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)

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

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