Measuring Tumor Epichaperome Expression Using [124I] PU-H71 Positron Emission Tomography as a Biomarker of Response for PU-H71 Plus Nab-Paclitaxel in HER2-Negative Metastatic Breast Cancer
Measuring Tumor Epichaperome Expression Using [124I] PU-H71 Positron Emission Tomography as a Biomarker of Response for PU-H71 Plus Nab-Paclitaxel in HER2-Negative Metastatic Breast Cancer
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DOI：
10.1200/po.20.00273
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发表时间：
2020-11-17
影响因子：
4.6
通讯作者：
Modi, Shanu
中科院分区：
文献类型：
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作者：
Jhaveri, Komal L.;dos Anjos, Carlos H.;Modi, Shanu
PU-H71是一种epichaperome抑制剂，与HSP 90的ATP结合位点结合，在乳腺癌异种移植模型中显示出抗肿瘤活性，在患者中显示出临床安全性。PU-正电子发射断层扫描（PET）是一种治疗诊断成像工具，可实现epichaperome靶点的可视化。在这个Ib期试验中，我们目前的安全性和耐受性PU-H71加上nabpaclitaxel在HER 2阴性转移性乳腺癌（MBC）患者和PU-PET作为一种非侵入性的预测biomarkers.METHODS的效用，我们进行了3 + 3剂量递增研究，逐步增加PU-H71剂量和标准nabpaclitaxel。主要目的是确定安全性并确定最大耐受剂量（MTD）/推荐的II期剂量。次要目的是评估药代动力学和临床疗效。结果：在12例入选的患者中，1例患者在剂量水平1时出现剂量限制性毒性（G3血小板减少性发热）; PU-H71的MTD为300 mg/m2，nab-紫杉醇260 mg/m2，每3周给药一次。常见毒性包括腹泻、疲劳、周围神经病变和恶心。PU-H71全身暴露未被白蛋白结合型紫杉醇给药改变。12例患者中有2例部分缓解（总缓解率为17%），临床获益率为42%（5/12）。进展时间与基线epichaperome阳性和PU-H71峰值标准摄取值（SUV），更持久的疾病控制观察高epichaperome level.CONCLUSION PU-H71和白蛋白结合型紫杉醇的组合是耐受性良好，临床活性的证据。在具有高基线epichaperome表达的患者中观察到更持久的疾病控制而无进展。目前计划将这种组合与PU-PET作为患者选择的伴随诊断的II期试验。(C)2020年美国临床肿瘤学会
PURPOSE Epichaperome network maintenance is vital to survival of tumors that express it. PU-H71 is an epichaperome inhibitor that binds to the ATP-binding site of HSP90 and has demonstrated antitumor activity in breast cancer xenograft models and clinical safety in patients. PU-positron emission tomography (PET) is a theragnostic imaging tool that allows visualization of the epichaperome target. In this phase Ib trial, we present safety and tolerability for PU-H71 plus nab-paclitaxel in HER2-negative patients with metastatic breast cancer (MBC) and the utility of PU-PET as a noninvasive predictive biomarker.METHODS We performed a 3 + 3 dose-escalation study with escalating PU-H71 doses and standard nabpaclitaxel. The primary objective was to establish safety and determine maximum tolerated dose (MTD)/recommended phase 2 dose. Secondary objectives were to assess pharmacokinetics and clinical efficacy. Patients could enroll in a companion PU-PET protocol to measure epichaperome expression before treatment initiation to allow exploratory correlation with treatment benefit.RESULTS Of the 12 patients enrolled, dose-limiting toxicity occurred in one patient (G3 neutropenic fever) at dose level 1; MTD of PU-H71 was 300 mg/m(2) plus nab-paclitaxel 260 mg/m(2) administered every 3 weeks. Common toxicities included diarrhea, fatigue, peripheral neuropathy, and nausea. PU-H71 systemic exposure was not altered by nab-paclitaxel administration. Two of 12 patients had partial response (overall response rate, 17%) and the clinical benefit rate was 42% (5 of 12). Time to progression was associated with baseline epichaperome positivity and PU-H71 peak standard uptake value (SUV), with more durable disease control observed with high epichaperome levels.CONCLUSION The combination of PU-H71 and nab-paclitaxel was well tolerated, with evidence of clinical activity. More durable disease control without progression was observed in patients with high baseline epichaperome expression. A phase II trial of this combination with PU-PET as a companion diagnostic for patient selection is currently planned. (C) 2020 by American Society of Clinical Oncology