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NCT Number: NCT05048797

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

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

Active, Not Recruiting

This study is active but is not currently recruiting participants.

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Key information

Conditions

Locally Advanced or Metastatic Non-small Cell Lung Cancer Bronchial Neoplasms Carcinoma, Bronchogenic Carcinoma, Non-Small-Cell Lung Lung Diseases Lung Neoplasms Neoplasms Neoplasms by Site Respiratory Tract Diseases Respiratory Tract Neoplasms Thoracic Neoplasms

Age range

18 year–123 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Research Site, Linz, Austria

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Participants at least 18 years of age
  • Locally advanced and unresectable NSCLC, 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 untreated brain metastases, including asymptomatic or clinically inactive brain metastases
  • 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

Treatment and study plan

Trastuzumab Deruxtecan

Drug

Trastuzumab Deruxtecan administered by intravenous infusion

Other names: DS-8201a; T-DXd

Cisplatin

Drug

Investigator's choice of platinum chemotherapy (cisplatin) administered by intravenous infusion

carboplatin

Drug

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

Pembrolizumab

Drug

Pembrolizumab administered by intravenous infusion

Pemetrexed

Drug

Pemetrexed administered by intravenous infusion

Primary outcomes

  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 outcomes

  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.

Sponsors and collaborators

Lead sponsor

AstraZeneca

Industry

Collaborators

  • Daiichi Sankyo

Registry information

Official study 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)

Important dates

Study start
2021
Primary completion
2026
Study completion
2027
First posted
Sep 17, 2021
Registry last updated
Jul 10, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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