Efficacy and Safety of T-DXd in HER2-mutant Advanced Lung Cancer Patients With Asymptomatic Brain Metastases - Trial NCT06250777

Timeline & Enrollment

Primary Outcome

Median Intracranial Progression-free survival(icPFS) as defined by RANO criteria

Summary

'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).

ICD-10 Classifications