Study of Trastuzumab Deruxtecan, Pembrolizumab, and Platinum-based Chemotherapy in First-line HER2 Overexpressing Non-small Cell Lung Cancer

Inclusion Criteria:

1. Sign and date the Tissue Screening ICF, prior to any Tissue Screening procedure.Sign and date the Main ICF, prior to the start of any trial-specific qualificationprocedures. Sign and date the Optional PGx ICF (included in the Main Screening ICF) prior to anyPGx procedure, and the Pregnant Partner ICF, if applicable.

2. Adults ≥18 years of age on the day of signing the ICF. Follow local regulatoryrequirements if the legal age of consent for trial participation is >18 years old.

3. Histologically documented non-squamous locally advanced unresectable or metastatic NSCLC and meets all of the following criteria: Has Stage IV NSCLC disease or Stage IIIB or IIIC disease but is not a candidate forsurgical resection or definitive chemoradiation at the time of randomization (basedon the American Joint Committee on Cancer, Eighth Edition). Has no known AGAs (basedon existing test result of local test) that have locally available therapiestargeting their AGAs in the first-line advanced/metastatic setting. Has no knownHER2 mutation based on existing test results (if approved or validated local test isavailable). Note: Participants with mixed histology are eligible if adenocarcinomais the predominant histology. Mixed tumors will be classified based on thepredominant cell type.

4. Has not been treated with systemic anticancer therapy for advanced or metastaticnon-squamous NSCLC. Participants who received adjuvant or neoadjuvant therapy otherthan those listed below, including ICI (ie, anti-PD-1/PD-L1) or a platinum-basedregimen, are eligible if the last dose of adjuvant/neoadjuvant therapy was given atleast 6 months before the date of the first trial dose and should not haveprogressed on or within 6 months of the last dose date of adjuvant/neoadjuvanttherapy.

5. Any agent, including an ADC, containing a chemotherapeutic agent targetingtopoisomerase I.

6. HER2-targeted antibody-based anticancer therapy.

7. Has adequate tumor tissue sample (not previously irradiated) available forassessment of HER2 and PD-L1 expression by central or Sponsor-specified laboratory.A new biopsy is required if the participant's most recent archival tumor tissuesample cannot be supplied.

Details pertaining to tumor tissue submission can be found in the Trial Laboratory Manual.

Exclusion Criteria:

1. Has a medical history of MI within 6 months before randomization/enrollment orsymptomatic CHF (NYHA Class II to Class IV). Participants with troponin levels abovethe ULN at Screening (as defined by the manufacturer) and without any MI-relatedsymptoms should have a cardiologic consultation during the Screening Period to ruleout MI.

2. Has a QTc prolongation to >480 ms based on the average of the Screening triplicate 12- lead ECG.

3. Has a history of (non-infectious) ILD/pneumonitis that required steroids, hascurrent ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out byimaging at Screening.

4. Has lung-specific, intercurrent, clinically significant illnesses including, but notlimited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 monthsof the trial randomization, severe asthma, severe COPD, restrictive lung disease,pleural effusion, etc.).

5. Had a prior complete pneumonectomy.