Multi-drug inhibition of the HER pathway in metastatic colorectal cancer: results of a phase I study of pertuzumab plus cetuximab in cetuximab-refractory patients.
Multi-drug inhibition of the HER pathway in metastatic colorectal cancer: results of a phase I study of pertuzumab plus cetuximab in cetuximab-refractory patients.
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DOI：
10.1007/s10637-013-9956-5
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发表时间：
2014-02
影响因子：
3.4
通讯作者：
Ng, Kimmie
中科院分区：
文献类型：
--
作者：
Rubinson, Douglas A.;Hochster, Howard S.;Ryan, David P.;Wolpin, Brian M.;McCleary, Nadine Jackson;Abrams, Thomas A.;Chan, Jennifer A.;Iqbal, Syma;Lenz, Heinz J.;Lim, Dean;Rose, Jeffrey;Bekaii-Saab, Tanios;Chen, Helen X.;Fuchs, Charles S.;Ng, Kimmie
结直肠癌 (CRC) 中对西妥昔单抗（一种针对上皮生长因子受体 (EGFR) 的单克隆抗体）的耐药性可能是通过 ErbB 受体、ErbB2/neu/HER2 (HER2) 和 ErbB3/HER3 (HER3) 的补偿信号传导所致。帕妥珠单抗是一种单克隆抗体，可阻断 HER2 异源二聚化；因此，帕妥珠单抗和西妥昔单抗的组合可能会克服西妥昔单抗耐药性。这项单臂、开放标签、多中心 I/II 期研究旨在评估帕妥珠单抗和西妥昔单抗在西妥昔单抗耐药的 KRAS 野生型转移性 CRC 患者中的安全性和有效性。 13 名患者入组，并在 3+3 设计中接受多个剂量水平的西妥昔单抗联合帕妥珠单抗治疗。在第一个周期期间对患者进行剂量限制毒性（DLT）评估。计划进行第二阶段部分，但由于毒性而未启动。 13 名患者中的 6 名（46%）经历了 DLT，因此该研究提前终止。 3 级或更高级别的 DLT 包括伴有脱屑和/或痤疮样皮疹的皮炎 (n=6)、粘膜炎或口腔炎 (n=5) 以及腹泻 (n=2)。发生 1 起因基础疾病导致的 5 级事件（心肌梗死）。在 13 名患者中，有 7 名 (54%) 的反应可评估。客观缓解率为 14%：一名患者出现持续 6 个月的部分缓解。两名患者病情稳定（29%），四名患者病情进展（57%）。中位无进展生存期为 2.1 个月（95% CI，1.5-4.9），中位总生存期为 3.7 个月（95% CI，1.6-7.9）。帕妥珠单抗和西妥昔单抗联合治疗难治性结直肠癌具有潜在的抗肿瘤活性；然而，由于重叠的毒性，该组合是不可接受的。
Resistance to cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), in colorectal cancer (CRC) may result from compensatory signaling through ErbB receptors, ErbB2/neu/HER2 (HER2) and ErbB3/HER3 (HER3). Pertuzumab is a monoclonal antibody that blocks HER2 hetero-dimerization; thus the combination of pertuzumab and cetuximab could possibly overcome cetuximab resistance. This single-arm, open-label, multicenter phase I/II study was designed to assess the safety and efficacy of pertuzumab and cetuximab in patients with cetuximab-resistant KRAS wild type metastatic CRC. Thirteen patients were enrolled and received cetuximab in combination with pertuzumab at several dose levels in a 3+3 design. Patients were assessed for dose-limiting toxicity (DLT) during the first cycle. A phase II portion was planned, but not initiated due to toxicity. Six of the thirteen patients (46%) experienced DLTs, therefore the study was terminated early. Grade 3 or higher DLTs included dermatitis with desquamation and/or acneiform rash (n=6), mucositis or stomatitis (n=5), and diarrhea (n=2). There was one Grade 5 event (myocardial infarction) attributed to underlying disease. Among the 13 patients, seven (54%) were evaluable for response. The objective response rate was 14%: one patient had a partial response lasting 6 months. Two patients had stable disease (29%), and four had progressive disease (57%). Median progression free survival was 2.1 months (95% CI, 1.5–4.9) and median overall survival was 3.7 months (95% CI, 1.6–7.9). Combination pertuzumab and cetuximab in refractory CRC was associated with potential antitumor activity; however, the combination was not tolerable due to overlapping toxicities.
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影响因子：
50.3
作者：
Agus, DB;Akita, RW;Sliwkowski, MX
通讯作者：
Sliwkowski, MX
影响因子：
3.6
作者：
Felip, Enriqueta;Ranson, Malcolm;Galdermans, Danny
通讯作者：
Galdermans, Danny
影响因子：
3.4
作者：
Takahashi, Toshiaki;Boku, Narikazu;Murakami, Haruyasu;Naito, Tateaki;Tsuya, Asuka;Nakamura, Yukiko;Ono, Akira;Machida, Nozomu;Yamazaki, Kentaro;Watanabe, Junichiro;Ruiz-Garcia, Ana;Imai, Keiji;Ohki, Emiko;Yamamoto, Nobuyuki
通讯作者：
Yamamoto, Nobuyuki
DOI：
10.1158/1078-0432.ccr-11-0370
发表时间：
2011-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Quesnelle KM;Grandis JR
通讯作者：
Grandis JR
影响因子：
3.7
作者：
De Potter, IY;Poumay, Y;Pittelkow, MR
通讯作者：
Pittelkow, MR