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

4\. Hypothesis T-DXd is actually approved for previously treated HER2m metastatic NSCLC patients but there is a gap of knowledge about intracranial response on T-DXd in NSCLC patients with brain metastasis. Therefore, in this study, the investigators aim to focus on the intracranial treatment outcome in HER2 mut NSCLC patients with brain metastasis. Additionally, T-DXd has been shown to harbor more efficacy in HER2-mutated patients rather than HER2-overexpressing NSCLC patients. However, severe life-threatening interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with T-DXd. A recent findings demonstrated that ILD occurred in less than 16% of patients with HER2-positive metastatic breast cancer following treatment with T-DXd. Although the majority of these cases were grade 1 or 2, ILD remains an important risk, which highlights the need for close monitoring and early identification of ILD. Several cytokines, which activate JAK/STAT pathway, such as IL-4, IL-13, IL-6, IL-11 and IL-31, are implicated in the pathogenicity of ILD. However, there is no prospective study which evaluated the association of cytokines with the onset of drug-induced ILD. Given the activity of T-DXd in HER2-mutant lung cancer, the investigators hypothesized that HER2-mutated tumors harbor susceptibility to HER2 ADCs and designed this phase 2 clinical trial of T-DXd in NSCLC HER2-mutant patients with brain metastases. 5\. Study procedure This is Phase 2, Single arm, multi-centres', Open labelled study to assess efficacy and safety of T-DXd in HER2-mutant advanced lung cancer patients with asymptomatic brain metastases. Advanced or metastatic non-squamous NSCLC with HER2 mutation regardless of HER2 expression with asymptomatic brain metastasis at baseline will be treated with T-DXd every 3weeks. * HER2 activating mutation is based on local assessment of archival tissue or plasma ctDNA analysis. HER2 activating mutation are included exon 19 or 20. * For resistance mechanism analysis, the investigators plan to conduct serial plasma collection from patients receiving T-DXd (before treatment and at the time of progression) to identify mechanisms of adaptive resistance using Guardant 360 panel. * To identify the profiling of interstial lung disease (ILD) after treatment of T-DXd, the investigators plan to perform the baseline and follow-up PFT. The high-resolution CT will be evaluated for ILD by radiologic expert. The investigators serially collected plama for evaluation of cytokine (every 6 weeks for the first 24 weeks and then every 12 weeks). Pulmonologist, expert for ILD, will involve the ILD management when the patients show the ILD pattern and the symptoms suspicious for ILD. \<Detailed Description\> 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) * 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). We recommend doing one HRCT at baseline and a second one in the event of ILD. 2. 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). 3. Hypothesis T-DXd is actually approved for previously treated HER2m metastatic NSCLC patients but there is a gap of knowledge about intracranial response on T-DXd in NSCLC patients with brain metastasis. Therefore, in this study, we aim to focus on the intracranial treatment outcome in HER2 mut NSCLC patients with brain metastasis. Additionally, T-DXd has been shown to harbor more efficacy in HER2-mutated patients rather than HER2-overexpressing NSCLC patients. However, severe life-threatening interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with T-DXd. A recent findings demonstrated that ILD occurred in less than 16% of patients with HER2-positive metastatic breast cancer following treatment with T-DXd. Although the majority of these cases were grade 1 or 2, ILD remains an important risk, which highlights the need for close monitoring and early identification of ILD. Several cytokines, which activate JAK/STAT pathway, such as IL-4, IL-13, IL-6, IL-11 and IL-31, are implicated in the pathogenicity of ILD. However, there is no prospective study which evaluated the association of cytokines with the onset of drug-induced ILD. Given the activity of T-DXd in HER2-mutant lung cancer, we hypothesized that HER2-mutated tumors harbor susceptibility to HER2 ADCs and designed this phase 2 clinical trial of T-DXd in NSCLC HER2-mutant patients with brain metastases. 4. Study procedure This is Phase 2, Single arm, multi-centres', Open labelled study to assess efficacy and safety of T-DXd in HER2-mutant advanced lung cancer patients with asymptomatic brain metastases. Advanced or metastatic non-squamous NSCLC with HER2 mutation regardless of HER2 expression with asymptomatic brain metastasis at baseline will be treated with T-DXd every 3weeks. * HER2 activating mutation is based on local assessment of archival tissue or plasma ctDNA analysis. HER2 activating mutation are included exon 19 or 20. * For resistance mechanism analysis, we plan to conduct serial plasma collection from patients receiving T-DXd (before treatment and at the time of progression) to identify mechanisms of adaptive resistance using Guardant 360 panel. * To identify the profiling of interstial lung disease (ILD) after treatment of T-DXd, we plan to perform the baseline and follow-up PFT. The high-resolution CT will be evaluated for ILD by radiologic expert. We serially collected plama for evaluation of cytokine (every 6 weeks for the first 24 weeks and then every 12 weeks). Pulmonologist, expert for ILD, will involve the ILD management when the patients show the ILD pattern and the symptoms suspicious for ILD.