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한지연
한지연 (Ji-Youn Han) 저자 이메일 보기
국립암센터
 
조회 361  인쇄하기 주소복사 트위터 공유 페이스북 공유 
Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study
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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

논문정보
- 형식: Research article
- 게재일: 2020년 02월 (BRIC 등록일 2020-02-07)
- 연구진: 국내+국외 연구진
- 분야: Cancer Biology/Oncology
NK세포에 의한 손상된 말초신경 제거 기전 – 새로운 만성통증 치료법[ Cell ]
오석배
발표: 오석배 (서울대학교)
일자: 2020년 3월 5일 (목) 오전 10시 (한국시간)
언어: 한국어
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박수형
발표: 박수형 (기초과학연구원)
일자: 2020년 3월 12일 (목) 오후 03시 (한국시간)
언어: 한국어
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오승현 (가천대학교 약학대학)
이진수 (국립암센터 폐암연구과)
이호영 (서울대학교)
관련분야 논문보기
Cancer Biology/Oncology

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날짜: 2020.03.31
주관: 서경배과학재단
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