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Investigating Trastuzumab Deruxtecan for Advanced Lung Cancer with HER2 Mutations

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)

Phase 3 Interventional AstraZeneca · NCT05048797

This study is testing if a new drug called Trastuzumab Deruxtecan can help people with advanced lung cancer that has HER2 mutations feel better and live longer compared to standard treatments.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment450 (estimated)
Ages18 Years to 123 Years
SexAll
SponsorAstraZeneca Industry-sponsored
Drugs / interventionspembrolizumab, chemotherapy, Trastuzumab
Locations163 sites (Anchorage, Alaska and 162 other locations)
Trial IDNCT05048797 on ClinicalTrials.gov

What this trial studies

This study evaluates the efficacy and safety of Trastuzumab Deruxtecan (T-DXd) as a first-line treatment for patients with unresectable, locally advanced or metastatic non-small cell lung cancer (NSCLC) that has HER2 mutations. Participants will be compared against those receiving standard of care treatments, which include cisplatin or carboplatin combined with pembrolizumab and pemetrexed. The study aims to determine if T-DXd can improve survival and quality of life for these patients. Eligible participants must be treatment-naïve and have measurable disease with specific HER2 mutations.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with unresectable, locally advanced or metastatic non-squamous NSCLC and specific HER2 mutations who have not received prior systemic therapy.

Not a fit: Patients with targetable alterations to EGFR or other specific mutations, as well as those with untreated brain metastases or active autoimmune disorders, may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new effective option for patients with advanced lung cancer that have HER2 mutations.

How similar studies have performed: Other studies have shown promise with similar targeted therapies, indicating potential for success with this approach.

Eligibility criteria

Show full inclusion / exclusion criteria 
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

Where this trial is running

Anchorage, Alaska and 162 other locations

+113 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Locally Advanced or Metastatic Non-Small Cell Lung CancerDS-8201aHER2 exon 19 or 20 mutationsERBB2 geneT-DXdTrastuzumab DeruxtecanLocally advanced and unresectable non-squamous NSCLCMetastatic non-squamous NSCLC
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.