A Single Arm, Phase 2 Study of Datopotamab Deruxtecan, Carboplatin, and Pembrolizumab for Treatment-naive Brain Metastases From NSCLC (Non-small Cell Lung Cancer)

Inclusion Criteria: \- Male/female participants who are at least 18 years of age on the day of signing informed consent with a histologically confirmed diagnosis of NSCLC will be enrolled in this study. Histologically confirmed metastatic non-squamous NSCLC with PD-L1 tumor proportion score \<50% determined by local or central laboratory using antibodies 22C3' * Documented negative test results for EGFR and ALK actionable genomic alterations by local test; * No known actionable genomic alterations in ROS1, NTRK, RET, HER2, or MET. * No prior systemic therapy for advanced or metastatic NSCLC. Patients who received chemotherapy or immunotherapy for localized or locally advanced NSCLC are eligible if progression occurred at least 6 months after the last dose of systemic treatment. * Participants who have AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have ≤Grade 2 neuropathy are eligible. * The participant (or legally acceptable representative if applicable) provides written informed consent for the trial. * Have measurable disease based on RECIST 1.1, including the following: Presence of 1 or more measurable central nervous system (CNS) metastases that have not received prior radiation therapy, or presence of 1 or more measurable central nervous system (CNS) metastases that has received prior radiation therapy but has unequivocally progressed within the radiation therapy field; Measurable brain metastasis is defined as any lesion that can be accurately measured in at least one dimension as ≥ 10mm. Patients with brain metastases lesions ≥ 5 mm and \< 10 mm are considered to have measurable disease and are allowed to be enrolled if MRI slice thickness is 1.5 mm or less. Presence of 1 or more measurable extracranial lesion; Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. \- No neurological symptoms that require immediate and significant intervention, in the opinion of the treating physician. Patients with neurologic symptoms that do not require significant medical intervention are allowed. Patients may also be enrolled after control of neurological symptoms that require immediate and significant intervention. Patients with neurologic symptoms that are controlled with anticonvulsants are allowed. Patients with neurologic symptoms that are controlled with stable (for at least 1 week), low dose dexamethasone (≤4 mg daily) are allowed. * No leptomeningeal carcinomatosis. * Archival tumor tissue sample or newly obtained \[core, incisional or excisional\] biopsy of a tumor lesion has been provided. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slide (preferably a minimum of 20 slides). Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention. Life expectancy of \> 12 weeks. Has had an adequate treatment washout period before Cycle 1 Day 1, defined as: Major surgery: ≥ 3 weeks. Chloroquine/hydroxychloroquine: \> 14 days. \- Participants who are HBsAg positive are eligible if they have received HBV anti-viral therapy for at least 4 weeks and have undetectable HBV viral load prior to inclusion. Note: Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention. \- Hepatitis B screening tests are not required unless: Known history of HBV infection. As mandated by local health authority. Participants with a history of HCV infection are eligible if HCV viral load is undetectable at screening. \- Note: Participants must have completed curative anti-viral therapy at least 4 weeks prior to inclusion. Hepatitis C screening tests are not required unless: Known history of HCV infection As mandated by local health authority \- HIV-infected participants must have well-controlled HIV on ART, defined as: Participants on ART must have a CD4+ T-cell count ≥350 cells/mm3 at the time of screening Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening. \- It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months. Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (Day 1) and agree to continue ART throughout the study The combination ART regimen must not contain any antiretroviral medications that interact with CYP3A4 inhibitors/inducers/substrates (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers) * Negative pregnancy test (serum) for women of childbearing potential. * Have adequate organ function. Specimens must be collected within 10 days prior to the start of study intervention. * Hematological: Absolute neutrophil count (ANC) ≥1500/µL; Platelets ≥100 000/µL; Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La; * Renal: Creatinine OR Measured or calculatedb creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels \>1.5 × institutional ULN * Hepatic: Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels \>1.5 × ULN AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases) * Coagulation: International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving ant