Dual targeting of HER1/EGFR and HER2 with cetuximab and trastuzumab in patients with metastatic pancreatic cancer after gemcitabine failure: results of the "THERAPY"phase 1-2 trial.
Dual targeting of HER1/EGFR and HER2 with cetuximab and trastuzumab in patients with metastatic pancreatic cancer after gemcitabine failure: results of the "THERAPY"phase 1-2 trial.
复制标题
DOI：
10.18632/oncotarget.3473
复制
发表时间：
2015-05-20
期刊：
影响因子：
--
通讯作者：
Pèlegrin A
中科院分区：
文献类型：
--
作者：
Assenat E;Azria D;Mollevi C;Guimbaud R;Tubiana-Mathieu N;Smith D;Delord JP;Samalin E;Portales F;Larbouret C;Robert B;Bibeau F;Bleuse JP;Crapez E;Ychou M;Pèlegrin A
为了提高治疗效果，我们决定用曲妥珠单抗和西妥昔单抗同时靶向 HER1 和 HER2。在取得有希望的临床前结果后，我们在一线吉西他滨化疗失败后的晚期胰腺癌患者中进行了一项 1-2 期试验。在这项单组、非随机、多中心试验中，患者每周接受西妥昔单抗治疗（400mg/m2，然后是 250mg/m2）。它们依次包含在两个曲妥珠单抗剂量水平中：每周3.0或4.0mg/kg，然后每周1.5或2.0mg/kg。终点包括客观缓解率、安全性、无进展生存期 (PFS) 和总生存期 (OS)。在第 1 阶段（n=10 名患者），除了经常引起依从性问题的皮肤毒性外，毒性分布均匀。较高剂量水平被定义为曲妥珠单抗推荐剂量。在第 2 阶段（n=39 名患者），毒性主要是皮肤反应和乏力。没有观察到客观反应。九名患者病情稳定，但因毒性而停止治疗。中位 PFS 为 1.8 个月（95% CI：1.7-2.0 个月），中位 OS 为 4.6 个月（95% CI：2.7-6.6 个月）。两者均与皮肤毒性严重程度呈正相关（分别为 P=0.027 和 P=0.001）。传统的一期剂量递增方案不适合靶向治疗，因为大多数皮肤毒性不被认为是剂量限制性毒性。由于毒性反应相关性，皮肤毒性引起的依从性问题尤其有害。
To improve treatment efficacy, we decided to simultaneously target HER1 and HER2 with trastuzumab and cetuximab. Following promising preclinical results, we conducted a phase 1-2 trial in advanced pancreatic cancer patients after first-line gemcitabine-based chemotherapy failure. In this single-arm, non-randomized, multicenter trial, patients received weekly cetuximab (400mg/m², then 250mg/m²). They were sequentially included in two trastuzumab dose levels: 3.0 or 4.0mg/kg, then 1.5 or 2.0mg/kg/weekly. Endpoints were the objective response rate, safety, progression-free (PFS) and overall survival (OS). During phase 1 (n=10 patients), toxicities were evenly distributed except for skin toxicities that frequently caused compliance issues. The higher dose level was defined as the trastuzumab recommended dose. During phase 2 (n=39 patients), toxicities were mainly cutaneous reactions and asthenia. No objective response was observed. Nine patients were stabilized but arrested treatment due to toxicity. Median PFS was 1.8 months (95%CI: 1.7-2.0 months) and median OS was 4.6 months (95%CI: 2.7–6.6 months). Both were positively correlated with skin toxicity severity (P=0.027 and P=0.001, respectively). Conventional phase 1 dose-escalation schedules are unsuitable for targeted therapies because most cutaneous toxicities are not considered dose-limiting toxicities. The compliance issues caused by skin toxicities were particularly detrimental because of the toxicity-response correlation.
登录
查看更多内容
影响因子：
24.5
作者：
Dahan L;Bonnetain F;Ychou M;Mitry E;Gasmi M;Raoul JL;Cattan S;Phelip JM;Hammel P;Chauffert B;Michel P;Legoux JL;Rougier P;Bedenne L;Seitz JF;Fédération Francophone de Cancérologie Digestive
通讯作者：
Fédération Francophone de Cancérologie Digestive
影响因子：
5.6
作者：
Saxby, AJ;Nielsen, A;Smith, RC
通讯作者：
Smith, RC
影响因子：
51.1
作者：
通讯作者：
--
影响因子：
8.8
作者：
Bramhall, SR;Schulz, J;Nemunaitis, J;Brown, PD;Baillet, M;Buckels, JAC
通讯作者：
Buckels, JAC
影响因子：
45.3
作者：
Moore, Malcolm J.;Goldstein, David;Parulekar, Wendy
通讯作者：
Parulekar, Wendy