한빛사 논문
Lecia V Sequist MDa,†, Prof Ji-Youn Han MDb,†, Prof Myung-Ju Ahn MDc, Byoung Chul Cho MDd, Helena Yu MDe, Prof Sang-We Kim MDf, Prof James Chih-Hsin Yang MDg, Jong Seok Lee MDh, Wu-Chou Su MDi, Dariusz Kowalski MDj, Sergey Orlov PhDk, Mireille Cantarini MDl, Remy B Verheijen PhDl, Anders Mellemgaard MDl, Lone Ottesen MDl, Paul Frewer MScm, Xiaoling Ou PhDm, Geoffrey Oxnard MDn,*
a Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
b Center for Lung Cancer, National Cancer Center, Goyang, South Korea
c Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, South Korea
d Department of Medicine, Yonsei Cancer Center, Seoul, South Korea
e Department of Medical Oncology, Memorial Sloan Kettering Cancer Centre, New York, NY, USA
f Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
g Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
h Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul, South Korea
i Department of Internal Medicine, National Cheng Kung University Hospital, Tainan City, Taiwan
j Department of Lung Cancer and Thoracic Oncology, Centrum Onkologii, Instytut im Marii Sklodowskiej-Curie, Warsaw, Poland
k BioEq, Saint Petersburg, Russia
l Oncology R&D, AstraZeneca, Cambridge, UK
m Oncology Biometrics, AstraZeneca, Cambridge, UK
n Department of Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
*Correspondence : Geoffrey Oxnard
†Joint lead authors
Abstract
Background
Preclinical data suggest that EGFR tyrosine kinase inhibitors (TKIs) plus MET TKIs are a possible treatment for EGFR mutation-positive lung cancers with MET-driven acquired resistance. Phase 1 safety data of savolitinib (also known as AZD6094, HMPL-504, volitinib), a potent, selective MET TKI, plus osimertinib, a third-generation EGFR TKI, have provided recommended doses for study. Here, we report the assessment of osimertinib plus savolitinib in two global expansion cohorts of the TATTON study.
Methods
In this multi-arm, multicentre, open-label, phase 1b study, we enrolled adult patients (aged ≥18 years) with locally advanced or metastatic, MET-amplified, EGFR mutation-positive non-small-cell lung cancer, who had progressed on EGFR TKIs. We considered two expansion cohorts: parts B and D. Part B consisted of three cohorts of patients: those who had been previously treated with a third-generation EGFR TKI (B1) and those who had not been previously treated with a third-generation EGFR TKI who were either Thr790Met negative (B2) or Thr790Met positive (B3). In part B, patients received oral osimertinib 80 mg and savolitinib 600 mg daily; after a protocol amendment (March 12, 2018), patients who weighed no more than 55 kg received a 300 mg dose of savolitinib. Part D enrolled patients who had not previously received a third-generation EGFR TKI and were Thr790Met negative; these patients received osimertinib 80 mg plus savolitinib 300 mg. Primary endpoints were safety and tolerability, which were assessed in all dosed patients. Secondary endpoints included the proportion of patients who had an objective response per RECIST 1.1 and was assessed in all dosed patients and all patients with centrally confirmed MET amplification. Here, we present an interim analysis with data cutoff on March 29, 2019. This study is registered with ClinicalTrials.gov, NCT02143466.
Findings
Between May 26, 2015, and Feb 14, 2019, we enrolled 144 patients into part B and 42 patients into part D. In part B, 138 patients received osimertinib plus savolitinib 600 mg (n=130) or 300 mg (n=8). In part D, 42 patients received osimertinib plus savolitinib 300 mg. 79 (57%) of 138 patients in part B and 16 (38%) of 42 patients in part D had adverse events of grade 3 or worse. 115 (83%) patients in part B and 25 (60%) patients in part D had adverse events possibly related to savolitinib and serious adverse events were reported in 62 (45%) patients in part B and 11 (26%) patients in part D; two adverse events leading to death (acute renal failure and death, cause unknown) were possibly related to treatment in part B. Objective partial responses were observed in 66 (48%; 95% CI 39–56) patients in part B and 23 (64%; 46–79) in part D.
Interpretation
The combination of osimertinib and savolitinib has acceptable risk–benefit profile and encouraging antitumour activity in patients with MET-amplified, EGFR mutation-positive, advanced NSCLC, who had disease progression on a previous EGFR TKI. This combination might be a potential treatment option for patients with MET-driven resistance to EGFR TKIs.
Funding
AstraZeneca.
Introduction
EGFR tyrosine kinase inhibitors (TKIs) are the preferred first-line treatment for patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (NSCLC).1, 2 However, patients treated with an EGFR TKI are likely to develop resistance through various mechanisms, including acquired EGFR resistance mutations such as Thr790Met, development of a bypass track (such as MET amplification, HER2 amplification, or acquired translocations), or a histological shift (such as small-cell lung cancer transformation).3, 4, 5, 6 The EGFR Thr790Met resistance mutation is observed in approximately 50% of patients who develop resistance to a first-generation or second-generation EGFR TKIs.7
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