A trial to learn if Dato-DXd with rilvegostomig, or rilvegostomig alone, is safe and works compared with pembrolizumab in people who have advanced non-squamous non-small cell lung cancer (NSCLC) with high levels of the PD-L1 protein

Prior treatment

• Prior systemic therapy for advanced/metastatic NSCLC.
• Active or prior documented autoimmune or inflammatory disorders (with exceptions).
• Spinal cord compression, or brain metastases unless participant treated and no longer symptomatic, radiologically stable, and who require no treatment with corticosteroids or anticonvulsants.

Other illness

• History of leptomeningeal carcinomatosis
• Known clinically significant corneal disease
• Active infection with TB, HBV, HCV, Hepatitis A, or known HIV infection that is not well controlled
• History of active primary immunodeficiency
• Squamous cell histology, or predominantly squamous cell histology NSCLC; mixed small cell lung cancer; NSCLC histology, sarcomatoid variant.
• History of another primary malignancy within 3 years.
• Any evidence of severe or uncontrolled systemic diseases, including, but not limited to active bleeding diseases, active infection, serious chronic gastrointestinal conditions, cardiac disease.
• History of any ILD/pneumonitis, including radiation pneumonitis, or drug- induced ILD/pneumonitis, has current or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.

Other

• Has clinically significant third-space fluid retention (for example pleural effusion) and is not amenable for repeated drainage.
• Has significant pulmonary function compromise, as determined by the investigator

• Histologically or cytologically documented non-squamous NSCLC.
• Stage IIIB or IIIC or Stage IV metastatic NSCLC (according to Edition 8 of the AJCC staging manual) not amenable to curative surgery or definitive chemoradiation.
• Absence of sensitising EGFR mutations, and ALK and ROS1 rearrangements, and abscence of documented local test result for any other known genomic alteration for which there are locally approved and available targeted first-line therapies.
• Must provide an available FFPE tumour sample collected ≤ 3 months prior to the start of screening. If such a sample is not available, then a FFPE tumour sample will be collected at biomarker screening (if applicable) or main screening.
• Known tumour PD-L1 expression status defined as TC ≥ 50%, determined prospectively using an FFPE tumour sample collected using the VENTANA PD-L1 (SP263) Assay).
• At least one lesion, not previously irradiated that qualifies as a RECIST 1.1 target lesion at baseline.
• ECOG performance status of 0 or 1, with no deterioration over the previous 2 weeks prior randomisation.
• Adequate bone marrow reserve and organ function as defined in inclusion criteria 13.
• Prior to the availability of the VENTANA TROP2 device, retrospective tumour material confirms eligibility. Once the VENTANA TROP2 device is available, prospective testing is implemented.