Phase III, Open-label Study of First-line Osimertinib With or Without Datopotamab Deruxtecan for EGFRm Locally Advanced or Metastatic Non-small Cell Lung Cancer

Eligibility Criteria

• 1. Participant must be ≥ 18 years; Participant from Japan must be ≥ 20 years, at the time of signing the ICF.
• 2. Histologically or cytologically documented nonsquamous NSCLC.
• 3. Stage IIIB or IIIC or Stage IV metastatic NSCLC or recurrent NSCLC (based on the American Joint Committee on Cancer Edition 8) not amenable to curative surgery or definitive chemoradiation at the time of randomisation.
• 4. Participants must not have received prior EGFR TKIs or other systemic therapy for Stage IIIB, IIIC or IV NSCLC.
• 5. The tumour harbors 1 of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del or L858R), either alone or in combination with other EGFR mutations.
• 6. For participants enrolled in randomisation period, mandatory provision of an unstained, archival tumour tissue sample in a quantity sufficient to allow for central confirmation of the EGFR mutation status.
• 7. WHO performance status of 0 or 1.
• 8. At least one lesion not previously irradiated that qualifies as a RECIST 1.1 TL at baseline and can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have short axis ≥15 mm) with CT or MRI and is suitable for accurate repeated measurements.
• 9. Adequate bone marrow reserve and organ function within 7 days before the first dose of study intervention .
• 10. Male and female Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• 11. All races, gender and ethnic groups are eligible for this study.
• 1. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active bleeding diseases, psychiatric illness/social situations), history of allogenic organ transplant, and/or substance abuse which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol.
• 2. Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of osimertinib.
• 3. History of another primary malignancy.
• 4. Spinal cord compression and unstable brain metastases.
• 5. Clinically significant corneal disease.
• 6. Has active or uncontrolled hepatitis B or C virus infection.
• 7. Known HIV infection that is not well controlled.
• 8. Uncontrolled infection requiring i.v. antibiotics, antivirals or antifungals; suspected infections (eg, prodromal symptoms); or inability to rule out infections (participants with localised fungal infections of skin or nails are eligible).
• 9. Resting ECG with clinically abnormal findings.
• 10. Uncontrolled or significant cardiac disease.
• 11. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
• 12. Has severe pulmonary function compromise.
• 13. Prior exposure to any agent including an ADC containing a chemotherapeutic agent targeting topoisomerase I, TROP2-targeted therapy.
• 14. Participants with a known history of severe hypersensitivity reactions to either Dato-DXd and osimertinib or any excipients of Dato DXd and osimertinib or drugs with a similar chemical structure or class to DXd and osimertinib.