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

Inclusion Criteria:

Age

1. Participant must be ≥ 18 years. Type of Participant and Disease Characteristics

2. Histologically or cytologically documented nonsquamous NSCLC. NSCLC of mixedhistology is allowed if adenocarcinoma is the predominant histology. Mixedsmall-cell lung cancer and NSCLC histology, and sarcomatoid variant of NSCLC isineligible.

3. Stage IIIB or IIIC or Stage IV metastatic NSCLC or recurrent NSCLC (based on theAmerican Joint Committee on Cancer Edition 8) not amenable to curative surgery ordefinitive chemoradiation at the time of randomisation.

4. Participants must not have received prior EGFR TKIs or other systemic therapy forStage IIIB, IIIC or IV NSCLC.

5. The tumour harbors at least 1 of the 2 common EGFR mutations known to be associatedwith EGFR-TKI sensitivity (Ex19del or L858R), either alone or in combination withother genomic alterations, which may include EGFR T790M, assessed by aCLIA-certified (US sites) or an accredited (outside of the US) local laboratory orby central prospective tissue testing.

6. For participants enrolled in randomisation period, mandatory provision of anunstained, archival tumour tissue sample in a quantity sufficient to allow forcentral 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 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 CT or MRI andis suitable for accurate repeated measurements.

9. Adequate bone marrow reserve and organ function within 7 days before the first doseof study intervention. Sex and Contraceptive/Barrier Requirements

10. Contraceptive use by males or females should be consistent with local regulationsregarding the methods of contraception for those participating in clinical studies. Other Inclusion Criteria

11. All races, gender and ethnic groups are eligible for this study.

Exclusion Criteria:

1. As judged by the investigator, any evidence of diseases (such as severe oruncontrolled systemic diseases, including active bleeding diseases, psychiatricillness/social situations), history of allogenic organ transplant, and/or substanceabuse which, in the investigator's opinion, makes it undesirable for the participantto participate in the study or that would jeopardise compliance with the protocol.

2. Refractory nausea and vomiting, chronic gastrointestinal disease, inability toswallow the formulated product, or previous significant bowel resection that wouldpreclude adequate absorption, distribution, metabolism, or excretion of osimertinib.

3. History of another primary malignancy.

4. Spinal cord compression and unstable brain metastases, as defined by Protocol.

5. Clinically significant corneal disease.

6. Has active or uncontrolled hepatitis B or C virus infection, as defined by Protocol.

7. Known HIV infection that is not well controlled, as defined by Protocol.

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, as defined by Protocol.

10. Uncontrolled or significant cardiac disease, as defined by Protocol.

11. Past medical history of ILD/penumonitis, including radiation pneumonitis (apart fromradiation pneumonitis that did not require steroids), or drug-inducedILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out byimaging at screening.

12. Pulmonary embolism within 3 months of the study enrolment or has severe pulmonaryfunction compromise. Prior/Concomitant Therapy

13. Prior exposure to any agent including an ADC containing a chemotherapeutic agenttargeting topoisomerase I, TROP2-targeted therapy. Prior/Concurrent Clinical Study Experience

14. Participants with a known history of severe hypersensitivity reactions to eitherDato-DXd and osimertinib or any excipients of Dato DXd and osimertinib or drugs witha similar chemical structure or class to DXd and osimertinib.