Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, UK.
International Breast Cancer Center (IBCC), Pangaea Oncology, Quironsalud Group, Barcelona, Spain.
Breast Cancer Res. 2023 Jun 12;25(1):67. doi: 10.1186/s13058-023-01649-w.
Xentuzumab is a humanised monoclonal antibody that binds to IGF-1 and IGF-2, neutralising their proliferative activity and restoring inhibition of AKT by everolimus. This study evaluated the addition of xentuzumab to everolimus and exemestane in patients with advanced breast cancer with non-visceral disease.
This double-blind, randomised, Phase II study was undertaken in female patients with hormone-receptor (HR)-positive/human epidermal growth factor 2 (HER2)-negative advanced breast cancer with non-visceral disease who had received prior endocrine therapy with or without CDK4/6 inhibitors. Patients received a weekly intravenous infusion of xentuzumab (1000 mg) or placebo in combination with everolimus (10 mg/day orally) and exemestane (25 mg/day orally). The primary endpoint was progression-free survival (PFS) per independent review.
A total of 103 patients were randomised and 101 were treated (n = 50 in the xentuzumab arm and n = 51 in the placebo arm). The trial was unblinded early due to high rates of discordance between independent and investigator assessment of PFS. Per independent assessment, median PFS was 12.7 (95% CI 6.8-29.3) months with xentuzumab and 11.0 (7.7-19.5) months with placebo (hazard ratio 1.19; 95% CI 0.55-2.59; p = 0.6534). Per investigator assessment, median PFS was 7.4 (6.8-9.7) months with xentuzumab and 9.2 (5.6-14.4) months with placebo (hazard ratio 1.23; 95% CI 0.69-2.20; p = 0.4800). Tolerability was similar between the arms, with diarrhoea (33.3-56.0%), fatigue (33.3-44.0%) and headache (21.6-40.0%) being the most common treatment-emergent adverse events. The incidence of grade ≥ 3 hyperglycaemia was similar between the xentuzumab (2.0%) and placebo (5.9%) arms.
While this study demonstrated that xentuzumab could be safely combined with everolimus and exemestane in patients with HR-positive/HER2-negative advanced breast cancer with non-visceral disease, there was no PFS benefit with the addition of xentuzumab. Trial registration ClinicalTrials.gov, NCT03659136. Prospectively registered, September 6, 2018.
Xentuzumab 是一种人源化单克隆抗体，可与 IGF-1 和 IGF-2 结合，使其增殖活性失活，并恢复依维莫司对 AKT 的抑制作用。本研究评估了 Xentuzumab 联合依维莫司和依西美坦在非内脏疾病晚期乳腺癌患者中的应用。
这是一项在接受过内分泌治疗联合或不联合 CDK4/6 抑制剂治疗的激素受体（HR）阳性/人表皮生长因子 2（HER2）阴性晚期乳腺癌且无内脏疾病的女性患者中进行的双盲、随机、II 期研究。患者接受每周一次静脉输注 Xentuzumab（1000mg）或安慰剂，联合依维莫司（每天 10mg 口服）和依西美坦（每天 25mg 口服）。主要终点是独立评估的无进展生存期（PFS）。
共有 103 名患者被随机分组，101 名患者接受了治疗（Xentuzumab 组 50 名，安慰剂组 51 名）。由于独立评估和研究者评估的 PFS 结果之间存在较高的差异，试验提前揭盲。根据独立评估，Xentuzumab 组的中位 PFS 为 12.7 个月（95%CI 6.8-29.3），安慰剂组为 11.0 个月（7.7-19.5）（风险比 1.19；95%CI 0.55-2.59；p=0.6534）。根据研究者评估，Xentuzumab 组的中位 PFS 为 7.4 个月（6.8-9.7），安慰剂组为 9.2 个月（5.6-14.4）（风险比 1.23；95%CI 0.69-2.20；p=0.4800）。两组的耐受性相似，最常见的治疗相关不良事件为腹泻（33.3%-56.0%）、疲劳（33.3%-44.0%）和头痛（21.6%-40.0%）。Xentuzumab 组（2.0%）和安慰剂组（5.9%）的 3 级及以上高血糖发生率相似。
尽管本研究表明 Xentuzumab 可与依维莫司和依西美坦联合安全应用于 HR 阳性/HER2 阴性、无内脏疾病的晚期乳腺癌患者，但添加 Xentuzumab 并未带来 PFS 获益。
ClinicalTrials.gov，NCT03659136。前瞻性注册，2018 年 9 月 6 日。
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