Phase III, Open-label, Study of First-line Dato-DXd in Combination With Rilvegostomig for Advanced Non-squamous NSCLC With High PD-L1 Expression (TC ≥ 50%) and Without Actionable Genomic Alterations

Inclusion Criteria:

• Histologically or cytologically documented non-squamous NSCLC.

• Stage IIIB or IIIC or Stage IV metastatic NSCLC (according to Edition 8 of the AJCCstaging manual) not amenable to curative surgery or definitive chemoradiation.

• Absence of sensitising EGFR mutations, and ALK and ROS1 rearrangements, and absenceof documented local test result for any other known genomic alteration for whichthere are locally approved and available targeted first-line therapies.

• Must provide tumor sample to determine PD-L1 status, TROP2 status and otherbiomarkers.

• Known tumour PD-L1 expression status defined as TC ≥ 50%

• At least one lesion, not previously irradiated that qualifies as a RECIST 1.1 targetlesion at baseline

• ECOG performance status of 0 or 1

• Adequate bone marrow reserve and organ function

Exclusion Criteria:

• Prior systemic therapy for advanced/metastatic NSCLC.

• Squamous cell histology, or predominantly squamous cell histology NSCLC; mixed smallcell lung cancer; NSCLC histology, sarcomatoid variant.

• History of another primary malignancy within 3 years

• Active or prior documented autoimmune or inflammatory disorders (with exceptions)

• Any evidence of severe or uncontrolled disease that makes it undesirable for theparticipant to participate in the study or that would jeopardies compliance with theprotocol.

• Has clinically significant third-space fluid retention (for example pleuraleffusion) and is not amenable for repeated drainage.

• History of any ILD/pneumonitis, including radiation pneumonitis (apart fromradiation pneumonitis that did not require steroids), or drug-inducedILD/pneumonitis, has current or suspected ILD/pneumonitis that cannot be ruled outby imaging at screening.

• Has significant pulmonary function compromise, as determined by the investigator

• Spinal cord compression, or brain metastases unless participant treated and nolonger symptomatic, radiologically stable, and who require no treatment withcorticosteroids or anticonvulsants.

• History of leptomeningeal carcinomatosis

• Known clinically significant corneal disease

• Active infection with TB, HBV, HCV, Hepatitis A, or known HIV infection that is notwell controlled

• History of active primary immunodeficiency