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Publications

Journal Article Ahead of print

PubMed: 42929693 DOI: 10.1056/NEJMoa2611335

Osimertinib-Savolitinib in Advanced NSCLC after Progression during EGFR-TKI Therapy.

N Engl J Med

Authors: Shun Lu, Nicolas Girard, James Chih-Hsin Yang, Frances A Shepherd, Xiaorong Dong, Surein Arulananda, Giulio Metro, Hidetoshi Hayashi, Laura Bonanno, Yu Jung Kim, Zhe Liu, Myung-Ju Ahn, Yuping Sun, Thuong Vu Le, Silvia Novello, Sang-We Kim, Yanqiu Zhao, Phuong Nguyen, Mariana Brandão, Yongsheng Wang, Missak Haigentz, Daniel Misch, Mariano Provencio Pulla, Wen-Tsung Huang, Clarissa Baldotto, Marcelo Tatangelo, Colin R Lindsay, Ryan J Hartmaier, Rafal Lolo, Balakumar Swaminathan, Alexander Gont, Francis Maria Esposito, Yusuke Okuma

Affiliations

  • Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai.
  • Paris-Saclay University, Université de Versailles Saint-Quentin-en-Yvelines, Versailles, France.
  • Department of Medical Oncology, Institut du Thorax Curie-Montsouris, Paris.
  • Department of Medical Oncology, National Taiwan University Hospital and Graduate Institute of Oncology, National Taiwan University, Taipei.
  • Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto.
  • Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • Department of Medical Oncology, Monash Health, Clayton, VIC, Australia.
  • Medical Oncology, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy.
  • Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan.
  • Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
  • Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padua, Italy.
  • Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.
  • Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing.
  • Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
  • Phase 1 Clinical Trial Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
  • Internal Medicine, University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam.
  • Respiratory Department, Ho Chi Minh City University Medical Center, Ho Chi Minh City, Vietnam.
  • Department of Oncology, University of Turin, San Luigi Hospital-Orbassano, Turin, Italy.
  • Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
  • Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China.
  • Department of Medical Oncology, Vietnam National Cancer Hospital (K Hospital), Hanoi.
  • Thoracic Oncology Functional Unit, Institut Jules Bordet, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels.
  • West China Hospital of Sichuan University, Chengdu, China.
  • Division of Thoracic Oncology, Rutgers Cancer Institute, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ.
  • Department of Pneumology, Heckeshorn Lung Clinic, Helios Klinikum Emil von Behring, Berlin.
  • Department of Medical Oncology, Hospital Universitario Puerta de Hierro, Madrid.
  • Division of Hematology-Oncology, Department of Internal Medicine, Chi Mei Medical Center Liouying, Tainan, Taiwan.
  • Department of Clinical Research, Institute D'Or for Research and Education, Rio de Janeiro.
  • Department of Clinical Oncology, Sanatorio Británico, Rosario, Argentina.
  • Christie NHS Foundation Trust, Manchester, United Kingdom.
  • Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom.
  • Cancer Research U.K. Lung Cancer Centre of Excellence, Manchester, United Kingdom.
  • Translational Medicine, Oncology R&D, AstraZeneca, Boston.
  • Precision Diagnostics Development, Oncology R&D, AstraZeneca, Warsaw, Poland.
  • Biometrics, Late-stage Development, Oncology R&D, AstraZeneca, Mississauga, ON, Canada.
  • Late Development Oncology, Oncology R&D, AstraZeneca, Mississauga, ON, Canada.
  • Late Development Oncology, Oncology R&D, AstraZeneca, Barcelona.
  • Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo.

Abstract

BACKGROUND

Savolitinib is an oral, potent, highly selective MET-tyrosine kinase inhibitor (TKI). Combination therapy with savolitinib and osimertinib, an epidermal growth factor receptor (EGFR)-TKI, has shown activity in patients with EGFR-mutated, advanced non-small-cell lung cancer (NSCLC) with MET overexpression, MET amplification, or both, after progression during EGFR-TKI therapy.

METHODS

In this international, phase 3, open-label trial, we randomly assigned, in a 1:1 ratio, patients with EGFR-mutated, locally advanced or metastatic NSCLC with MET overexpression (staining intensity of 3+ for MET in ≥90% of tumor cells on immunohistochemical analysis), MET amplification (≥10 gene copies on fluorescence in situ hybridization), or both whose disease had progressed during osimertinib therapy to receive osimertinib (at a dose of 80 mg once daily) plus savolitinib (300 mg twice daily) or intravenous platinum-pemetrexed. The primary end point was progression-free survival, as assessed by blinded independent central review. Secondary end points included overall survival and safety.

RESULTS

Of the 1746 patients screened, 338 were randomly assigned to receive osimertinib-savolitinib (171 patients) or platinum-pemetrexed (167 patients). Osimertinib-savolitinib led to significantly longer progression-free survival than platinum-pemetrexed (hazard ratio for disease progression or death, 0.55; 95% confidence interval [CI], 0.42 to 0.72; P<0.001), as well as significantly longer overall survival (hazard ratio for death, 0.68; 95% CI, 0.50 to 0.91; P = 0.01; final analysis). The Kaplan-Meier estimate of 12-month progression-free survival was 36% in the osimertinib-savolitinib group and 10% in the platinum-pemetrexed group, and the estimate of 12-month overall survival was 70% and 53%, respectively. The most frequently reported adverse events that occurred during treatment in the osimertinib-savolitinib group were peripheral edema (in 49% of the patients), anemia (in 26%), and diarrhea (in 26%). Grade 3 or higher adverse events during treatment were reported in 64% of the patients in the osimertinib-savolitinib group and in 63% of those in the platinum-pemetrexed group.

CONCLUSIONS

Osimertinib-savolitinib led to significantly longer progression-free and overall survival than platinum-pemetrexed among patients with EGFR-mutated, locally advanced or metastatic NSCLC with MET overexpression, MET amplification, or both that had progressed during osimertinib therapy (Funded by AstraZeneca; SAFFRON ClinicalTrials.gov number, NCT05261399.).

MeSH

Cells, Pemetrexed, Progression-Free Survival, Neoplasms, Carcinoma, Non-Small-Cell Lung, Drug-Related Side Effects And Adverse Reactions, Therapeutics