Multicenter Phase II Study of Cabazitaxel in Advanced Gastroesophageal Cancer: Association of HER2 Expression and M2-Like Tumor-Associated Macrophages with Patient Outcome.
Multicenter Phase II Study of Cabazitaxel in Advanced Gastroesophageal Cancer: Association of HER2 Expression and M2-Like Tumor-Associated Macrophages with Patient Outcome.
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DOI：
10.1158/1078-0432.ccr-19-3920
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发表时间：
2020-09-15
期刊：
影响因子：
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通讯作者：
Lenz HJ
中科院分区：
文献类型：
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作者：
Shah MA;Enzinger P;Ko AH;Ocean AJ;Philip PA;Thakkar PV;Cleveland K;Lu Y;Kortmansky J;Christos PJ;Zhang C;Kaur N;Elmonshed D;Galletti G;Sarkar S;Bhinder B;Pittman ME;Plotnikova OM;Kotlov N;Frenkel F;Bagaev A;Elemento O;Betel D;Giannakakou P;Lenz HJ
我们在一项多中心 II 期研究中检查了卡巴他赛（一种新型下一代紫杉醇）对转移性胃癌患者的作用。先前接受一种或多种局部晚期、不可切除或转移性疾病治疗后病情进展的患者符合资格，并且允许接受先前的紫杉烷治疗。独立分析紫杉烷初治组和预处理组的疗效。两个队列的主要终点是使用 RECIST 1.1 的无进展生存期 (PFS)，对两个队列均使用 Simon 的两阶段设计（10% 显着性，80% 功效）。全面的分子注释包括全外显子组和批量 RNA 测序。 2013 年 1 月 8 日至 2015 年 4 月 8 日期间，53 名患者入组未接受过紫杉烷治疗的队列（A 组），23 名患者入组接受过紫杉烷治疗的患者（B 组）：中位年龄 61.7 岁（范围 35.5 – 91.8 岁），其中 66% 为男性，66% 为白人。最常见的不良事件包括中性粒细胞减少症（A 组 17%，B 组 39%）、疲劳/肌肉无力（13%）和血尿（12%）。在 A 组中，3 个月 PFS 率为 28%（95%CI 17-42%），未达到预先指定的疗效目标。 B 组的 3 个月 PFS 率为 35%（95% CI 16-57%），超过了其疗效目标。 HER2 扩增或过度表达与疾病控制 (P=0.003)、PFS (p=0.04) 和总生存率 (p=0.002) 的改善相关。 M2 巨噬细胞特征也与生存率提高相关 (p=0.031)。卡巴他赛对晚期胃癌（包括先前接受紫杉烷类治疗的患者）具有适度的活性。 Her2 扩增/过度表达和 M2 高巨噬细胞特征是紫杉烷功效的潜在生物标志物，值得进一步评估。
We examined cabazitaxel, a novel next generation taxoid, in patients with metastatic gastric cancer in a multicenter phase II study. Patients that have progressed on 1 or more prior therapies for locally advanced, unresectable or metastatic disease, were eligible and prior taxane therapy was allowed. Taxane-naïve and pretreated cohorts were analyzed independently for efficacy. The primary endpoint for both cohorts was progression-free survival (PFS) using RECIST 1.1, using a Simon’s two-stage design (10% significance, 80% power) for both cohorts. Comprehensive molecular annotation included whole exome and bulk RNA sequencing. Fifty-three patients enrolled in the taxane-naïve cohort (Arm A), and 23 patients in the prior-taxane cohort (Arm B), from January 8, 2013 to April 8, 2015: median age 61.7 years (range 35.5 – 91.8 years), 66% male, 66% Caucasian. The most common adverse events included neutropenia (17% Arm A, 39% Arm B), fatigue/muscle weakness (13%), and hematuria (12%). In Arm A, the 3-month PFS rate was 28% (95%CI 17–42%), and did not meet the pre-specified efficacy target. The 3-month PFS rate in Arm B was 35% (95% CI 16–57%), and surpassed its efficacy target. HER2 amplification or over-expression was associated with improved disease control (P=0.003), PFS (p=0.04) and overall survival (p=0.002). An M2 macrophage signature was also associated with improved survival (p=0.031). Cabazitaxel has modest activity in advanced gastric cancer, including in patients previously treated with taxanes. Her2 amplification/overexpression and M2 high macrophage signature are potential biomarkers for taxane efficacy that warrant further evaluation.