Note: Participants on osimertinib treatment (osimertinib only arm or who have discontinued Datopotamab Deruxtecan while are still receiving osimertinib) are required to attend visits to perform assessments every 6 weeks from Cycle 7 until Cycle 17 and then visits every 12 weeks until disease progression, IP discontinuation or primary PFS DCO. Participants who are receiving osimertinib + Datopotamab Deruxtecan are still required to attend visit to perform assessment every 3 weeks (q3w) per SoA. conditions: Non-small Cell Lung Cancer studyType: INTERVENTIONAL phases: PHASE3 allocation: RANDOMIZED interventionModel: PARALLEL primaryPurpose: TREATMENT masking: NONE count: 582 type: ESTIMATED name: Osimertinib name: Datopotamab Deruxtecan measure: To demonstrate the superiority of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of PFS by BICR in all randomised participants. measure: To demonstrate the superiority of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of OS in all randomised participants. measure: To demonstrate the effectiveness of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of PFS on CNS metastases in participants with CNS metastases at baseline measure: To demonstrate the effectiveness of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of PFS by investigator in all randomised participants. measure: To demonstrate the effectiveness of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of ORR in all randomised participants with measurable disease at baseline. measure: To demonstrate the effectiveness of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of DoR in all randomised participants with measurable disease at baseline. measure: To demonstrate the effectiveness of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib on the prevention of CNS metastases measure: To demonstrate the effectiveness of osimertinib in combination with Datopotamab Deruxtecan relative to osimertinib by assessment of PFS2 in all randomised participants measure: To assess the PK of osimertinib and Datopotamab Deruxtecan measure: To investigate the immunogenicity of Datopotamab Deruxtecan measure: To compare the local EGFR mutation test result used for patient selection with the retrospective central cobas® EGFR Mutation Test v2 results from baseline tumour samples measure: To demonstrate the effectiveness of osimertinib in combination with Datopotamab Deruxtecan vs. osimertinib monotherapy based on the cobas® EGFR Mutation Test v2 plasma screening test result for Ex19del or L858R EGFR mutations sex: ALL minimumAge: 18 Years stdAges: ADULT stdAges: OLDER_ADULT facility: Research Site city: Clayton zip: 3168 country: Australia lat: -37.91667 lon: 145.11667 facility: Research Site city: Kogarah zip: 2217 country: Australia lat: -33.98333 lon: 151.11667 facility: Research Site city: Changchun zip: 130000 country: China lat: 43.88 lon: 125.32278 facility: Research Site city: Chongqing zip: 400030 country: China lat: 29.56278 lon: 106.55278 facility: Research Site city: Jinan zip: 250021 country: China lat: 36.66833 lon: 116.99722 facility: Research Site city: Jinan zip: 250117 country: China lat: 36.66833 lon: 116.99722 facility: Research Site city: Kunming zip: 650118 country: China lat: 25.03889 lon: 102.71833 facility: Research Site city: Linhai zip: 318000 country: China lat: 28.85535 lon: 121.14469 facility: Research Site city: Shanghai zip: 200030 country: China lat: 31.22222 lon: 121.45806 facility: Research Site city: Seoul zip: 06351 country: Korea, Republic of lat: 37.566 lon: 126.9784 facility: Research Site city: Seoul zip: 120-752 country: Korea, Republic of lat: 37.566 lon: 126.9784 facility: Research Site city: Seoul zip: 13620 country: Korea, Republic of lat: 37.566 lon: 126.9784 facility: Research Site city: Taipei City zip: 106 country: Taiwan lat: 25.04776 lon: 121.53185 facility: Research Site city: Taipei zip: 10002 country: Taiwan lat: 25.04776 lon: 121.53185 facility: Research Site city: Taoyuan zip: 333 country: Taiwan lat: 24.95233 lon: 121.20193 hasResults: False