A Study to Investigate the Efficacy and Safety of Dato-DXd With or Without Osimertinib Compared With Platinum Based Doublet Chemotherapy in Participants With EGFR-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Inclusion Criteria:

• Histologically or cytologically confirmed non-squamous NSCLC.

• Must have evidence of documented pre-existing EGFRm information (EGFRm known to beassociated with (epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor [TKis] sensitivity [Ex19del, L858R, G719X, S768I, or L861Q], either alone or incombination with other EGFR mutations, which may include T790M).

• Documented extra-cranial radiologic progression on prior osimertinib monotherapy (asmost recent line of treatment) in the adjuvant, locally advanced, or metastaticsetting.

• Less than or equal to (<=2) prior lines of EGFR TKIs (osimertinib is the onlypermitted prior third generation EGFR TKI).

• At least one lesion, not previously irradiated, that qualifies as a RECIST v1.1 TLat baseline and can be accurately measured at baseline.

• World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG)performance status of 0 or 1.

• Adequate bone marrow reserve and organ function within 7 days before randomization.

Exclusion Criteria:

• Use of chemotherapy, vascular endothelial growth factor inhibitor, immunotherapy orany anti-cancer therapy in the metastatic setting. Platinum-based chemotherapy innon-metastatic setting within 12 months prior to randomization.

• History of another primary malignancy except for malignancy treated with curativeintent with no known active disease within 2 years before the first dose of studyintervention.

• Any evidence of severe or uncontrolled systemic diseases, including, but not limitedto active bleeding diseases, active infection, active ILD/pneumonitis, cardiacdisease.

• Has significant third-space fluid retention (example [eg.], ascites or pleuraleffusion) as judged by the investigator and is not amenable for required repeateddrainage.

• History of non-infectious ILD/pneumonitis including radiation pneumonitis thatrequired steroids or drug-induced ILD, has current ILD/pneumonitis, or has suspectedILD/pneumonitis that cannot be ruled out by imaging at screening.

• Has severe pulmonary function compromise resulting from intercurrent pulmonaryillnesses.

• Unstable spinal cord compression and/or unstable brain metastases.

• Participants with symptomatic brain metastases (including leptomeningealinvolvement).

• Clinically significant corneal disease.

• Uncontrolled infection requiring systemic antibiotics, antivirals, or antifungals,suspected infections or inability to rule out infections. Use of systemicantibiotics within 14 days of randomization.

• Has known human immunodeficiency virus (HIV) infection that is not well controlled.