Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib.
Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib.
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DOI：
10.1136/esmoopen-2016-000063
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发表时间：
2016
期刊：
影响因子：
7.3
通讯作者：
Nakagawa K
中科院分区：
文献类型：
--
作者：
Azuma K;Hirashima T;Yamamoto N;Okamoto I;Takahashi T;Nishio M;Hirata T;Kubota K;Kasahara K;Hida T;Yoshioka H;Nakanishi K;Akinaga S;Nishio K;Mitsudomi T;Nakagawa K
表皮生长因子受体（EGFR）激活突变阳性的非小细胞肺癌（NSCLC）患者对EGFR酪氨酸激酶抑制剂（EGFR-TKI）反应良好，但在大多数情况下最终会产生耐药性。肝细胞生长因子/c-Met（HGF/c-Met）途径被报道为各种癌症的不良预后因素。由于c-Met与EGFR-TKI耐药性有关，因此c-Met抑制剂和EGFR-TKI联合用药可能逆转耐药性。本研究评价了c-Met选择性抑制剂tivantinib（ARQ 197）与厄洛替尼联合治疗在EGFR TKI治疗期间进展的日本EGFR突变阳性NSCLC患者的疗效和安全性。本研究入组了45例对EGFR-TKI获得性耐药的NSCLC患者，这些患者每日口服tivantinib/厄洛替尼联合给药。主要终点为总缓解率（ORR），次要终点包括疾病控制率、无进展生存期（PFS）和总生存期（OS）。患者在EGFR-TKI治疗进展后立即接受强制性第二次活检。使用肿瘤和血液样本对预测性生物标志物进行了广泛分析。ORR为6.7%（95% CI 1.4%-18.3%），95% CI的下限未超过目标5%。中位PFS（mPFS）和中位OS（mOS）分别为2.7个月（95% CI 1.4 - 4.2）和18.0个月（95% CI 13.4 - 22.2）。 在c-Met高水平患者中，两者均较长（c-Met高水平vs低水平：mPFS 4.1 vs 1.4个月; mOS 20.7 vs 13.9个月）。 在3例患者中观察到部分缓解，所有患者均为c-Met和HGF高。常见的不良事件及其发生频率与已知单独使用tivantinib或厄洛替尼时发生的不良事件及其发生频率相似。虽然这项研究没有证明tivantinib在获得性EGFR-TKI耐药患者中的临床获益，但激活的HGF/c-Met信号传导（一种不良预后因素）可能定义了与tivantinib/厄洛替尼联合治疗延长生存期相关的患者亚组。NCT 01580735。
Patients with epidermal growth factor receptor (EGFR) activation mutation-positive non-small-cell lung cancer (NSCLC) respond well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but eventually become resistant in most cases. The hepatocyte growth factor/c-Met (HGF/c-Met) pathway is reported as a poor prognostic factor in various cancers. As c-Met is involved in EGFR-TKI resistance, a c-Met inhibitor and EGFR-TKI combination may reverse the resistance. This study evaluated the efficacy and safety of a c-Met selective inhibitor, tivantinib (ARQ 197), in combination with erlotinib, in Japanese EGFR mutation-positive patients with NSCLC who progressed while on EGFR-TKIs. This study enrolled 45 patients with NSCLC with acquired resistance to EGFR-TKIs, who were orally administered a daily combination of tivantinib/erlotinib. The primary end point was the overall response rate (ORR) and secondary end points included disease control rate, progression-free survival (PFS) and overall survival (OS). The patients underwent a mandatory second biopsy just after progression on EGFR-TKIs. The predictive biomarkers were extensively analysed using tumour and blood samples. The ORR was 6.7% (95% CI 1.4% to 18.3%), and the lower limit of 95% CI did not exceed the target of 5%. The median PFS (mPFS) and median OS (mOS) were 2.7 months (95% CI 1.4 to 4.2) and 18.0 months (95% CI 13.4 to 22.2), respectively. Both were longer in c-Met high patients (c-Met high vs low: mPFS 4.1 vs 1.4 months; mOS 20.7 vs 13.9 months). Partial response was observed in three patients, all of whom were c-Met and HGF high. The common adverse events and their frequencies were similar to those known to occur with tivantinib or erlotinib alone. Although this study did not prove clinical benefit of tivantinib in patients with acquired resistance to EGFR-TKIs, activated HGF/c-Met signalling, a poor prognostic factor, may define a patient subset associated with longer survival by the tivantinib/erlotinib combination. NCT01580735.