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

NCT06250777 | Enrolling By Invitation Phase 2

• 1 other identifier: 4-2023-1364
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief 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).

Conditions

Non Small Cell Lung Cancer

Keywords

Non small cell lung cancer(NSCLC); Human epidermal growth factor receptor 2 (HER-2)

Outcome Measures

Primary Outcomes (1)

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

  When all enrolled patients have completed 12 months of follow-up

Secondary Outcomes (9)

• Progression free survival as defined by RECIST 1.1

  When all enrolled patients have completed 12 months of follow-up

• Median Intracranial Progression-free survival as defined by RECIST 1.1

  When all enrolled patients have completed 12 months of follow-up

• Intracranial objective response rate(icORR) as defined by RECIST 1.1

  When all enrolled patients have completed 12 months of follow-up

• Overall response rate as defined by RECIST 1.1

  When all enrolled patients have completed 12 months of follow-up

• Duration of response as defined by RECIST 1.1

  When all enrolled patients have completed 12 months of follow-up

Study Arms (1)

Trastuzumab Deruxtecan

EXPERIMENTAL

Drug: Trastuzumab deruxtecan

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

Trastuzumab Deruxtecan

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 20 or more than 20 years-old
• Histologically confirmed, "locally advanced and unresectable NSCLC not amenable to treatment with curative intent (surgery or chemoradiotherapy) or recurrent or de novo-metastatic non-squamous NSCLC (according to Version 8 of the IASLC Staging Manual in Thoracic Oncology) locally advanced or metastatic non-squamous NSCLC (Participants with mixed histology are eligible if adenocarcinoma is the predominant histology).
• Activating HER2-mutation documented by NGS in tissue or plasma (include activating HER2 mutation in exon 19 or 20, i.e. , Exon 20: A775\_G776insYVMA insertion/duplication; point mutations, L755S and G776C; transmembrane and the juxtamembrane domains G660D, R678Q, E693K and Q709Ldocumented mutation) regardless of HER2 expression.
• HER2 expression on tissue based on IHC (IHC 1+, 2+, or 3+)
• Asymptomatic brain metastases at baseline without local therapy for brain metastasis or stable brain metastasis after local therapy (WBRTx, SRS, GKS etc), which is defined as patients who are not requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
• Prior failure on any systemic chemotherapy platinum-based chemotherapy
• Measurable disease according to RECIST version 1.1Response Assessment in Neuro-Oncology Criteria (RANO)
• LVEF ≥ 50% within 28 days before randomization/enrollmentfirst dose .
• Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1.
• Table 1 Parameters for Adequate Organ and Bone Marrow Function Adequate bone marrow function Platelet Count ≥ 100000/mm3. Haemoglobin ≥ 9.0 g/dL Absolute neutrophil count ≥ 1500/mm3 Adequate hepatic function Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3×ULN (\< 5×ULN in participants with liver metastases) Total Bilirubin ≤ 1.5×ULN if no liver metastases or \< 3×ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline Serum albumin ≥ 2.5 g/dL Adequate renal function CrCL ≥ 30 mL/min as determined by Cockcroft Gault (using actual body weight).
• Males:
• CLcr (mL/min) = "\[140 - age (years)\] × weight (kg)" /"72 × serum creatinine (mg/dL)"
• Females:
• (CLcr (mL/min) = "\[140 - age (years)\] × weight (kg)" /"72 × serum creatinine (mg/dL)" × 0.85 Adequate blood clotting function International normalised ratio or Prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN
• \*CrCL = calculated creatinine clearance; ULN = upper limit of normal

You may not qualify if:

• Active brain metastases that require intervention
• Leptomeningeal metastases
• Systemic antitumor therapy within 28 days(Targeted therapy, ≥ 2 weeks or 5 half-lives) before initiation of T-DXd
• Radiation therapy(excluding palliative stereotactic radiation therapy to chest) or gamma-knife surgery within 2weeks before initiation of T-DXd
• Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results.
• Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with untreated but clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment/randomization.
• Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 2 or baseline
• Patients with a medical history of myocardial infarction (MI) within 6 months before enrolment, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV),
• History of (non-infectious) ILD / pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.(Using for prophylactic antibiotics is allowed.)
• Active primary immunodeficiency, known uncontrolled active HIV infection or active hepatitis B or C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1 Day 1. Subjects with past or resolved hepatitis B virus (HBV) infection who are anti-HBc positive (+) are eligible only if they are HBsAg negative (-).
• Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Subjects should be tested for HIV prior to randomization/enrollment if required by local regulations or institutional review board (IRB)/ethics committee (EC).
• Receipt of live, attenuated vaccine within 30 days prior to the first dose of trastuzumab deruxtecan. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of trastuzumab deruxtecan. Note: Participants, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of study intervention.
• Clinically significant pleural effusion, ascites or pericardial effusion that requires drainage.(Stable
• Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary emboli within three months of the study enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion etc.)

Sponsors & Collaborators

• Yonsei University: lead

Study Sites (1)

Yonsei University Health system, Severance Hospital

Seoul, South Korea

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

trastuzumab deruxtecan

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Hye Ryun Kim

  Yonsei University Health system, Severance Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 21, 2024
• First Posted: February 9, 2024
• Study Start: July 11, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: February 9, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

KR (1)