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
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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DOI：
10.1016/s1470-2045(19)30785-5
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发表时间：
2020-03-01
期刊：
影响因子：
51.1
通讯作者：
Oxnard, Geoffrey
中科院分区：
文献类型：
--
作者：
Sequist, Lecia, V;Han, Ji-Youn;Oxnard, Geoffrey
背景临床前数据表明，EGFR酪氨酸激酶抑制剂（TKI）联合MET TKI是一种可能的治疗EGFR突变阳性肺癌伴MET驱动的获得性耐药的方法。savolitinib（也称为AZD 6094、HMPL-504、volitinib）（一种强效、选择性MET TKI）+奥希替尼（一种第三代EGFR TKI）的I期安全性数据为研究提供了推荐剂量。在这里，我们报告的评估奥希替尼加savolitinib在两个全球扩展队列的TATTON study.Methods在这个多臂，多中心，开放标签，1b期研究，我们招募成人患者（年龄=18岁）与局部晚期或转移性，MET扩增，EGFR突变阳性的非小细胞肺癌，EGFR TKI进展。我们考虑了两个扩展队列：部分B和D。B部分包括3个患者队列：既往接受过第三代EGFR TKI治疗的患者（B1）和既往未接受过第三代EGFR TKI治疗的Thr 790 Met阴性（B2）或Thr 790 Met阳性（B3）患者。在B部分，患者每日口服奥希替尼80 mg和savolitinib 600 mg;方案修订后（2018年3月12日），体重不超过55 kg的患者接受300 mg剂量的savolitinib。D部分入组了既往未接受过第三代EGFR TKI治疗且Thr 790 Met阴性的患者;这些患者接受了奥希替尼80 mg + savolitinib 300 mg治疗。主要终点是安全性和耐受性，在所有给药患者中进行了评估。次要终点包括根据RECIST 1.1达到客观缓解的患者比例，并在所有给药患者和所有中心确认MET扩增的患者中进行评估。在这里，我们提供了一项中期分析，数据截止日期为2019年3月29日。本研究注册于ClinicalTrials.gov，NCT 02143466。结果在2015年5月26日至2019年2月14日期间，我们在部分B入组了144例患者，在部分D入组了42例患者。在B部分，138例患者接受奥希替尼+savolitinib 600 mg（n=130）或300 mg（n=8）。在D部分，42例患者接受奥希替尼+savolitinib 300 mg。B部分138例患者中的79例（57%）和D部分42例患者中的16例（38%）发生了3级或更严重的不良事件。B部分115例（83%）患者和D部分25例（60%）患者发生可能与savolitinib相关的不良事件，B部分62例（45%）患者和D部分11例（26%）患者报告了严重不良事件; 2例导致死亡的不良事件（急性肾衰竭和死亡，原因不明）可能与B部分的治疗相关。在部分B和部分D中分别在66例（48%; 95%CI 3956）和23例（64%; 4679）患者中观察到客观部分缓解。解释奥希替尼和savolitinib联合治疗在MET扩增、EGFR突变阳性、晚期NSCLC患者中具有可接受的风险-获益特征和令人鼓舞的抗肿瘤活性，这些患者在既往EGFR TKI治疗后出现疾病进展。这种联合治疗可能是MET驱动的EGFR TKI耐药患者的潜在治疗选择。版权所有（C）2020爱思唯尔有限公司保留所有权利。
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 3956) patients in part B and 23 (64%; 4679) in part D.Interpretation The combination of osimertinib and savolitinib has acceptable riskbenefit 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. Copyright (C) 2020 Elsevier Ltd. All rights reserved.