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A Study to Investigate the Efficacy and Safety of Trastuzumab Deruxtecan as the First Treatment Option for Unresectable, Locally Advanced/Metastatic Non-Small Cell Lung Cancer With HER2 Mutations

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05048797
Recruitment Status : Recruiting
First Posted : September 17, 2021
Last Update Posted : June 7, 2022
Sponsor:
Collaborator:
Daiichi Sankyo, Inc.
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
DESTINY-Lung04 will investigate the efficacy and safety of Trastuzumab Deruxtecan (T-DXd) versus Standard of Care (SoC) as first-line treatment of Non-Small Cell Lung Cancer (NSCLC) with HER2 Exon 19 or 20 mutations

Condition or disease Intervention/treatment Phase
Locally Advanced or Metastatic Non-Small Cell Lung Cancer Drug: Trastuzumab Deruxtecan Drug: Cisplatin Drug: Carboplatin Drug: Pembrolizumab Drug: Pemetrexed Phase 3

Detailed Description:

Eligible participants will be those diagnosed with unresectable, locally advanced or metastatic histologically documented non-squamous NSCLC with HER2 exons 19 or 20 mutations and who are treatment-naïve for palliative intent systemic therapy for locally advanced or metastatic disease.

The study aims to evaluate the efficacy, safety and tolerability of trastuzumab deruxtecan as first-line treatment of Non-Small Cell Lung Cancer (NSCLC) as compared with Standard of Care treatment (Investigator's choice of cisplatin or carboplatin + pembrolizumab + pemetrexed). This study aims to see if trastuzumab deruxtecan allows patients to live longer without the cancer getting worse or simply to live longer, compared to patients receiving standard of care treatment. This study is also looking to see how the treatment and the cancer affects patients' quality of life.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 264 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

This study consists of two open-label treatment arms:

Arm 1: Trastuzumab Deruxtecan Arm 2: Standard of Care treatment (platinum, pemetrexed and pembrolizumab)

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Randomized, Multicenter, Phase 3 Study to Assess the Efficacy and Safety of Trastuzumab Deruxtecan as First-line Treatment of Unresectable, Locally Advanced, or Metastatic NSCLC Harboring HER2 Exon 19 or 20 Mutations (DESTINY-Lung04)
Actual Study Start Date : October 28, 2021
Estimated Primary Completion Date : January 17, 2025
Estimated Study Completion Date : March 1, 2027

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Trastuzumab

Arm Intervention/treatment
Experimental: Arm 1
Trastuzumab Deruxtecan (T-DXd)
Drug: Trastuzumab Deruxtecan
Trastuzumab Deruxtecan administered by intravenous infusion
Other Name: DS-8201a; T-DXd

Active Comparator: Arm 2
Standard of Care Treatment (platinum, pemetrexed and pembrolizumab)
Drug: Cisplatin
Investigator's choice of platinum chemotherapy (cisplatin) administered by intravenous infusion

Drug: Carboplatin
Investigator's choice of platinum chemotherapy (carboplatin) administered by intravenous infusion

Drug: Pembrolizumab
Pembrolizumab administered by intravenous infusion

Drug: Pemetrexed
Pemetrexed administered by intravenous infusion




Primary Outcome Measures :
  1. Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) [ Time Frame: Until progression or death, assessed up to approximately 12 months ]
    Defined as time from randomization until progression per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR), or death due to any cause.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Until death, assessed up to approximately 28 months. ]
    Defined as time from randomization until the date of death due to any cause.

  2. Progression Free Survival (PFS) by investigator assessment [ Time Frame: Until progression, assessed up to approximately 12 months ]
    Defined as time from randomization until progression per RECIST 1.1 as assessed by the investigator, or death due to any cause.

  3. Objective Response Rate (ORR) [ Time Frame: Until progression, assessed up to approximately 12 months ]
    Defined as the proportion of participants who have a complete response (CR) or partial response (PR) as assessed by Blinded Independent Central Review (BICR) and investigator according to RECIST 1.1

  4. Duration of Response (DoR) [ Time Frame: Until progression, assessed up to approximately 12 months ]
    Defined as the time from the date of first documented response until date of documented progression as assessed by Blinded Independent Central Review (BICR) and investigator assessment according to RECIST 1.1.

  5. Time to second progression or death (PFS2) [ Time Frame: Assessed up to approximately 20 months ]
    Defined as the time from randomization until second progression on next-line of treatment as assessed by investigator at the local site using assessments conducted per local standard clinical practice, or death due to any cause.

  6. Landmark analysis of PFS (PFS12) [ Time Frame: Assessed up to approximately 12 months ]
    Defined as proportion of participants alive and progression-free at 12 months, as assessed by Blinded Independent Central Review (BICR) and investigator.

  7. Landmark analysis of OS (OS24) [ Time Frame: Assessed up to approximately 24 months ]
    Defined as proportion of participants alive at 24 months

  8. Central Nervous System (CNS) - Progression Free Survival (PFS) [ Time Frame: Until CNS progression or death, assessed up to approximately 12 months ]
    Defined as time from randomization until Central Nervous System (CNS) progression per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR) or death due to any cause in the absence of CNS progression.

  9. Safety and tolerability of T-DXd versus Standard of Care treatment [ Time Frame: Until progression or death, assessed up to approximately 28 months ]
    Assessed by the occurrence of AEs, SAEs, and changes from baseline in laboratory parameters, vital signs, ECG, and ECHO/MUGA scan results.

  10. Pharmacokinetics (PK) of T-DXd, total anti-HER2 antibody and DXd in serum [ Time Frame: Up to cycle 4, approximately 12 weeks ]
    Serum concentration of T-DXd, total anti-HER2 antibody and DXd.

  11. Immunogenicity of T-DXd [ Time Frame: Until progression, assessed up to approximately 13 months ]
    Presence of anti-drug antibodies (ADAs) for T-DXd.

  12. Patient-reported pulmonary symptoms associated with Non-Small Cell Lung Cancer [ Time Frame: Until progression, assessed up to approximately 13 months ]
    Time to sustained deterioration in pulmonary symptoms (cough, dyspnea, chest pain) while on treatment using the Non-Small Cell Lung Cancer-Symptom Assessment Questionnaire (NSCLC-SAQ).

  13. Patient-reported tolerability of T-DXd described using symptomatic AEs [ Time Frame: Until progression, assessed up to approximately 13 months ]
    Symptomatic AEs: Descriptive summary of the proportion of participants reporting symptomatic AEs while on treatment, as assessed by the Patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) and items from the European Organisation for Research and Treatment of Cancer (EORTC) Item Library.

  14. Patient-reported tolerability of T-DXd described using overall side-effect bother [ Time Frame: Until progression, assessed up to approximately 13 months ]
    Overall side-effect bother: Descriptive summary of the proportion of participants reporting overall side-effect bother on the Patient's Global Impression of Treatment Tolerability (PGI-TT) while on treatment.

  15. Patient-reported tolerability of T-DXd described using physical function [ Time Frame: Until progression, assessed up to approximately 13 months ]
    Physical Function: The proportion of participants with maintained or improved physical function while on treatment, based on the European Organisation for Research and Treatment of Cancer 30-item core quality of life questionnaire (EORTC-QLQ-C30) physical functioning scale.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 123 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants at least 18 years of age
  • Locally advanced not amenable to curative therapy, or metastatic disease
  • Histologically documented non-squamous NSCLC with HER2 mutation in exons 19 or 20 by tissue NGS or ctDNA
  • Treatment-naïve for palliative intent systemic therapy for locally advanced or metastatic disease
  • Left ventricular ejection fraction (LVEF) ≥ 50%
  • Measurable disease assessed by Investigator based on RECIST 1.1
  • Protocol-defined adequate organ function including cardiac, renal, hepatic function
  • ECOG 0-1
  • Having tumour tissue available for central testing

Exclusion Criteria:

  • Tumors with targetable alterations to EGFR (or other targetable mutations including but not limited to ALK, if routinely tested as a targetable alteration with approved available therapy)
  • Any clinically active brain metastases; previously treated brain metastases allowed
  • Active autoimmune or inflammatory disorders
  • Medical history of myocardial infarction within 6 months prior to randomization
  • History of non-infectious pneumonitis/ILD, current or suspected ILD
  • Lung-specific intercurrent clinical significant severe illness
  • Contraindication to platinum-based doublet chemotherapy or pembrolizumab

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05048797


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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Sponsors and Collaborators
AstraZeneca
Daiichi Sankyo, Inc.
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT05048797    
Other Study ID Numbers: D967SC00001
First Posted: September 17, 2021    Key Record Dates
Last Update Posted: June 7, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
DS-8201a
HER2 exon 19 or 20 mutations
ERBB2 gene (coding for the HER2 protein)
T-DXd
Trastuzumab Deruxtecan
Locally advanced and unresectable non-squamous NSCLC
Metastatic non-squamous NSCLC
Non-small cell lung cancer
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Carboplatin
Pembrolizumab
Trastuzumab
Pemetrexed
Antineoplastic Agents
Antineoplastic Agents, Immunological
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors