PURPOSE: We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status. METHODS: Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR). RESULTS: On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR. CONCLUSION: Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases.

1st Faculty of Medicine Charles University Thomayer Hospital Prague Czech Republic

Department of Clinical Oncology Rondebosch Oncology Centre Cape Town South Africa

Department of Internal Medicine Prince of Songkla University Songkhla Thailand

Department of Life Sciences National Chung Hsing University Taichung Taiwan

Department of Medical Oncology and Hematology University Health Network Princess Margaret Cancer Centre Toronto ON Canada

Department of Medical Oncology Cancer Care Centre St George Hospital Kogarah NSW Australia

Department of Medical Oncology Harbin Medical University Cancer Hospital Harbin China

Department of Medical Oncology Lowe Center for Thoracic Oncology Dana Farber Cancer Institute Boston MA

Department of Medical Oncology Thoracic Group and International Center for Thoracic Cancers Gustave Roussy Villejuif France

Department of Oncology Biometrics AstraZeneca Cambridge United Kingdom

Department of Oncology Instituto Nacional de Enfermedades Neoplasicas Lima Peru

Department of Oncology National Taiwan University Hospital and National Taiwan University Cancer Center National Taiwan University Taipei Taiwan

Department of Respiratory Medicine Saitama Medical University International Medical Center Hidaka Japan

Department of Respiratory Medicine Shanghai Chest Hospital Shanghai Jiao Tong University Shanghai China

Department of Thoracic Oncology Jilin Cancer Hospital Changchun China

Department of Thoracic Oncology Kanagawa Cancer Center Yokohama Japan

Division of Chest Medicine Department of Internal Medicine Taichung Veterans General Hospital Taichung Taiwan

Division of Oncology Department of Internal Medicine Faculty of Medicine Chiang Mai University Chiang Mai Thailand

Division of Thoracic Oncology Shizuoka Cancer Center Shizuoka Japan

Faculty of Medicine Paris Saclay University Paris France

Federal State Budgetary Institution N N Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation Moscow Russia

Late Development Oncology AstraZeneca Cambridge United Kingdom

Late Development Oncology AstraZeneca Gaithersburg MD

Medical Oncology Department Bradford Hill Clinical Research Center Santiago Chile

Research Institute for Diseases of the Chest Graduate School of Medical Sciences Kyushu University Fukuoka Japan

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