Peter Schmid, Javier Cortes, Ana Joaquim, Noelia Martínez Jañez, Serafín Morales, Tamara Díaz-Redondo, Sibel Blau, Patrick Neven, Julie Lemieux, José Ángel García-Sáenz, Lowell Hart, Tsvetan Biyukov, Navid Baktash, Dan Massey, Howard A Burris, Hope S Rugo
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This study evaluated the addition of xentuzumab to everolimus and exemestane in patients with advanced breast cancer with non-visceral disease.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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. 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This study evaluated the addition of xentuzumab to everolimus and exemestane in patients with advanced breast cancer with non-visceral disease.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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. 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引用次数: 4
摘要
背景:Xentuzumab是一种人源化单克隆抗体,与IGF-1和IGF-2结合,中和它们的增殖活性,恢复依维莫司对AKT的抑制作用。本研究评估了依维莫司和依西美坦在晚期乳腺癌合并非内脏疾病患者中的应用。方法:这项双盲、随机、II期研究是在患有激素受体(HR)阳性/人表皮生长因子2 (HER2)阴性的晚期乳腺癌合并非内脏疾病的女性患者中进行的,这些患者之前接受过有或没有CDK4/6抑制剂的内分泌治疗。患者接受每周静脉输注xentuzumab (1000mg)或安慰剂联合依维莫司(10mg /天口服)和依西美坦(25mg /天口服)。主要终点是每次独立审查的无进展生存期(PFS)。结果:共有103名患者被随机分组,101名患者接受了治疗(在xentuzumab组n = 50,在安慰剂组n = 51)。由于独立评估和研究者对PFS的评估之间存在很高的不一致性,该试验很早就进行了非盲法分析。根据独立评估,xentuzumab组的中位PFS为12.7 (95% CI 6.8-29.3)个月,安慰剂组为11.0(7.7-19.5)个月(风险比1.19;95% ci 0.55-2.59;p = 0.6534)。根据研究者评估,单抗组的中位PFS为7.4(6.8-9.7)个月,安慰剂组为9.2(5.6-14.4)个月(风险比1.23;95% ci 0.69-2.20;p = 0.4800)。两组患者的耐受性相似,腹泻(33.3-56.0%)、疲劳(33.3-44.0%)和头痛(21.6-40.0%)是最常见的治疗不良事件。≥3级高血糖的发生率在xentuzumab组(2.0%)和安慰剂组(5.9%)之间相似。结论:虽然这项研究表明,对于hr阳性/ her2阴性的晚期乳腺癌合并非内脏疾病患者,xentuzumab可以安全地与依维莫司和依西美坦联合使用,但添加xentuzumab并没有PFS获益。临床试验注册:ClinicalTrials.gov, NCT03659136。预期注册,2018年9月6日。
XENERA-1: a randomised double-blind Phase II trial of xentuzumab in combination with everolimus and exemestane versus everolimus and exemestane in patients with hormone receptor-positive/HER2-negative metastatic breast cancer and non-visceral disease.
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.