Efficacy and Safety of T-DXd in HER2-mutant Advanced Lung Cancer Patients With Asymptomatic Brain Metastases

Sponsor
Yonsei University
Study ID
NCT06250777
Phase
PHASE2
Status
Enrolling By Invitation

Conditions

Eligibility Criteria

Sex
ALL
Age
20 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • Trastuzumab deruxtecan — DRUG
    Chemotherapy : Every 3weeks as below until withdrawal of patient consent, progression, death or loss to follow-up: \- Trastuzumab Deruxtecan (T-DXd) 5.4mg/kg

Study Details

'1. Objective * Primary objective \- Median Intracranial Progression-free survival(icPFS) as defined by RANO(Response Assessment in Neuro-Oncology) criteria * Secondary objective * Progression free survival(PFS) as defined by RECIST 1.1 * Median Intracranial progression free survival(icPFS) as defined by RECIST 1.1 * Intracranial objective response rate(icORR) as defined by RECIST 1.1 * Overall response rate(ORR) as defined by RECIST 1.1 * Duration of response(DoR) as defined by RECIST 1.1 * Disease control rate (DCR) defined by RECIST 1.1 * Overall survival (OS) ; The time from the date of inital IP administration to death due to any cause * Pattern of Progression ; Site of next progression * Safety objective * To evaluate the safety and tolerability of Trastuzumab deruxtecan.(AEs/SAEs, Vital signs, Collection of clinical chemistry/haematology parameters, ECGs) 2. Exploratory Purpose * To identify mechanisms of adaptive resistance using Guardant 360 panel. To conduct NGS using Guardant 360 panel in serial plasma collection before treatment and at the time of progression. * To identify the profiling of interstitial lung disease (ILD) after treatment of T-DXd. To perform the baseline and follow-up PFT. To perform high-resolution chest CT to evaluate for ILD by radiologic expert. To evaluate cytokine level in serially collected plasma (every 6 weeks for the first 24 weeks and then every 12 weeks). The investigators recommend doing one HRCT at baseline and a second one in the event of ILD. 3\. Background Human epidermal growth factor receptor 2 (HER2, ERBB2)-activating mutations occur in 2% of lung cancers as a distinct molecular target. HER2-targeted therapy is standard of care for HER2-mutation positive non-small cell lung cancer (NSCLC). Trastuzumab deruxtecan (T-DXd, DS-8201, Enhertu) is a novel antibody drug conjugate that is comprised of 3 components: a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab; a topoisomerase I inhibitor payload, an exatecan derivative; and a tetrapeptide-based cleavable linker. Recently, T-DXd induced a confirmed objective response rate (ORR) of almost 61% and a durable benefit in heavily pre-treated patients with advanced HER2-positive breast cancer, according to results from the phase II DESTINY-Breast01 trial. In addition, the DESTINY-Gastric trial showed the superiority of T-DXd compared with standard chemotherapy in terms of response rate and progression-free and overall survival in this setting. Altogether, T-DXd received breakthrough therapy designation and orphan drug designation in gastric cancer, and approval for the treatment of advanced HER2-positive breast cancer. Recently, T-DXd showed durable systemic disease control along with CNS response. Ongoing trials are assessing the activity of T-DXd in patients with breast cancer and active brain metastases. T-DXd has been approved in the US for the treatment of adult patients with unresectable or metastatic NSCLC whose tumours have activating HER2 mutations, as detected by a FDA-approved test, and who have received a prior systemic therapy. The accelerated approval by the FDA was based on the results from the DESTINY-Lung02 Phase II trial. An interim efficacy analysis in a pre-specified patient cohort showed T-DXd (5.4mg/kg) demonstrated a confirmed ORR of 57.7% (n=52; 95% CI 43.2-71.3), as assessed by blinded independent central review, in patients with previously treated unresectable or metastatic non-squamous HER2-mutant NSCLC. Complete responses (CR) were seen in 1.9% of patients and partial responses (PR) in 55.8% of patients with a median DoR of 8.7 months (95% CI 7.1-NE).

Key Dates

Start date
Jul 11, 2024
Status verified
Feb 2026
Primary completion
Dec 31, 2026
Completion
Dec 31, 2026

Study Design

Enrollment
27 participants (estimated)
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT

Arms

  • Experimental: Trastuzumab Deruxtecan

Primary Outcome Measure

Median Intracranial Progression-free survival(icPFS) as defined by RANO criteria [ Time Frame: When all enrolled patients have completed 12 months of follow-up ]

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