Background: The phase II YO28252 study (NCT01590719) examined first-line onartuzumab plus mFOLFOX6 in patients with metastatic, human epidermal growth factor receptor 2-negative adenocarcinoma of the stomach or gastroesophageal junction. MET immunohistochemistry expression as a biomarker of onartuzumab activity was also examined.
Patients and methods: Patients were randomized 1:1 to receive standard mFOLFOX6 plus onartuzumab (10 mg/kg) or placebo in 2-week cycles for 12 cycles, followed by onartuzumab or placebo until disease progression. Coprimary endpoints were progression-free survival (PFS) in intent-to-treat (ITT) and MET-positive populations. The target hazard ratio (HR) was 0.70 for patients in the ITT group and 0.60 in the MET-positive population. Secondary endpoints were overall survival (OS), overall response rate (ORR), and safety.
Results: Overall, 123 patients were enrolled (n = 62 onartuzumab, n = 61 placebo). Median PFS was 6.77 versus 6.97 months for onartuzumab versus placebo, respectively (HR, 1.08; 95% confidence interval [CI], 0.71-1.63; p = .71). In the MET-positive population, median PFS was 5.95 versus 6.80 months, onartuzumab versus placebo (HR, 1.38; 95% CI, 0.60-3.20; p = .45). Median OS was 10.61 months for onartuzumab versus 11.27 months for placebo) (HR, 1.06, 0.64-1.75; p = .83). In the MET-positive population, median OS was 8.51 versus 8.48 months for onartuzumab versus placebo, respectively (HR, 1.12, 95% CI, 0.45-2.78; p = .80). ORR was 60.5% for the onartuzumab group and 57.1% for placebo. Grade 3-5 adverse events (AEs) were seen in 88.3% of patients receiving onartuzumab and in 78.3% of patients receiving placebo, with serious AEs in 55% and 40%, respectively.
Conclusion: The addition of onartuzumab to mFOLFOX6 in gastric cancer did not improve efficacy in an unselected population or in a MET immunohistochemistry-positive population.
Implications for practice: The YO28252 study demonstrated that the addition of the anti-MET agent onartuzumab to mFOLFOX6 for treatment of gastric cancer did not improve efficacy in an overall study population or those selected for positive MET status by immunohistochemistry. This highlights the importance of correctly selecting biomarkers for targeted therapies. A multivariate analysis suggested that MET positivity may still be prognostic for worse median overall survival in gastric cancer; therefore, it is important to continue investigation into the optimal approach to inhibit MET signaling in gastric cancer.
摘要
背景. II 期 YO28252 研究 (NCT01590719) 对 onartuzumab 联合 mFOLFOX6 一线治疗人类表皮生长因子受体 2 (HER2) 阴性的转移性胃或胃食道结合部腺癌患者进行了检验。同时还对 MET 免疫组化表达作为 onartuzumab 的生物标记物进行了检验。
患者与方法. 患者按 1:1 随机分配接受标准 mFOLFOX6 联合 onartuzumab (10 mg/kg) 或安慰剂治疗, 每 2 周为一周期, 共 12 周期; 后继以 onartuzumab 或安慰剂治疗直至发生疾病进展。联合主要终点为意向性治疗 (ITT) 人群和 MET 阳性人群的无进展生存 (PFS)。ITT人群的目标风险比 (HR) 为 0.70, MET 阳性人群为 0.60。次要终点包括总生存 (OS)、总缓解率 (ORR) 和安全性。
结果. 共纳入 123 例患者 (onartuzumab 组 62 例, 安慰剂组 61 例)。Onartuzumab 组中位 PFS 为 6.77 个月, 安慰剂组为 6.97 个月[HR: 1.08, 95%置信区间 (CI): 0.71∼1.63, P=0.71]。在 MET 阳性人群中, onartuzumab 组和安慰剂组的中位 PFS 分别为 5.95 个月和 6.80 个月 (HR: 1.38, 95%CI: 0.60∼3.20, P=0.45)。Onartuzumab 组和安慰剂组的中位 OS 分别为 10.61 个月和 11.27 个月 (HR: 1.06, 95%CI: 0.64∼1.75, P=0.83)。MET 阳性人群的中位 OS 分别为onartuzumab组 8.51 个月和安慰剂组 8.48 个月 (HR: 1.12, 95%CI: 0.45∼2.78, P=0.80)。Onartuzumab 组的 ORR 为 60.5%, 安慰剂组为 57.1%。Onartuzumab 组的 3∼5 级不良事件 (AE) 发生率为 88.3%, 安慰剂组为 78.3%, 严重 AE 发生率分别为 55% 和 40%。
结论. 在未经选择及MET免疫组化阳性的胃癌患者中, mFOLFOX6联合onartuzumab均未能改善有效性。The Oncologist 2016;21:1085–1090
对临床实践的提示: YO28252 研究证实在 mFOLFOX6 基础上联合抗 MET 制剂 onartuzumab 用于治疗胃癌, 未能在总人群及经选 MET 免疫组化阳性患者中改善有效性。这提出了正确选择靶向治疗的生物标记物的重要性。多变量分析提示 MET 阳性可能仍然是胃癌中位总生存较差的预后因素, 因此对抑制胃癌中 MET 信号转导的最佳方案继续开展研究非常重要。
Keywords: Chemotherapy; First line; Gastric cancer; HER2-negative; MET; Onartuzumab.
©AlphaMed Press.