Background: Icrucumab (ICR) and ramucirumab (RAM) bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. This open-label, randomized phase II study evaluated their efficacy and safety in combination with capecitabine (CAP) in patients with previously treated unresectable, locally advanced or metastatic breast cancer.
Methods: Patients were randomly assigned (1:1:1) to receive CAP (1,000 mg/m2 orally twice daily, days 1-14) alone or in combination with RAM (10 mg/kg intravenously [IV], days 1 and 8) (RAM + CAP) or ICR (12 mg/kg IV, days 1 and 8) (ICR + CAP) every 21 days. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), tumor response, safety, and pharmacokinetics.
Results: Of 153 patients randomized, 150 received treatment. Median PFS (95% confidence interval) was 22.1 (12.1-36.1) weeks on RAM + CAP, 7.3 (6.3-13.0) weeks on ICR + CAP, and 19.0 (12.1-24.3) weeks on CAP (hazard ratios [HRs]: 0.691, p = .1315, RAM + CAP versus CAP; 1.480, p = .0851, ICR + CAP versus CAP). Median OS was 67.4 weeks on RAM + CAP, 62.1 weeks on ICR + CAP, and 71.6 weeks on CAP (HRs: 1.833, p = .0283, RAM + CAP versus CAP; 1.468, p = .1550, ICR + CAP versus CAP). There was no statistically significant difference in PFS or OS between either combination arm and CAP. Treatment-related adverse events more frequent (by ≥10%) on RAM + CAP than on CAP were constipation, decreased appetite, headache, epistaxis, and hypertension. Those more frequent (by ≥10%) on ICR + CAP than CAP were anemia, increased lacrimation, periorbital edema, nausea, vomiting, peripheral edema, facial edema, dehydration, and dyspnea.
Conclusion: Combining RAM or ICR with CAP did not improve PFS in the targeted study population. The Oncologist 2017;22:245-254 IMPLICATIONS FOR PRACTICE: Icrucumab and ramucirumab are recombinant human IgG1 monoclonal antibodies that bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. VEGFR-1 activation on endothelial and tumor cell surfaces increases tumor vascularization and growth and supports tumor growth via multiple mechanisms, including contributions to angiogenesis and direct promotion of cancer cell proliferation. Strong preclinical and clinical evidence suggests key roles for VEGF and angiogenesis in breast cancer growth, invasion, and metastasis. This randomized phase II study evaluated the efficacy and safety of each antibody in combination with capecitabine in patients with previously treated unresectable, locally advanced or metastatic breast cancer.
摘要
背景. Icrucumab（ICR）和Ramucirumab（RAM）分别与血管内皮细胞生长因子（VEGF）受体1和2（VEGFR‐1和‐2）结合。本项开放标签、随机、II期研究评价了ICR和RAM与卡培他滨（CAP）联合治疗不可切除局部晚期或转移性乳腺癌既往经治患者的疗效和安全性。
方法. 患者随机分配（1:1:1）接受CAP（1 000mg/m2, 第1‐14天每日口服两次）单药治疗或者与RAM[10mg/kg, 第1天和第8天静脉注射（IV）；RAM+CAP]或ICR（12mg/kg, 第1天和第8天IV；ICR+CAP）联合治疗, 每21天为一个周期。主要终点为无进展生存期（PFS）。次要终点包括总生存期（OS）、肿瘤反应、安全性和药代动力学。
结果. 共对153例患者进行随机分组, 其中150例接受了治疗。RAM+CAP组、ICR+CAP组和CAP组的中位PFS（95%置信区间）分别为22.1（12.1‐36.1）周、7.3（6.3‐13.0）周和19.0（12.1‐24.3）周[RAM+CAP与CAP比较的风险比（HR）为0.691, p=0.1315；ICR+CAP与CAP比较的HR为1.480, p=0.0851]。RAM+CAP组、ICR+CAP组和CAP组的中位OS分别为67.4周、62.1周和71.6周（RAM+CAP与CAP比较的HR为1.833, p=0.0283；ICR+CAP与CAP比较的HR为1.468, p=0.1550）。两个联合治疗组与CAP治疗组间的PFS或OS均无统计学显著差异。RAM+CAP组中发生率高于CAP组（差异≥10%）的治疗相关不良事件为便秘、食欲下降、头痛、鼻衄和高血压。ICR+CAP组中发生率高于CAP组（差异≥10%）的治疗相关不良事件为贫血、流泪增加、眶周水肿、恶心、呕吐、外周水肿、面部水肿、脱水和呼吸困难。
结论. RAM或ICR与CAP联用未改善目标研究人群的PFS。
对临床实践的提示：Icrucumab和Ramucirumab均为重组人IgG1单克隆抗体, 二者分别与VEGFR‐1和‐2结合。内皮细胞和肿瘤细胞表面的VEGFR‐1活化可促进肿瘤血管化和生长, 并通过多种机制支持肿瘤生长, 包括参与血管生成和直接促进癌细胞增殖。强有力的临床前和临床证据表明, VEGF和血管生成在乳腺癌生长、侵袭和转移中发挥关键作用。本项随机化II期研究评价了这两种抗体与卡培他滨联合治疗不可切除局部晚期或转移性乳腺癌既往经治患者的疗效和安全性。
Trial registration: ClinicalTrials.gov NCT01234402.
Keywords: Breast cancer; Capecitabine; Drug resistance; Metastasis; Monoclonal antibodies.
© AlphaMed Press 2017.