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

Inclusion Criteria:

• Participants at least 18 years of age

• Locally advanced and unresectable NSCLC, not amenable to curative therapy, ormetastatic disease

• Histologically documented non-squamous NSCLC with HER2 mutation in exons 19 or 20 bytissue NGS or ctDNA

• Treatment-naïve for palliative intent systemic therapy for locally advanced ormetastatic 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 includingbut not limited to ALK, if routinely tested as a targetable alteration with approvedavailable therapy)

• Any untreated brain metastases, including asymptomatic or clinically inactive brainmetastases

• 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