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:

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

Exclusion Criteria:

1. 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)
2. Any clinically active brain metastases; previously treated brain metastases allowed
3. Active autoimmune or inflammatory disorders
4. Medical history of myocardial infarction within 6 months prior to randomization
5. History of non-infectious pneumonitis/ILD, current or suspected ILD
6. Lung-specific intercurrent clinical significant severe illness
7. Contraindication to platinum-based doublet chemotherapy or pembrolizumab