Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, UK.
Department of Drug Development and Innovation, Institut Curie, Paris, France.
Breast Cancer Res. 2021 Jan 15;23(1):8. doi: 10.1186/s13058-020-01382-8.
Xentuzumab-a humanised IgG1 monoclonal antibody-binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC).
Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS).
MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3-not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7-9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57-1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05-0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]).
Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136).
ClinicalTrials.gov, NCT02123823 . Prospectively registered, 8 March 2013.
Xentuzumab 是一种人源化 IgG1 单克隆抗体，可与 IGF-1 和 IGF-2 结合，抑制其促生长信号，并抑制依维莫司对 AKT 的激活。这项 Ib/II 期探索性试验评估了 Xentuzumab 联合依维莫司和依西美坦治疗激素受体阳性、局部晚期和/或转移性乳腺癌（LA/MBC）。
招募了对非甾体类芳香酶抑制剂耐药的激素受体阳性/HER2 阴性 LA/MBC 患者。在 I 期（单臂、剂量递增）中确定了 Xentuzumab/依维莫司/依西美坦的最大耐受剂量（MTD）和推荐的 II 期剂量（RP2D）。在 II 期（开放标签）中，患者按 1:1 随机分配至 Xentuzumab/依维莫司/依西美坦的 RP2D 或依维莫司/依西美坦单药治疗。随机分组按是否存在内脏转移分层。主要终点是无进展生存期（PFS）。
MTD 确定为 Xentuzumab 每周 1000mg 联合依维莫司 10mg/天和依西美坦 25mg/天。共有 140 名患者入组 II 期（每组 70 名）。在内部数据监测委员会进行了由赞助商任命的不利获益风险评估后，停止了进一步的招募。停止使用 Xentuzumab；如果临床需要，患者可以接受依维莫司/依西美坦。Xentuzumab/依维莫司/依西美坦组的中位 PFS 为 7.3 个月（95%CI 3.3-无计算），依维莫司/依西美坦组为 5.6 个月（3.7-9.1）（风险比 0.97，95%CI 0.57-1.65；P=0.9057）。在筛选时无内脏转移的预先指定亚组患者中，与依维莫司/依西美坦相比，Xentuzumab/依维莫司/依西美坦显示出 PFS 获益的证据（风险比 0.21[0.05-0.98]；P=0.0293）。II 期最常见的任何原因不良事件是腹泻（Xentuzumab/依维莫司/依西美坦组 29 例[41.4%]，依维莫司/依西美坦组 20 例[29.0%]）、粘膜炎症（27 例[38.6%]，21 例[30.4%]）、口腔炎（24 例[34.3%]，24 例[34.8%]）和乏力（21 例[30.0%]，24 例[34.8%]）。
在总体人群中，添加 Xentuzumab 至依维莫司/依西美坦并未改善 PFS，导致试验提前停止。在未发生内脏转移的患者中观察到 Xentuzumab/依维莫司/依西美坦治疗的 PFS 获益，从而启动了 XENERA™-1 试验（NCT03659136）。
ClinicalTrials.gov，NCT02123823。前瞻性注册，2013 年 3 月 8 日。
