德国科隆大学医院Jürgen Wolf团队研究了卡马替尼治疗MET外显子14跳跃突变或MET扩增的非小细胞肺癌的效果。2020年9月3日，《新英格兰医学杂志》发表了该项成果。

在非小细胞肺癌（NSCLC）患者中，MET外显子14跳跃突变发生率为3-4％，而MET扩增发生率为1-6％。卡马替尼是MET受体的选择性抑制剂，已在各种MET激活类型的癌症模型中显示出抗肿瘤活性。

研究组进行了一项多队列、临床2期研究，招募了364名MET失调的晚期NSCLC患者。根据既往治疗方案和MET状态对患者进行分组，所有患者接受卡马替尼治疗。主要终点是总体缓解率，关键次要终点是缓解持续时间。

对于MET外显子14跳跃突变的NSCLC患者，先前接受过一线或二线治疗的69名患者中有41%、未接受过治疗的28名患者中有68%获得总体缓解，中位缓解持续时间分别为9.7个月和12.6个月。对于先前接受过治疗的MET扩增、且基因拷贝数少于10的患者，治疗效果有限。对于MET扩增且基因拷贝数在10以上的患者，先前接受过治疗的患者中有29%、未接受过治疗的患者中有40%获得总体缓解。最常见的不良反应为外周水肿和恶心，发生率分别为51%和45%，但均为1级或2级。

总之，卡马替尼治疗患有MET外显子14跳跃突变的晚期NSCLC患者显示出明显的抗肿瘤活性，尤其是先前未接受治疗的患者。对于MET扩增的晚期NSCLC患者，基因拷贝数高的患者获益更高。

附：英文原文

Title: Capmatinib in MET Exon 14–Mutated or MET-Amplified Non–Small-Cell Lung Cancer

Author: Jürgen Wolf, M.D.,, Takashi Seto, M.D.,, Ji-Youn Han, M.D., Ph.D.,, Noemi Reguart, M.D., Ph.D.,, Edward B. Garon, M.D.,, Harry J.M. Groen, M.D., Ph.D.,, Daniel S.W. Tan, M.D., Ph.D.,, Toyoaki Hida, M.D., Ph.D.,, Maja de Jonge, M.D., Ph.D.,, Sergey V. Orlov, M.D.,, Egbert F. Smit, M.D., Ph.D.,, Pierre-Jean Souquet, M.D.,, Johan Vansteenkiste, M.D., Ph.D.,, Maximilian Hochmair, M.D.,, Enriqueta Felip, M.D., Ph.D.,, Makoto Nishio, M.D., Ph.D.,, Michael Thomas, M.D.,, Kadoaki Ohashi, M.D., Ph.D.,, Ryo Toyozawa, M.D., Ph.D.,, Tobias R. Overbeck, M.D.,, Filippo de Marinis, M.D., Ph.D.,, Tae-Min Kim, M.D., Ph.D.,, Eckart Laack, M.D.,, Anna Robeva, M.S.,, Sylvie Le Mouhaer, M.Sc.,, Maeve Waldron-Lynch, M.D.,, Banu Sankaran, Ph.D.,, O. Alejandro Balbin, Ph.D.,, Xiaoming Cui, Ph.D.,, Monica Giovannini, M.D.,, Mikhail Akimov, M.D., Ph.D.,, and Rebecca S. Heist, M.D., M.P.H.

Issue&Volume: 2020-09-02

Abstract: Background

Among patients with non–small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET 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 MET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and MET status (MET exon 14 skipping mutation or MET 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 MET 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 MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with MET 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 MET exon 14 skipping mutation, particularly in those not treated previously. The efficacy in MET-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.

DOI: 10.1056/NEJMoa2002787

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2002787