卡马替尼治疗外显子 14 突变或扩增的非小细胞肺癌。
Capmatinib in Exon 14-Mutated or -Amplified Non-Small-Cell Lung Cancer.
机构信息
From the Department I of Internal Medicine, Center for Integrated Oncology, University Hospital Cologne and University of Cologne, Cologne (J.W.), Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg, Heidelberg (M.T.), the Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen (T.R.O.), and Hämato-Onkologie Hamburg, Hamburg (E.L.) - all in Germany; the National Hospital Organization Kyushu Cancer Center, Fukuoka (T.S.), Aichi Cancer Center, Nagoya (T.H.), the Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo (M.N.), the Department of Respiratory Medicine, Okayama University Hospital, Okayama (K.O.), and the National Kyushu Cancer Center, Fukuoka (R.T.) - all in Japan; the National Cancer Center, Gyeonggi-do (J.-Y.H.), and the Department of Internal Medicine, Seoul National University Hospital, Seoul (T.-M.K.) - both in South Korea; the Hospital Clinic of Barcelona (N.R.), Translational Genomic and Targeted Therapeutics in Solid Tumors (IDIBAPS) (N.R.), and Vall d'Hebron University Hospital-Vall d'Hebron Institute of Oncology (E.F.), Barcelona; David Geffen School of Medicine at UCLA, Los Angeles (E.B.G.); the University of Groningen and University Medical Center Groningen, Groningen (H.J.M.G.), Erasmus MC Cancer Institute, Rotterdam (M.J.), and the Netherlands Cancer Institute, Amsterdam (E.F.S.) - all in the Netherlands; the National Cancer Centre Singapore, Singapore (D.S.W.T.); St. Petersburg Pavlov State Medical University, St. Petersburg, Russia (S.V.O.); University Hospital of Lyon-Sud, Lyon (P.-J.S.), and Novartis Pharma, Rueil-Malmaison (S.L.M.) - both in France; the Respiratory Oncology Unit, University Hospitals KU Leuven, Leuven, Belgium (J.V.); the Department of Respiratory and Critical Care Medicine, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Vienna (M.H.); the Thoracic Oncology Division, European Institute of Oncology, IRCCS, Milan (F.M.); Novartis Pharmaceuticals, East Hanover, NJ (A.R., M.G.); Novartis Pharma, Basel, Switzerland (M.W.-L., M.A.); and Novartis Institutes for BioMedical Research, Cambridge (B.S., O.A.B., X.C.), and Massachusetts General Hospital, Boston (R.S.H.) - both in Massachusetts.
出版信息
N Engl J Med. 2020 Sep 3;383(10):944-957. doi: 10.1056/NEJMoa2002787.
BACKGROUND
Among patients with non-small-cell lung cancer (NSCLC), exon 14 skipping mutations occur in 3 to 4% and amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation.
METHODS
We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with -dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and status ( exon 14 skipping mutation or amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments.
RESULTS
A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2.
CONCLUSIONS
Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a exon 14 skipping mutation, particularly in those not treated previously. The efficacy in -amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.).
背景
在非小细胞肺癌（NSCLC）患者中，exon14 跳跃突变发生率为 3%至 4%，扩增发生率为 1%至 6%。卡马替尼是一种 MET 受体的选择性抑制剂，在具有多种 MET 激活类型的癌症模型中显示出活性。
方法
我们进行了一项多队列、二期研究，评估卡马替尼在 MET 失调的晚期 NSCLC 患者中的作用。患者根据既往治疗线数和状态（肿瘤组织中根据基因拷贝数判断 exon14 跳跃突变或扩增）分配到队列中。患者接受卡马替尼（400mg 片剂）每日两次。主要终点是总缓解（完全或部分缓解），关键次要终点是缓解持续时间；两个终点均由独立审查委员会评估，该委员会成员不知道队列分配。
结果
共有 364 名患者被分配到队列中。在先前接受过 1 或 2 线治疗的 69 例 NSCLC 患者中，exon14 跳跃突变患者的总体缓解率为 41%（95%CI，29 至 53），未接受治疗的 28 例患者的缓解率为 68%（95%CI，48 至 84）；中位缓解持续时间分别为 9.7 个月（95%CI，5.6 至 13.0）和 12.6 个月（95%CI，5.6 至无法估计）。先前接受治疗且基因拷贝数小于 10 的扩增患者疗效有限（患者的总体缓解率为 7%至 12%）。在基因拷贝数为 10 或更高的扩增患者中，先前接受治疗的患者的总体缓解率为 29%（95%CI，19 至 41），未接受治疗的患者的总体缓解率为 40%（95%CI，16 至 68）。最常报告的不良事件是外周水肿（51%）和恶心（45%）；这些事件大多为 1 级或 2 级。
结论
卡马替尼在晚期 NSCLC 患者中表现出显著的抗肿瘤活性，尤其是在未接受治疗的患者中。exon14 跳跃突变患者的疗效高于扩增患者，在基因拷贝数高的肿瘤中高于基因拷贝数低的肿瘤。低级别外周水肿和恶心是主要的毒性作用。（由诺华制药公司资助；GEOMETRY mono-1 临床试验.gov 编号，NCT02414139。）
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