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

Progression-Free Survival (PFS) in the FAS population.

PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause. The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy, receives another anti cancer therapy or clinically progresses prior to RECIST 1.1 progression, in the following population: • FAS population The measure of interest is the HR of PFS. PFS by investigator will be reported as a sensitivity analysis.

Time frame: Approximately 4 years

Overall Survival (OS) in the FAS population.

OS is defined as the time from randomisation until the date of death due to any cause. The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anti-cancer therapy, in the following population: • FAS population The measure of interest is the HR of OS.

Time frame: Approximately 6 years

Assessment of Objective Response Rate (ORR) by BICR in TROP2 biomarker positive and FAS populations

ORR is defined as the proportion of participants who have a CR or PR, as determined by BICR per RECIST 1.1. The analyses will include all randomised participants, as randomised, with measurable disease at baseline, in the following populations: * TROP2 biomarker positive population * FAS population Data obtained from randomisation up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of ORR, regardless of whether the participant withdraws from therapy. Participants who go off treatment without a response or progression, receive a subsequent therapy, and then respond will not be included as responders in the ORR. The measure of interest is the OR of the ORR. ORR by investigator will be reported as a sensitivity analysis.

Time frame: Approximately 4 years

Assessment of Duration of Response (DoR) by BICR in TROP2 biomarker positive and FAS populations

DoR is defined as the time from the date of first documented response until date of documented progression per RECIST 1.1, as assessed by BICR and investigator assessment or death due to any cause. The analyses will include all randomised participants who have a response, as randomised, regardless of whether the participant withdraws from randomised therapy, receives another anti cancer therapy or clinically progresses prior to RECIST 1.1 progression, in the following populations: * TROP2 biomarker positive population * FAS population The measure of interest is the median of DoR. DoR by investigator will be reported as a sensitivity analysis.

Time frame: Approximately 4 years

Participant-reported lung cancer symptoms of NSCLC and participant-reported GHS/QOL in participants treated with Dato-DXd in combination with rilvegostomig relative to pembrolizumab.

Time to deterioration in: pulmonary symptoms (dyspnoea, cough, and chest pain) as measured by the NSCLC-SAQ, in overall lung cancer symptoms as measured by the NSCLC-SAQ, and in GHS/QoL as measured by the GHS/QoL scale from EORTC IL172. Time to deterioration is defined as the time from randomisation until the date of deterioration. Deterioration is defined as change from baseline that reaches a clinically meaningful deterioration threshold. The analyses will include all randomised participants, in the following populations: * TROP2 biomarker positive population * FAS population The measure of interest is the HR of time to deterioration in pulmonary symptoms, HR of time to deterioration in overall lung cancer symptoms, and HR of time to deterioration in GHS/QoL.

Time frame: Approximately 6 years

Participant-reported physical functioning in participants treated with Dato DXd in combination with rilvegostomig relative to pembrolizumab.

Time to deterioration in physical functioning as measured by PROMIS Physical Function short form 8c. Time to deterioration is defined as the time from randomisation until the date of deterioration. Deterioration is defined as change from baseline that reaches a clinically meaningful deterioration threshold. The analyses will include all randomised participants, in the following populations: * TROP2 biomarker positive population * FAS population The measure of interest is the HR of time to deterioration in physical functioning.

Time frame: Approximately 6 years

Pharmacokinetics (PK)

Concentration of rilvegostomig, Dato-DXd, total anti TROP2 antibody, and MAAA 1181a (payload deruxtecan) in plasma or serum and PK parameters (peak and trough concentrations).

Time frame: Approximately 6 years

Immunogenicity

Presence of ADA for Dato-DXd and rilvegostomig (confirmatory results, titres and neutralising antibodies for confirmed positive samples).

Time frame: Approximately 6 years

Second Progression-Free Survival (PFS2).

PFS2 is defined as the time from randomisation to the earliest of the progression events (following the initial progression), subsequent to first subsequent therapy, or death. Progression event includes radiological (RECIST 1.1) or clinical disease progression. The date of second progression will be recorded by the investigator in the eCRF and defined according to local standard practice. The analyses will include all randomised participants, as randomised, regardless of whether the participant withdraws from subsequent therapy and regardless of missed visits, in the following populations: * TROP2 biomarker positive population * FAS population The measure of interest is the HR of PFS2.

Time frame: Approximately 6 years