Osimertinib after definitive chemoradiotherapy in unresectable stage III epidermal growth factor receptor-mutated non-small-cell lung cancer: analyses of central nervous system efficacy and distant progression from the phase III LAURA study

S Lu; M-J Ahn; T Reungwetwattana; M Özgüroğlu; T Kato; J C-H Yang; M Huang; F Fujiki; T Inoue; L-V Quang; V Sriuranpong; D Vicente; C Fuentes; A A Chaudhry; L Poole; E Armenteros Monterroso; Y Rukazenkov; T van der Gronde; S S Ramalingam

doi:10.1016/j.annonc.2024.08.2243

Osimertinib after definitive chemoradiotherapy in unresectable stage III epidermal growth factor receptor-mutated non-small-cell lung cancer: analyses of central nervous system efficacy and distant progression from the phase III LAURA study

Ann Oncol. 2024 Sep 11:S0923-7534(24)03823-7. doi: 10.1016/j.annonc.2024.08.2243. Online ahead of print.

Authors

S Lu¹, M-J Ahn², T Reungwetwattana³, M Özgüroğlu⁴, T Kato⁵, J C-H Yang⁶, M Huang⁷, F Fujiki⁸, T Inoue⁹, L-V Quang¹⁰, V Sriuranpong¹¹, D Vicente¹², C Fuentes¹³, A A Chaudhry¹⁴, L Poole¹⁵, E Armenteros Monterroso¹⁶, Y Rukazenkov¹⁷, T van der Gronde¹⁸, S S Ramalingam¹⁹

Affiliations

¹ Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: shun_lu@hotmail.com.
² Department of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
³ Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
⁴ Department of Internal Medicine, Division of Medical Oncology, Clinical Trial Unit, Istanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, Istanbul, Türkiye.
⁵ Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan.
⁶ Department of Oncology, National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan.
⁷ Division of Thoracic Tumor Multimodality Treatment and Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Sichuan, China.
⁸ ICESP-Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil.
⁹ Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.
¹⁰ Department of Oncology, Hanoi Medical University, Hanoi, Vietnam.
¹¹ Division of Medical Oncology, Faculty of Medicine, Chulalongkorn University and the King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
¹² Medical Oncology Department, Hospital Universitario Virgen de Macarena, Sevilla, Spain.
¹³ Department of Oncology, Centro Médico Dra. De Salvo, Buenos Aires, Argentina.
¹⁴ Late-stage Development, Oncology R&D, AstraZeneca, Gaithersburg, USA.
¹⁵ Biometrics, Late-stage Development, Oncology R&D, AstraZeneca, Cambridge, UK.
¹⁶ Late-stage Development, Oncology R&D, AstraZeneca, Barcelona, Spain.
¹⁷ Late-stage Development, Oncology R&D, AstraZeneca, Cambridge, UK.
¹⁸ Late-stage Development, Oncology R&D, AstraZeneca, New York.
¹⁹ Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, USA.

PMID: 39289145
DOI: 10.1016/j.annonc.2024.08.2243

Abstract

Background: Distant metastases in non-small-cell lung cancer (NSCLC) are a poor prognostic factor that negatively impact quality of life. The central nervous system (CNS) is a common site of distant progression in epidermal growth factor receptor-mutated (EGFRm) NSCLC. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor recommended for advanced EGFRm NSCLC and as adjuvant treatment for resected EGFRm NSCLC. In LAURA (NCT03521154), osimertinib demonstrated statistically significant improvement in progression-free survival (PFS) versus placebo in unresectable stage III EGFRm NSCLC without progression during/following chemoradiotherapy (CRT). CNS efficacy and time to death or distant metastases (TTDM) analyses are reported here.

Patients and methods: Patients without progression during/following definitive platinum-based CRT were randomised 2 : 1 to receive osimertinib (80 mg daily) or placebo until progression [by blinded independent central review (BICR)] or discontinuation. The primary endpoint was PFS by BICR. CNS PFS by neuroradiologist BICR and TTDM by BICR were secondary endpoints.

Results: Overall, 216 patients were randomised (143 osimertinib, 73 placebo). Median CNS PFS by neuroradiologist BICR was not reached [95% confidence interval (CI) not calculable (NC)-NC] with osimertinib versus 14.9 months (95% CI 7.4 months-NC) with placebo; hazard ratio (HR) for CNS PFS: 0.17 (95% CI 0.09-0.32). CNS PFS analysis by investigator assessment was consistent with BICR assessment. The cumulative incidence of CNS progression at 12 months was 9% (95% CI 5% to 14%) with osimertinib and 36% (95% CI 24% to 47%) with placebo. There was clinically meaningful improvement in TTDM with osimertinib versus placebo; HR for TTDM: 0.21 (95% CI 0.11-0.38). The cumulative incidence of distant metastases at 12 months was 11% (95% CI 6% to 17%) with osimertinib and 37% (95% CI 26% to 48%) with placebo.

Conclusions: Osimertinib demonstrated clinically meaningful improvements in CNS PFS and TTDM versus placebo, supporting osimertinib post-CRT as the standard of care in unresectable stage III EGFRm NSCLC.

Keywords: central nervous system metastases; distant metastases; epidermal growth factor receptor mutation; locally advanced stage III; non-small-cell lung cancer; osimertinib.