Schuler M, Berardi R, Lim W-T, de Jonge M, Bauer T M, Azaro A, Gottfried M, Han J-Y, Lee D H, Wollner M, Hong D S, Vogel A, Delmonte A, Akimov M, Ghebremariam S, Cui X, Nwana N, Giovannini M, Kim T M
Department of Medical Oncology, West German Cancer Center, University Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany.
Clinica Oncologica, Università Politecnica delle Marche-Ospedali Riuniti, Ancona, Italy.
Ann Oncol. 2020 Jun;31(6):789-797. doi: 10.1016/j.annonc.2020.03.293. Epub 2020 Mar 30.
Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%-4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC.
Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats.
Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4-33.0). In patients with MET GCN ≥6 (n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8-11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%).
MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479).
通过各种机制导致的受体酪氨酸激酶MET失调在3%-4%的非小细胞肺癌（NSCLC）中出现，并与不良预后相关。虽然MET是肺癌中已验证的药物靶点，但用于富集易感患者群体的最佳生物标志物策略仍有待确定。为此，我们在此分析了MET抑制剂卡马替尼在晚期MET失调NSCLC患者中的I期剂量扩展研究的原始数据。
符合条件的患者[≥18岁；东部肿瘤协作组（ECOG）体能状态≤2]患有MET失调的晚期NSCLC，定义为（i）免疫组织化学（MET IHC）检测MET状态为2+或3+或H评分≥150，或MET/着丝粒比率≥2.0或基因拷贝数（GCN）≥5，或（ii）表皮生长因子受体野生型（EGFRwt）且中心评估MET IHC为3+，接受卡马替尼，推荐剂量为400mg（片剂）或600mg（胶囊），每日两次。主要目标是确定安全性和耐受性；关键次要目标是探索抗肿瘤活性。探索性终点是临床活性与不同生物标志物形式的相关性。
在55例晚期MET失调的NSCLC患者中，40/55（73%）接受过两种或更多先前的全身治疗。所有患者均停止治疗，主要原因是疾病进展（69.1%）。中位治疗持续时间为10.4周。根据RECIST标准的总体缓解率为20%（95%置信区间，10.4-33.0）。在MET GCN≥6的患者（n = 15）中，研究者评估和中心评估的总体缓解率均为47%。MET GCN≥6的患者经研究者评估的中位无进展生存期为9.3个月（95%置信区间，3.8-11.9）。在所有4例METex14患者中均观察到肿瘤反应。最常见的毒性反应为恶心（42%）、外周水肿（33%）和呕吐（31%）。
MET GCN≥6和/或METex14适合预测卡马替尼在NSCLC患者中的临床活性（NCT01324479）。
