate at 12 Months | 12 months after randomization. | Kaplan-Meier estimate of the percentage of participants alive at 12 months after randomization. |
| Overall Survival Rate at 24 Months | 24 months after randomization. | Kaplan-Meier estimate of the percentage of participants alive at 24 months after randomization. |
| Incidence of Adverse Events (AEs) | Assessed up to approximately 36 months. | AEs graded by CTCAE version 6.0 |
Contacts
CONTACTMing Chen, MD
CONTACTChenfei Wu, MD
Outcome results
None listed