Datopotamab Deruxtecan (Dato-DXd) and Pembrolizumab With or Without Platinum Chemotherapy in 1L Non-Small Cell Lung Cancer (TROPION-Lung07)

Key Inclusion Criteria:

1. Sign and date the Main ICF, prior to the start of any study- specific qualificationprocedures. Is willing and able to comply with scheduled visits, drug administrationplan, laboratory tests, other study procedures, and study restrictions.

2. Adults ≥18 at the time the Main ICF is signed. (Follow local regulatory requirementsif the legal age of adult voluntary consent for study participation is >18 yearsold).

3. Has tumor with PD-L1 TPS <50% as determined by PD-L1 IHC 22C3 pharmDx assay bycentral testing (minimum of 6 slides). PD-L1 expression results available at thesame central laboratory from screening for the purpose of entry into anotherDato-DXd study may be used for tissue screening purposes in this study as long asthe subject has not been randomized/enrolled in the other study.

4. Has provided a formalin-fixed tumor tissue sample (minimum of 4 × 4-micron sectionsor block equivalent) for the measurement of TROP2 protein expression and for theassessment of other exploratory biomarkers. This tissue requirement is in additionto the tissue required for PD-L1 testing for tissue screening purposes. If adocumented law or regulation prohibits (or does not approve) sample collection, thensuch sample will not be collected, and the subject is still eligible for the study.

5. Has not been treated with systemic anticancer therapy for advanced or metastaticnon-squamous NSCLC. Subjects who received adjuvant or neoadjuvant therapy other thanthose listed in the exclusion criteria are eligible if the adjuvant/ neoadjuvanttherapy was completed at least 6 months prior to the diagnosis ofadvanced/metastatic disease and should not have progressed on or within the 6 monthsof completion.

6. Has measurable disease based on local imaging assessment using RECIST v1.1;radiographic tumor assessment must be performed within 28 days before randomization.

Key Exclusion Criteria:

1. Has received prior systemic treatment for advanced/metastatic NSCLC.

2. Has received prior treatment with any of the following, including in theadjuvant/neoadjuvant setting (for NSCLC):

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

4. TROP2-targeted therapy

5. Any anti-PD-1, anti-PD-L1, or anti-programmed death-ligand 2 (PD-L2) agent orwith an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137)

6. Any other ICIs Subjects who received adjuvant or neoadjuvant therapy other thanthose listed above are eligible if the adjuvant/neoadjuvant therapy wascompleted at least 6 months prior to the diagnosis of advanced or metastaticdisease.

7. Has received a live vaccine within 30 days prior to the first dose of studytreatment. Examples of live vaccines include, but are not limited to, the following: measles,mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BacillusCalmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines forinjection are generally killed virus vaccines and are allowed; however, intranasalinfluenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.For any subject receiving an approved severe acute respiratory syndromecoronavirus-2 (SARS-CoV-2) vaccine, please follow the vaccine label and/or localguidance. The vaccine manufacturer and the date of administration should be recordedon the electronic case report form (Concomitant Medications page), as should any AEsrelating to the vaccine (including hypersensitivity or allergies). Note: Anylicensed SARS-CoV2 vaccine (including those authorized for emergency use) in aparticular country is allowed in the study as long as the vaccine is an mRNAvaccine, replication-incompetent adenoviral vaccine, or inactivated vaccine. Suchvaccines will be treated just as any other concomitant therapy. Investigational vaccines (ie, those not licensed or authorized for emergency use)are not allowed.

8. Has spinal cord compression or clinically active untreated CNS metastases and/orcarcinomatous meningitis. Subjects with previously treated brain metastases mayparticipate provided they are radiologically stable (ie, without evidence ofprogression) for at least 2 weeks by repeat imaging (Note: Repeat imaging should beperformed during study screening), clinically stable, and without requirement ofsteroid treatment for at least 7 days before the first dose of study drug. Note: Acontrasted computed tomography (CT) scan or magnetic resonance imaging (MRI) scan ofthe brain at baseline (MRI with contrast preferred) is required for all subjects.For those subjects in whom CNS metastases are first discovered at the time ofscreening, the treating investigator must delay of study treatment to documentstability of CNS metastases with repeat imaging at least 2 weeks later (in whichcase, repeat of all screening activity may be required).

9. Has uncontrolled or significant cardiovascular disease not controlled by maximalmedical therapy, including:

10. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF)interval >470 msec regardless of sex (based on the 12-lead electrocardiogram [ECG] performed at screening).

11. Myocardial infarction within 6 months prior to Cycle 1 Day 1.

12. History of a serious cardiac arrhythmia requiring treatment

13. Uncontrolled angina pectoris within 6 months prior to Cycle 1 Day 1.

14. Left ventricular ejection fraction (LVEF) <50% by echocardiogram (ECHO) ormultigated acquisition (MUGA) scan within 28 days before randomization.

15. New York Heart Association (NYHA) Class II-IV congestive heart failure (CHF) atscreening. Subjects with a history of Class II to IV CHF prior to screening,must have returned to Class I CHF and have LVEF ≥50% (by either an ECHO or MUGAscan within 28 days before randomization) in order to be eligible.

16. Uncontrolled hypertension (resting systolic blood pressure >180 mmHg ordiastolic blood pressure >110 mmHg within 28 days before randomization that isnot resolved despite maximal medical therapy).

17. Clinically severe pulmonary compromise as judged by the investigator resulting fromintercurrent pulmonary illnesses including, but not limited to, any underlyingpulmonary disorder (eg, pulmonary emboli diagnosed within 3 months of Cycle 1 Day 1,severe asthma, severe chronic obstructive pulmonary disease, restrictive lungdisease, pleural effusion, etc) or any autoimmune, connective tissue or inflammatorydisorders with pulmonary involvement (eg, rheumatoid arthritis, Sjögren's syndrome,sarcoidosis, etc), or prior complete pneumonectomy.