Background: Regorafenib is a multikinase inhibitor with antiangiogenic effects that improves overall survival (OS) in metastatic colorectal cancer (mCRC) after failure of standard therapies. We investigated the efficacy and safety of regorafenib in antiangiogenic therapy-naïve chemotherapy-refractory advanced colorectal cancer.
Patients and methods: This single-center, single-arm, phase IIb study (NCT02465502) enrolled adults with mCRC whose disease had progressed on, or who were intolerant to, standard therapy, but who were antiangiogenic therapy-naïve. Patients received regorafenib 160 mg once daily for 3 weeks per 4-week cycle. The primary endpoint was progression-free survival (PFS) rate at week 8.
Results: Of 59 treated patients, almost half had received at least four prior lines of therapy. Patients received a median of 86% of the planned dose. The week 8 PFS rate was 53% (95% confidence interval [CI], 39.1-64.3); median PFS was 3.5 months (95% CI, 1.8-3.6). Median OS was 7.4 months (95% CI, 5.3-8.9). Tumor response (RECIST version 1.1) was 2%, and metabolic response rate (criteria from the European Organisation for Research and Treatment of Cancer) was 41%. The most frequently reported regorafenib-related grade ≥3 adverse events were hypertension (36%), hand-foot skin reaction (HFSR, 25%), and hypophosphatemia (24%). There were no regorafenib-related deaths. An exploratory analysis showed that patients with grade ≥2 HFSR had longer OS (10.2 months) with regorafenib treatment versus those with grades 0-1 (5.4 months).
Conclusion: These findings support the antitumor activity of regorafenib in antiangiogenic-naïve patients with chemotherapy-refractory mCRC.
Implications for practice: The multikinase inhibitor regorafenib improved overall survival in the phase III CORRECT and CONCUR trials in heavily pretreated patients with treatment-refractory metastatic colorectal cancer (mCRC). Exploratory subgroup analysis from CONCUR suggested that regorafenib treatment prior to targeted therapy (including bevacizumab) may improve outcomes. In this single-center, single-arm phase IIb study, regorafenib demonstrated antitumor activity in 59 antiangiogenic-naïve patients with chemotherapy-refractory mCRC. Further studies should assess the efficacy of regorafenib in this patient population, as well as explore the reasons behind improved outcomes among patients who had a metabolic response and those who developed hand-foot skin reaction.
摘要
背景。瑞戈非尼是一种多激酶抑制剂，具有抗血管生成作用，在标准疗法失败后，采用瑞戈非尼治疗可延长转移性结直肠癌 (mCRC) 患者的总生存期 (OS)。我们对瑞戈非尼用于从未接受抗血管生成治疗且化疗难以控制的晚期结直肠癌患者的疗效和安全性进行了研究。
患者和方法。此为一项单中心、单组 2b 期研究(NCT02465502)，纳入的受试者为接受标准疗法后病情进展或对标准疗法耐受、但从未接受抗血管生成治疗的mCRC成人患者。患者接受瑞戈非尼160 mg，每日一次，持续 3 周，每 4 周为一个周期。主要终点是第 8 周时无进展生存 (PFS) 率。
结果。在接受治疗的 59 名患者中，近一半患者既往至少接受过四线治疗。患者接受的计划剂量中位数为 86%。第 8 周PFS率为 53% [95% 置信区间(CI)，39.1–64.3]；中位PFS为 3.5 个月(95% CI，1.8–3.6)。中位OS为 7.4 个月(95% CI，5.3–8.9)。肿瘤反应率为(根据RECIST 1.1 版) 为 2%，代谢反应率(根据欧洲癌症研究和治疗组织制定的标准)为 41%。最常报告的因瑞戈非尼引起的 ≥3 级不良事件为高血压 (36%)、手足皮肤反应(HFSR，25%)及低磷血症 (24%)。无因瑞戈非尼造成死亡的案例。探索性分析表明，采用瑞戈非尼治疗后出现 ≥2 级HFSR 的患者OS为 10.2 个月，比 0–1 级(5.4 个月)的患者长。
结论。本研究支持瑞戈非尼对于从未接受抗血管生成治疗且化疗难以控制的mCRC患者具有抗肿瘤活性。
实践意义:在 3 期 CORRECT 和 CONCUR 试验中，对于先前已接受治疗且治疗难以控制的转移性结直肠癌 (mCRC) 患者，多激酶抑制剂瑞戈非尼改善了总生存期。来自 CONCUR 试验的探索性亚组分析表明，在进行靶向治疗(包括贝伐单抗)之前，采用瑞戈非尼治疗可改善预后。在此项单中心、单组 2b 期研究中，瑞戈非尼对 59 例从未接受抗血管生成治疗且化疗难以控制的mCRC患者显示出抗肿瘤活性。在进一步研究中，应评估瑞戈非尼对此类患者的疗效，同时针对存在代谢反应和手足皮肤反应的患者能够改善预后的原因进行深入研究。
Keywords: Angiogenesis inhibitors; Colorectal neoplasms; Computed tomography; Positron emission tomography; Regorafenib.
© AlphaMed Press 2019.