Phase III Study of Datopotamab Deruxtecan Versus Docetaxel in Previously Treated TROP2-positive Advanced or Metastatic Non-squamous NSCLC Without Actionable Genomic Alterations

Inclusion Criteria:

• Pathologically documented Stage IIIB, IIIC, or Stage IV non-squamous non-small celllung cancer (NSCLC) without actionable genomic alterations (AGA) at the time ofrandomisation and meets the criteria for NSCLC:

• Participants must have documented negative test results for epidermal growthfactor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROSproto-oncogene 1 (ROS1) genomic alterations.

• Has no known tumour genomic alterations in neurotrophic tyrosine receptorkinase (NTRK), proto-oncogene B-raf (BRAF), rearranged during transfection (RET), mesenchymal-epithelial transition (MET) exon 14 skipping, Kirsten ratsarcoma viral oncogene homolog (KRAS) G12C, human epidermal growth factorreceptor 2 (HER2) or any other actionable driver oncogenes for which there arelocally approved and available targeted first-line therapies.

• Prospectively assessed trophoblast cell surface protein 2 (TROP2) normalisedmembrane ratio (NMR) positive.

• Documentation of radiographic disease progression while on or after receiving themost recent treatment regimen for advanced or metastatic NSCLC.

• Participants must have received platinum based chemotherapy (PBC) in combinationwith anti-programmed death-protein 1 (anti-PD-1)/anti-programmed death-ligand 1 (anti-PD-L1) monoclonal antibody (mAb) as the only prior line of therapy or receivedPBC and anti-PD-1/anti-PD-L1 monoclonal antibody (in either order) sequentially asthe only 2 prior lines of therapy.

• Provision of acceptable formalin fixed and paraffin embedded (FFPE) tumour samplefor assessment of TROP2.

• At least one lesion not previously irradiated that qualifies as a ResponseEvaluation Criteria in Solid Tumours, Version 1.1 (RECIST 1.1) target lesion (TL) atbaseline and can be accurately measured at baseline as ≥ 10 mm in the longestdiameter (except lymph nodes, which must have short axis ≥ 15 mm) with computedtomography (CT) or magnetic resonance imaging (MRI) and is suitable for accuraterepeated measurements.

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.

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

Exclusion Criteria:

• Squamous, mixed NSCLC, or small cell lung cancer (SCLC) histology.

• NSCLC disease that is eligible for definitive local therapy alone.

• History of another primary malignancy other than NSCLC, except for malignancytreated with curative intent with no known active disease within 3 years beforerandomisation and of low potential risk for recurrence.

• Spinal cord compression or brain metastases, unless asymptomatic, stable, and notrequiring treatment with corticosteroids or anticonvulsants for at least 7 daysprior to randomisation.

• Clinically significant corneal disease.

• Has active or uncontrolled hepatitis B or C virus infection.

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

• Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, orantifungals.

• History of non-infectious interstitial lung disease (ILD)/pneumonitis includingradiation pneumonitis that required steroids, has current ILD/pneumonitis, or hassuspected ILD/pneumonitis that cannot be ruled out by imaging at screening.

• Severe pulmonary function compromise per Investigator discretion.