A trial to learn how safe Dato-DXd is when given with osimertinib, and how well it works compared to osimertinib alone in people who have advanced or metastatic non-small cell lung cancer (NSCLC) with a mutation in the EGFR gene

Prior treatment

• Has clinically severe pulmonary function compromise resulting from intercurrent pulmonary illnesses, including, but not limited to: (a) any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the study enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc). (b) Any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement (eg, rheumatoid arthritis, Sjögren’s syndrome, sarcoidosis, etc). (c) Prior pneumonectomy.
• Prior exposure to any agent including an ADC containing a chemotherapeutic agent targeting topoisomerase I, TROP2-targeted therapy.
• Received prior radiotherapy to the brain within 2 weeks, or received radiotherapy to chest within 4 weeks of start of study intervention.
• 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.
• History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 2 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected non-melanoma skin cancer (basal cell carcinoma of the skin or squamous cell carcinoma of the skin) and curatively treated in situ disease.

Other illness

• As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active bleeding diseases), history of allogenic organ transplant 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.
• Uncontrolled or significant cardiac disease, as defined by Protocol.
• Past medical history of ILD/penumonitis, including radiation pneumonitis (apart from radiation pneumonitis that did not require steroids), or drug-induced ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
• 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.
• Clinically significant corneal disease.
• Has active or uncontrolled hepatitis B or C virus infection, as defined by Protocol.
• Known HIV infection that is not well controlled, as defined by Protocol.
• Uncontrolled infection requiring systemic 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). Use of systemic antibiotics within 14 days of randomization.

Other

• Spinal cord compression and/or unstable brain metastases, as defined by Protocol.
• Resting ECG with clinically abnormal findings, as defined by Protocol.

• Participant must be ≥ 18 years at the time of signing the ICF.
• Adequate bone marrow reserve and organ function.
• Male and/or female, assigned at birth, inclusive of all gender identities. Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
• All races, gender and ethnic groups are eligible for this study.
• Histologically or cytologically documented non-squamous NSCLC. NSCLC of mixed histology is allowed if adenocarcinoma is the predominant histology. Mixed smallcell lung cancer and NSCLC histology, and sarcomatoid variant of NSCLC is ineligible.
• 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.
• Participants must not have received prior EGFR TKIs or other systemic therapy for Stage IIIB, IIIC or IV NSCLC.
• The tumour harbors at least 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 genomic alterations, which may include EGFR T790M, assessed by a CLIA-certified (US sites) or an accredited (outside of the US) local laboratory or by central prospective tissue testing.
• 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.
• WHO performance status of 0 or 1, with no deterioration over the previous 2 weeks prior the first dose of study intervention.
• Minimum life expectancy of 12 weeks.
• 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.