Background: Seribantumab (MM-121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3/ErbB3) to block heregulin (HRG/NRG)-mediated ErbB3 signaling and induce receptor downregulation. This open-label, randomized phase 1/2 study evaluated safety and efficacy of seribantumab plus erlotinib in advanced non-small cell lung cancer (NSCLC). Here, we report the activity of seribantumab plus erlotinib, versus erlotinib alone, in patients with EGFR wild-type tumors and describe the potential predictive power of HRG.
Materials and methods: Patients with EGFR wild-type NSCLC were assigned randomly to receive seribantumab + erlotinib or erlotinib alone. Patients underwent pretreatment core needle biopsy and archived tumor samples were collected to support prespecified biomarker analyses.
Results: One hundred twenty-nine patients received seribantumab + erlotinib (n = 85) or erlotinib alone (n = 44). Median estimated progression-free survival (PFS) in the unselected intent-to-treat (ITT) population was 8.1 and 7.7 weeks in the experimental and control arm, respectively (hazard ratio [HR], 0.822; 95% confidence interval [CI], 0.37-1.828; p = 0.63), and median estimated overall survival was 27.3 and 40.3 weeks in the experimental and control arm, respectively (HR, 1.395; 95% CI, 0.846 to 2.301; p = .1898) In patients whose tumors had detectable HRG mRNA expression, treatment benefit was observed in the seribantumab + erlotinib combination (HR, 0.35; 95% CI, 0.16-0.76; p = .008). In contrast, in patients whose tumors were HRG negative, the HR was 2.15 (95% CI, 0.97-4.76; p = .059, HRG-by-treatment interaction, p value = .0016).
Conclusion: The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, predefined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial of seribantumab, in combination with docetaxel, is underway in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216).
Implications for practice: The poor prognosis of patients with non-small cell lung cancer (NSCLC) underscores the need for more effective treatment options, highlighting the unmet medical need in this patient population. The results of this study show that a novel biomarker, heregulin, may help to identify patients with advanced NSCLC who could benefit from treatment with seribantumab. On the basis of the observed safety profile and promising clinical efficacy, a prospective, randomized, open-label, international, multicenter phase II trial (SHERLOC, NCT02387216) is under way to investigate the efficacy and safety of seribantumab in combination with docetaxel in patients with heregulin-positive advanced adenocarcinoma.
摘要
背景。司里班妥单抗 (Seribantumab) (MM‐121) 是一种完全人 IgG2 单克隆抗体，与人表皮生长因子受体 3 (HER3/ErbB3) 结合，阻断调节蛋白 (HRG/NRG)介导的 ErbB3 信号通路，诱导受体下调。本项研究为开放标签、随机的 1/2期研究，评估了司里班妥单抗联合厄洛替尼治疗晚期非小细胞肺癌 (NSCLC) 的安全性和有效性。研究介绍了在 EGFR 野生型肿瘤患者中，司里班妥单抗联合厄洛替尼与厄洛替尼单药治疗的活性，并介绍了 HRG 的潜在预测能力。
材料和方法。将 EGFR 野生型NSCLC患者随机分为两组，一组给予司里班妥单抗联合厄洛替尼治疗，另一组单独给予厄洛替尼治疗。患者均接受预处理芯针穿刺活组织检查，并收集存档的肿瘤样本，对预先指定的生物标志物进行分析。
结果。129 名患者接受了司里班妥单抗联合厄洛替尼 (n = 85) 或单独使用厄洛替尼 (n = 44) 治疗。非选择性意向性治疗 (ITT) 人群的中位估算无进展生存期 (PFS)，实验组为 8.1 周， 对照组为 7.7 周 [风险比 (HR), 0.822; 95% 可信区间(CI), 0.37‐1.828; p = 0.63]，实验组和对照组的中位估算总生存期分别为 27.3 周和 40.3 周 (HR, 1.395; 95% CI, 0.846 ~ 2.301; p = 0.189 8)。在肿瘤中检测到 HRG mRNA 表达的患者中，联合使用司里班妥单抗与厄洛替尼的治疗效果明显(HR, 0.35; 95% CI, 0.16‐0.76; p = 0.008)。而在 HRG 阴性的患者中，HR 为 2.15(95% CI, 0.97‐4.76; p = 0.059, HRG‐治疗相互作用，p = 0.001 6)。
结论。在非选择性患者中，在厄洛替尼基础上加用司里班妥单抗并没有改善 PFS。然而，预定义的回顾性探索性分析结果表明，可检测到的 HRG mRNA 水平确定了可能受益于司里班妥单抗的患者。目前，在晚期 NSCLC 和高 HRG mRNA 表达的患者中，正在进行一项司里班妥单抗联合多西紫杉醇临床试验 (NCT02387216)。
实践意义:非小细胞肺癌 (NSCLC) 患者预后差，说明需要更有效的治疗方案，该患者群体的医疗需求尚未得到满足。本研究的结果表明，一种新的生物标志物，调节蛋白，可能帮助我们发现可以从司里班妥单抗治疗中受益的晚期 NSCLC 患者。基于已观察到的安全性和可喜的临床疗效，正在进行一项前瞻性、随机、开放标签、国际、多中心 II 期试验 (SHERLOC, NCT02387216)，研究司里班妥单抗联合多西紫杉醇治疗调节蛋白阳性晚期腺癌的疗效和安全性。
Keywords: Antibody; Biomarkers; HER3/ErbB3; Heregulin; Seribantumab; Targeted therapy; Translational.
© AlphaMed Press 2019.