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【2017ASCO GI】【失败】依维莫司折戟晚期胃癌二线治疗

2017年01月29日

整理：Max

来源：医脉通肿瘤科

依维莫司（everolimus）是一种口服哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂。而mTOR是一类丝氨酸/苏氨酸蛋白激酶，在细胞内信号传导中发挥至关重要的作用，尤其是对细胞生长、增殖、代谢、存活和分化等有重要的影响。国际上，依维莫司被批准用于治疗晚期肾细胞癌（RCC）、结节性硬化症相关室管膜下巨细胞星型细胞瘤（TSC-SEGA）及肾血管平滑肌脂肪瘤（TSCAML）、晚期胰腺神经内分泌肿瘤（pNET）、绝经后雌激素受体阳性/HER-2阴性的晚期乳腺癌（BC）等肿瘤。

2017年1月，ASCO胃肠肿瘤研讨会（GI）在美国旧金山召开。当地时间19日的口头报告上，来自德国Nordwest医院临床癌症研究所的Salah-Eddin Al-Batran博士以“A randomized, double-blind, multicenter phase III study evaluating paclitaxel with and without RAD001 in patients with gastric cancer who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen(RADPAC)”为题，报道了mTOR抑制剂依维莫司联合紫杉醇治疗经治晚期胃癌的Ⅲ期临床研究结果。

对于晚期胃癌患者，优化二线及后线治疗仍是一项不小的挑战。mTOR通路能否在胃癌中成为有效的治疗靶点，依维莫司能否在胃癌二线治疗中复制乳腺癌的成功，先别急着乐观。

研究内容

RADPAC是一项随机双盲，多中心Ⅲ期临床试验，纳入300例氟尿嘧啶/铂类化疗失败后，疾病进展的胃癌或胃食管结合部腺癌的患者。1:1随机将患者分配进紫杉醇（80mg/m2）+依维莫司（10mg/d）组或紫杉醇+安慰剂组，作为二、三、四线治疗。

主要终点是总生存（OS），次要终点包括最佳总缓解，疾病控制率，无进展生存和毒性。

研究结果

紫杉醇+依维莫司组患者的缓解率（完全+部分）为8.0%，与紫杉醇单药治疗缓解率7.3%相比无明显差异。

在OS和PFS方面，两组也比较接近。紫杉醇+依维莫司组和紫杉醇单药组的中位OS分别为6.1 vs 5.1个月，中位PFS分别为2.2 vs 2.07个月。

安全性方面，患者对紫杉醇联合依维莫司治疗可耐受，但单药紫杉醇组的不良事件发生率更低，包括黏膜炎（15.8% vs 37.2%）、发热（10.3% vs 20.7%）、白细胞减少（11.6% vs 21.4%）、中性粒细胞减少（13.0% vs 27.6%）和血小板减少（2.1% vs 14.5%）。

研究结论

在紫杉醇基础上增加依维莫司并不能明显改善经治晚期胃癌患者的预后。下一步拟根据生物标志物进行亚组分析，观察哪些患者群体可能获益。

A randomized, double-blind, multicenter phase III study evaluating paclitaxel with and without RAD001 in patients with gastric cancer who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen (RADPAC).

J Clin Oncol 35, 2017 (suppl 4S; abstract 4)

Author(s):

Salah-Eddin Al-Batran,et al.

Abstract:

Background:

There is a need for effective treatments in the second- or further line setting in advanced gastric cancer, especially for new agents. In the current trial we evaluated paclitaxel with RAD001 (everolimus) in patients with gastric carcinoma who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen. Methods: This is a randomized, double-blind, multi-center phase III study. Patients with gastric carcinoma or adenocarcinoma of the esophagogastric junction which has progressed after treatment with a fluoropyrimidine/platinum-containing regimen were randomly assigned to receive Paclitaxel (80 mg/m2) on day 1, 8 and 15 plus placebo (arm A) or RAD001 (10mg daily, arm B) d1-d28, repeated every 28 days as 2nd, 3rd or 4thline therapy. Primary end point was overall survival (OS), secondary endpoints were best overall response, disease control rate, progression free survival (PFS) and toxicity.

Results:

300 patients (median age: 62 years; median lines prior therapy: 2) were randomly assigned (Arm A, 150, Arm B, 150). Response rate (complete and partial response) was 8.0% (95%CI: 4.2%-13.6%) in the paclitaxel/RAD001 arm and 7.3% (95% CI: 3.7%-12.7%) in the paclitaxel/placebo arm (p = 0.4).There was no significant difference in median PFS (placebo, 2.07 vs. RAD001, 2.2 months, HR 0.88, p = 0.3) and median OS (placebo, 5.1 vs. RAD001, 6.1 months, HR 0.92, p = 0.48). Combination of paclitaxel and RAD001 was tolerable, but the placebo arm was associated with significantly less (any grade) mucositis (15.8% vs. 37.2%), fever (10.3% vs 20.7%), leukopenia (11.6% vs. 21.4%), neutropenia (13.0% vs. 27.6%) and thrombocytopenia (2.1% vs 14.5%).

Conclusions:

The addition of RAD001 to paclitaxel/RAD001 did not significantly improve outcomes in pretreated metastatic gastric or esophagogastric junction adenocarcinoma. Additional biomarker studies are planned to look for subgroups that may have a benefit.

Clinical trial information:

NCT01248403

参考文献：

Salah-Eddin Al-Batran. et al. J Clin Oncol 35, 2017 (suppl 4S; abstract 4)

编辑：肿瘤资讯-小编