Sign and date the Main ICF, prior to the start of any study- specific qualification procedures. Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions. 2. Adults ≥18 at the time the Main ICF is signed. (Follow local regulatory requirements if the legal age of adult voluntary consent for study participation is >18 years old). 3. Has tumor with PD-L1 TPS <50% as determined by PD-L1 IHC 22C3 pharmDx assay by central testing (minimum of six slides). PD-L1 expression results available at the same central laboratory from screening for the purpose of entry into another Dato-DXd study may be used for tissue screening purposes in this study as long as the subject has not been randomized/enrolled in the other study. 4. Has provided a formalin-fixed tumor tissue sample (minimum of 4 × 4-micron sections or block equivalent) for the measurement of TROP2 protein expression and for the assessment of other exploratory biomarkers. This tissue requirement is in addition to the tissue required for PD-L1 testing for tissue screening purposes. If a documented law or regulation prohibits (or does not approve) sample collection, then such 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 metastatic non-squamous NSCLC. Subjects who received adjuvant or neoadjuvant therapy other than those listed in the exclusion criteria are eligible if the adjuvant/ neoadjuvant therapy was completed at least 6 months prior to the diagnosis of advanced/metastatic disease and should not have progressed on or within the 6 months of 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. 7. Histologically documented NSCLC that meets all of the following criteria: • Has Stage IIIB or IIIC disease who is not a candidate for surgical resection or definitive chemoradiation, or Stage IV non-squamous NSCLC disease at the time of randomization (based on the American Joint Committee on Cancer, Eighth Edition24). • Has documented negative test results for EGFR, ALK, and ROS1 actionable genomic alterations (AGAs) based on analysis of tumor tissue. If test results for EGFR, ALK, and ROS1 are not available prior to consenting, subjects will be required to undergo testing performed locally for these genomic alterations. Subjects with unknown or indeterminate EGFR, ALK and ROS1 status are excluded. • Has no known actionable genomic alterations in NTRK, BRAF, RET, MET, or other actionable driver kinases with locally approved therapies. (Testing for genomic alterations besides EGFR, ALK, and ROS1 is not required prior to enrollment.). Subjects with tumors that harbor KRAS mutations are eligible for this study. 8. Has an ECOG performance status of 0 or 1 at screening 9. Has adequate laboratory parameters documented within 7 days before randomization as defined as follows: Parameter Laboratory Value Bone Marrow Function Platelet count Platelet count ≥100,000/mm3 (platelet transfusion is not allowed within 1 week prior to screening assessment). Hemoglobin (Hgb) Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L (criteria must be met without packed red blood cell/plasma transfusion within 2 weeks prior to screening assessment. Subjects can be on stable dose of erythropoietin [≥approximately 3 months]). Absolute neutrophil count (ANC) ANC ≥1500/mm3 (granulocyte-colony stimulating factor [G-CSF] administration is not allowed within 1 week prior to screening assessment). Blood Clotting Function International normalized ratio (INR) or prothrombin time and activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) ≤1.5 × upper limit of normal (ULN), unless the subject is receiving anticoagulant therapy, as long as prothrombin time/INR or aPTT/PTT is within the therapeutic range of intended use of anticoagulants. Renal Function Creatinine clearance (CrCl) ≥50 mL/min, as calculated using the Cockcroft-Gault equationa (or measured by 24-hour urine collection per local guidelines) (≥60 mL/min for subjects receiving cisplatin, as calculated using the Cockcroft-Gault equationa [or measured by 24-hour urine collection per local guidelines]) Hepatic Function Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN for subjects with liver metastases). Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ULN for subjects with total bilirubin >1.5 × ULN. a Cockcroft-Gault equation16 CrCl (mL/min) = [140 - age (years)] × weight (kg) 72 × serum creatinine (mg/dL) {× 0.85 for female subjects} Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies. 10. If the subject is a female of reproductive/childbearing potential, she must have a negative serum pregnancy test at screening and 72 hours before the first dose of Dato-DXd and must be willing to use highly effective birth control (Section 10.3.5) upon randomization, during the Treatment Period, and for 7 months following the last dose of study treatment if the last dose is Dato-DXd, or carboplatin/cisplatin or pemetrexed, and for 4 months if the last dose is pembrolizumab, whichever is longer. A female is considered of reproductive/childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy). 11. If male, the subject must be surgically sterile or must use a condom in addition to their partner using a highly effective method of birth control (Section 10.3.5) if their partner is of reproductive/childbearing potential upon enrollment, during the Treatment Period, and for 4 months following the last dose of study drug of the doublet (pembrolizumab and Dato-DXd) therapy. If the male subject is receiving the triplet therapy (with either carboplatin or cisplatin) or pemetrexed, then he must agree to the above for at least 6 months if the last dose of study treatment is carboplatin/cisplatin or pemetrexed or 4 months if the last dose of study treatment is Dato-DXd/pembrolizumab. 12. Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and for at least 4 months after the last dose of Dato-DXd. If the male subject is receiving the triplet therapy (with either carboplatin or cisplatin) or pemetrexed, then he must agree to not freeze or donate sperm for at least 6 months if the last dose of study treatment is carboplatin/cisplatin or pemetrexed, or 4 months if the last dose of study treatment is Dato-DXd/pembrolizumab. Preservation of sperm should be considered prior to enrollment in this study. 13. Female subjects must not donate or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the last dose of study drug if receiving either the doublet (pembrolizumab and Dato-DXd), or triplet (with either carboplatin or cisplatin) therapy or pemetrexed. Preservation of ova should be considered prior to enrollment in this study. 14. Has an adequate treatment washout period before Cycle 1 Day 1, defined as follows: Treatment Washout Period Major surgery ≥3 weeks. Radiation therapy, including palliative radiation to the chest ≥4 weeks No more than 30 Gy can be received in the lung fields within the past 6 months. Palliative radiation to nonthoracic and to non-central nervous system regions ≥2 weeks. Radiation treatment to the brain ≥2 weeks washout is required. 15. Is willing and able to participate in the collection of PRO data. 16. Subjects who have AEs due to previous adjuvant/neoadjuvant therapies must have recovered to Grade ≤1 or baseline. Subjects with endocrine-related AEs who are adequately treated with hormone replacement or subjects who have Grade ≤2 neuropathy are eligible.

Has received prior systemic treatment for advanced/metastatic NSCLC. 2. Has received prior treatment with any of the following, including in the adjuvant/neoadjuvant setting (for NSCLC): a. Any agent, including an ADC, containing a chemotherapeutic agent targeting topoisomerase I b. TROP2-targeted therapy c. Any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137) d. Any other ICIs Subjects who received adjuvant or neoadjuvant therapy OTHER than those listed above are eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the diagnosis of advanced or metastatic disease. 3. Has received a live vaccine within 30 days prior to the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. For any subject receiving an approved severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) vaccine, please follow the vaccine label and/or local guidance. The vaccine manufacturer and the date of administration should be recorded on the electronic case report form (Concomitant Medications page), as should any AEs relating to the vaccine (including hypersensitivity or allergies). Note: Any licensed SARS-CoV2 vaccine (including those authorized for emergency use) in a particular country is allowed in the study as long as the vaccine is an mRNA vaccine, replication-incompetent adenoviral vaccine, or inactivated vaccine. Such vaccines will be treated just as any other concomitant therapy. Investigational vaccines (ie, those not licensed or authorized for emergency use) are not allowed. 4. Has spinal cord compression or clinically active untreated CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 2 weeks by repeat imaging (Note: Repeat imaging should be performed during study screening), clinically stable, and without requirement of steroid treatment for at least 7 days before the first dose of study drug. Note: A contrasted computed tomography (CT) scan or magnetic resonance imaging (MRI) scan of the 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 of screening, the treating investigator must delay of study treatment to document stability of CNS metastases with repeat imaging at least 2 weeks later (in which case, repeat of all screening activity may be required). 5. Has uncontrolled or significant cardiovascular disease not controlled by maximal medical therapy, including: a. 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). b. Myocardial infarction within 6 months prior to Cycle 1 Day 1. c. History of a serious cardiac arrhythmia requiring treatment d. Uncontrolled angina pectoris within 6 months prior to Cycle 1 Day 1. e. Left ventricular ejection fraction (LVEF) 180 mmHg or diastolic blood pressure >110 mmHg within 28 days before randomization that is not resolved despite maximal medical therapy). 6. Clinically severe pulmonary compromise as judged by the investigator resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli diagnosed within 3 months of Cycle 1 Day 1, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc.) or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (eg, rheumatoid arthritis, Sjögren’s syndrome, sarcoidosis, etc.), or prior complete pneumonectomy. 7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosage >10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy ≤7 days prior to the first dose of study drug 8. History of another primary malignancy (beyond NSCLC) except for: • Malignancy treated with curative intent and with no known active disease ≥3 years before the first dose of study treatment and of low potential risk for recurrence • Adequately treated non-melanoma skin cancer, lentigo maligna, or lentigo maligna melanoma without evidence of disease • Adequately treated carcinoma in situ without evidence of disease

Subjects with a history of prostate cancer (tumor/node/metastasis stage) of Stage ≤T2cN0M0 without biochemical recurrence or progression and who in the opinion of the investigator are not deemed to require active intervention 9. Has a history of severe hypersensitivity reactions to either the drugs or inactive ingredients (including but not limited to polysorbate 80) of Dato-DXd, pembrolizumab, carboplatin, cisplatin, or pemetrexed 10. Has a history of severe hypersensitivity reactions to other monoclonal antibodies. 11. Has evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection. Note: Subjects with localized fungal infections of skin or nails are eligible. 12. Has known human immunodeficiency virus (HIV) infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA, CD4+ counts/levels ≥350, no history of AIDS-defining opportunistic infection within the past 12 months, and clinically stable for at least 4 weeks on the same anti-HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen). If an HIV infection meets the above criteria, monitoring of the subjects’ viral RNA load as well as the CD4+ count levels is recommended. Subjects must be tested for HIV if acceptable by local regulations or independent institutional review board (IRB)/ethics committee (EC). Note: Subjects should remain on antiviral therapy throughout study intervention and follow local guidelines for HIV antiviral therapy post-completion of study intervention. 13. Has active or uncontrolled hepatitis B or C infection. Subjects are eligible if they: a. Have been curatively treated for HCV infection as demonstrated clinically and by viral serologies b. Have received HBV vaccination with only anti-HBs (anti-hepatitis B surface antigen) positivity and no clinical signs of hepatitis c. Are HBsAg- and anti-HBc+ (ie, those who have cleared HBV after infection) and meet conditions i-iii below: d. Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meet conditions i-iii below: i. HBV DNA viral load <2000 IU/mL ii. Have normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT <3 × ULN, which are not attributable to HBV infection iii. Start or maintain antiviral treatment if clinically indicated as per the investigator. 14. Females who are pregnant or breastfeeding or intend to become pregnant. 15. Any other medical conditions, including cardiac disease or psychological disorders, and/or substance abuse, that may, in the opinion of the investigator, interfere with the subject’s participation in the clinical study or evaluation of the clinical study results. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. 17. Has active, known, or suspected autoimmune disease (has an active autoimmune disease that has required systemic treatment in the past 2 years [ie, with use of systemic disease-modifying agents, corticosteroids, or immunosuppressive drugs]). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. Inhaled, intranasal, intraocular, intra-articular, or topical steroids and adrenal replacement steroids are permitted in the absence of active autoimmune disease. 18. Has clinically significant corneal disease 19. Has had an allogeneic tissue/solid organ transplantation 20. Has received prior radiotherapy ≤4 weeks of start of study intervention or more than 30 Gy to the lung within 6 months of Cycle 1 Day 1. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 2-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS or non-chest disease. 21. Subjects known to be positive for SARS-Cov-2 infection at the time of Screening will be excluded. Note: testing for SARS-Cov-2 infection at the time of Screening is not mandatory. 22. Subjects who are employees of the investigator, Sponsor or the study site should be excluded 23. Specifically to potential subjects in Germany: subjects who are housed in an institution due to an official or court order, cf. § 40 para. 1 clause 3 no. 4 AMG (old edition) in conjunction with § 148 para. 2 AMG will be excluded