A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer.
A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer.
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DOI：
10.1186/s13058-017-0879-5
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发表时间：
2017-08-02
期刊：
影响因子：
--
通讯作者：
Modi S
中科院分区：
文献类型：
--
作者：
Jhaveri K;Wang R;Teplinsky E;Chandarlapaty S;Solit D;Cadoo K;Speyer J;D'Andrea G;Adams S;Patil S;Haque S;O'Neill T;Friedman K;Esteva FJ;Hudis C;Modi S
HER 2阳性转移性乳腺癌的靶向治疗可显著改善结局，但疗效受到治疗耐药性的限制。HER 2是一种急性敏感的热休克蛋白90（HSP 90）客户，HSP 90抑制可以克服曲妥珠单抗耐药性。临床前数据表明，HSP 90抑制与紫杉烷类具有协同作用，具有显著的临床活性。因此，我们在曲妥珠单抗难治性HER 2阳性转移性乳腺癌患者中测试了热休克蛋白90抑制剂ganetespib与紫杉醇和曲妥珠单抗联合治疗。在这项I期剂量递增研究中，曲妥珠单抗耐药的HER 2阳性转移性乳腺癌患者每周接受一次曲妥珠单抗（2 mg/kg）和紫杉醇治疗。（80 mg/m2），28天周期的第1、8、15和22天，加奈替匹剂量递增在第1、8和15天（100 mg/m2、150 mg/m2和第三组125 mg/m2，如果需要）。持续治疗直至疾病进展或出现毒性。主要目的是确定该疗法的安全性和最大耐受剂量和/或推荐的II期剂量（RP 2D）。次要目的包括评价ganetespib对紫杉醇药代动力学的影响，并对联合治疗的疗效进行初步评估。两个主要队列完成了剂量递增，未观察到任何剂量限制性毒性。9名患者接受了治疗。中位既往抗HER 2治疗线数为3（范围2-4），包括9/9例患者中的既往帕妥珠单抗和8/9例患者中的ado-曲妥珠单抗美坦新偶联物（T-DM 1）。最常见的1/2级不良事件（AE）为腹泻、疲乏、贫血和皮疹。未发生与ganetespib相关的4级AE。总体缓解率为22%（2/9例患者部分缓解），56%（5/9例患者）的疾病稳定。临床受益率为44%（4/9例患者）。中位无进展生存期为20周（范围8-55）。加奈替匹的RP 2D为150 mg/m2，与每周一次的紫杉醇+曲妥珠单抗联合给药。该组合是安全的，耐受性良好。尽管既往有紫杉烷类、帕妥珠单抗和T-DM 1，但该三联方案在该重度预治疗队列中的临床活性是有希望的，值得在HER 2阳性转移性乳腺癌中进一步研究。ClinicalTrials.gov NCT02060253。2014年1月30日注册。
Targeted therapies in HER2-positive metastatic breast cancer significantly improve outcomes but efficacy is limited by therapeutic resistance. HER2 is an acutely sensitive Heat Shock Protein 90 (HSP90) client and HSP90 inhibition can overcome trastuzumab resistance. Preclinical data suggest that HSP90 inhibition is synergistic with taxanes with the potential for significant clinical activity. We therefore tested ganetespib, a HSP90 inhibitor, in combination with paclitaxel and trastuzumab in patients with trastuzumab-refractory HER2-positive metastatic breast cancer. In this phase I dose-escalation study, patients with trastuzumab-resistant HER2-positive metastatic breast cancer received weekly trastuzumab (2 mg/kg) and paclitaxel (80 mg/m2) on days 1, 8, 15, and 22 of a 28-day cycle with escalating doses of ganetespib (100 mg/m2, 150 mg/m2, and a third cohort of 125 mg/m2 if needed) on days 1, 8, and 15. Therapy was continued until disease progression or toxicity. The primary objective was to establish the safety and maximum tolerated dose and/or recommended phase II dose (RP2D) of this therapy. The secondary objectives included evaluation of the effects of ganetespib on the pharmacokinetics of paclitaxel, and to make a preliminary assessment of the efficacy of the combination therapy. Dose escalation was completed for the two main cohorts without any observed dose-limiting toxicities. Nine patients received treatment. The median prior lines of anti-HER2 therapy numbered three (range 2–4), including prior pertuzumab in 9/9 patients and ado-trastuzumab emtansine (T-DM1) in 8/9 patients. The most common grade 1/2 adverse events (AEs) were diarrhea, fatigue, anemia, and rash. There were no grade 4 AEs related to ganetespib. The overall response rate was 22% (2/9 patients had partial response) and stable disease was seen in 56% (5/9 patients). The clinical benefit rate was 44% (4/9 patients). The median progression-free survival was 20 weeks (range 8–55). The RP2D of ganetespib is 150 mg/m2 in combination with weekly paclitaxel plus trastuzumab. The combination was safe and well tolerated. Despite prior taxanes, pertuzumab, and T-DM1, clinical activity of this triplet regimen in this heavily pretreated cohort is promising and warrants further study in HER2-positive metastatic breast cancer. ClinicalTrials.gov NCT02060253. Registered 30 January 2014.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
NVP-AUY922：一种小分子 HSP90 抑制剂，在临床前乳腺癌模型中具有有效的抗肿瘤活性。
DOI：
10.1186/bcr1996
发表时间：
2008
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Jensen MR;Schoepfer J;Radimerski T;Massey A;Guy CT;Brueggen J;Quadt C;Buckler A;Cozens R;Drysdale MJ;Garcia-Echeverria C;Chène P
通讯作者：
Chène P
影响因子：
11.5
作者：
Bao, Rudi;Lai, Cheng-Jung;Qian, Changgeng
通讯作者：
Qian, Changgeng
影响因子：
3.8
作者：
Modi, Shanu;Saura, Cristina;Baselga, Jose
通讯作者：
Baselga, Jose
影响因子：
4
作者：
Jhaveri K;Modi S
通讯作者：
Modi S