Wainberg Zev A, Soares Heloisa P, Patel Ravi, DiCarlo Brian, Park David J, Liem Andre, Wang He-jing, Yonemoto Lisa, Martinez Diego, Laux Isett, Brennan Meghan, Hecht J Randolph
Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, USA,
Cancer Chemother Pharmacol. 2015 Jul;76(1):61-7. doi: 10.1007/s00280-015-2744-5. Epub 2015 May 13.
Our study was designed to evaluate the efficacy and safety of everolimus in patients with pre-treated metastatic gastric and esophagus cancers in a US-based population focusing on biomarker correlation.
Patients with advanced upper GI adenocarcinomas who progressed after 1-2 prior regimens received everolimus 10 mg PO daily. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression-free survival (PFS), toxicity, overall survival (OS) and biomarker correlatives of the mTOR pathway. Target accrual was 50 patients based on one-sided type I error of 10 % and power of 90 %.
Forty-five patients were evaluable, 21 gastric, 11 esophagus and 13 from the GEJ. The median age was 64 (range 38-73); all patients had an ECOG of 0 or 1; and 18 patients (40 %) had only 1 prior regimen. The most common grade 3-4 adverse events included fatigue (24 %) and thrombocytopenia (22 %). We observed 1 partial response with 39 % of evaluable patients having stable disease. Median OS was 3.4 months (95 % CI 2.7-5.6 months), and PFS was 1.8 months (95 % CI 1.7-2.2 months). There was a strong correlation between ≥2 + IHC staining for p-S6 in tumor samples with better PFS (p < 0.0001) and DCR (p = 0.0001).
Our clinical outcomes were inferior to the Asian studies, which may be explained by disease heterogeneity. However, there was a similar strong correlation between clinical benefit and tumor high pS6. Testing this biomarker in patient samples from the randomized phase III Granite trial may lead to a positive predictive marker.
我们的研究旨在评估依维莫司在接受过治疗的转移性胃癌和食管癌患者中的疗效和安全性，该研究以美国人群为对象，重点关注生物标志物相关性。
先前接受1 - 2种治疗方案后病情进展的晚期上消化道腺癌患者，每日口服依维莫司10毫克。主要终点为疾病控制率（DCR）。次要终点包括无进展生存期（PFS）、毒性、总生存期（OS）以及mTOR通路的生物标志物相关性。基于10%的单侧I型错误率和90%的检验效能，目标入组患者为50例。
45例患者可评估，其中21例为胃癌，11例为食管癌，13例为胃食管交界部癌。中位年龄为64岁（范围38 - 73岁）；所有患者的东部肿瘤协作组（ECOG）评分为0或1；18例患者（40%）仅接受过1种先前治疗方案。最常见的3 - 4级不良事件包括疲劳（24%）和血小板减少（22%）。我们观察到1例部分缓解，39%的可评估患者病情稳定。中位总生存期为3.4个月（95%置信区间2.7 - 5.6个月），无进展生存期为1.8个月（95%置信区间1.7 - 2.2个月）。肿瘤样本中p - S6的≥2 + IHC染色与更好的无进展生存期（p < 0.0001）和疾病控制率（p = 0.0001）之间存在强相关性。
我们的临床结果不如亚洲的研究，这可能是由疾病异质性所致。然而，临床获益与肿瘤高pS6之间存在相似的强相关性。在随机III期Granite试验的患者样本中检测该生物标志物可能会产生一个阳性预测标志物。
