Princess Margaret Cancer Centre, Toronto, ON, Canada.
Department of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Medical College, Cornell University, New York, NY, USA.
Lancet Oncol. 2018 Dec;19(12):1641-1653. doi: 10.1016/S1470-2045(18)30576-X. Epub 2018 Nov 12.
B-cell maturation antigen (BCMA) is a cell-surface receptor of the tumour necrosis superfamily required for plasma cell survival. BMCA is universally detected on patient-derived myeloma cells and has emerged as a selective antigen to be targeted by novel treatments in multiple myeloma. We assessed the safety, tolerability, and preliminary clinical activity of GSK2857916, a novel anti-BCMA antibody conjugated to microtubule-disrupting agent monomethyl auristatin F, in patients with relapsed and refractory multiple myeloma.
We did an international, multicentre, open-label, first-in-human phase 1 study with dose escalation (part 1) and dose expansion (part 2) phases, at nine centres in the USA, Canada, and the UK. Adults with histologically or cytologically confirmed multiple myeloma, Eastern Cooperative Oncology Group performance status 0 or 1, and progressive disease after stem cell transplantation, alkylators, proteasome inhibitors, and immunomodulators were recruited for this study. In part 1, patients received GSK2857916 (0·03-4·60 mg/kg) through 1 h intravenous infusions once every 3 weeks. In part 2, patients received the selected recommended phase 2 dose of GSK2857916 (3·40 mg/kg) once every 3 weeks. Primary endpoints were maximum tolerated dose and recommended phase 2 dose. Secondary endpoints for part 2 included preliminary anti-cancer clinical activity. All patients who received one or more doses were included in this prespecified administrative interim analysis (data cutoff date June 26, 2017), which was done for internal purposes. This study is registered with ClinicalTrials.gov, number NCT02064387, and is ongoing, but closed for recruitment.
Between July 29, 2014, and Feb 21, 2017, we treated 73 patients: 38 patients in the dose-escalation part 1 and 35 patients in the dose-expansion part 2. There were no dose-limiting toxicities and no maximum tolerated dose was identified in part 1. On the basis of safety and clinical activity, we selected 3·40 mg/kg as the recommended phase 2 dose. Corneal events were common (20 [53%] of 38 patients in part 1 and 22 [63%] of 35 in part 2); most (18 [47%] in part 1 and 19 [54%] in part 2) were grade 1 or 2 and resulted in two treatment discontinuations in part 1 and no discontinuations in part 2. The most common grade 3 or 4 events were thrombocytopenia (13 [34%] of 38 patients in part 1 and 12 [34%] of 35 in part 2) and anaemia (6 [16%] in part 1 and 5 [14%] in part 2). There were 12 treatment-related serious adverse events and no treatment-related deaths. In part 2, 21 (60·0%; 95% CI 42·1-76·1) of 35 patients achieved an overall response.
At the identified recommended phase 2 dose, GSK2857916 was well tolerated and had good clinical activity in heavily pretreated patients, thereby indicating that this might be a promising candidate for the treatment of relapsed or refractory multiple myeloma.
GlaxoSmithKline.
B 细胞成熟抗原（BCMA）是肿瘤坏死超家族的细胞表面受体，是浆细胞存活所必需的。BMCA 普遍存在于患者来源的骨髓瘤细胞上，并已成为多发性骨髓瘤中多种新型治疗方法的选择性抗原。我们评估了新型抗 BCMA 抗体 GSK2857916 与微管破坏剂单甲基奥瑞他汀 F 偶联物在复发和难治性多发性骨髓瘤患者中的安全性、耐受性和初步临床活性。
我们在美国、加拿大和英国的 9 个中心进行了一项国际、多中心、开放性、首次人体、剂量递增（第 1 部分）和剂量扩展（第 2 部分）的 1 期研究。招募了组织学或细胞学证实的多发性骨髓瘤、东部合作肿瘤学组表现状态 0 或 1 和干细胞移植后疾病进展、烷化剂、蛋白酶体抑制剂和免疫调节剂的成年患者。在第 1 部分中，患者接受 GSK2857916（0.03-4.60mg/kg）静脉输注 1 小时，每 3 周 1 次。在第 2 部分中，患者接受选定的推荐的 2 期剂量 GSK2857916（3.40mg/kg），每 3 周 1 次。主要终点是最大耐受剂量和推荐的 2 期剂量。第 2 部分的次要终点包括初步抗癌临床活性。所有接受 1 次或更多剂量的患者均包括在本次预先指定的行政中期分析中（数据截止日期为 2017 年 6 月 26 日），该分析仅供内部使用。该研究在 ClinicalTrials.gov 上注册，编号为 NCT02064387，正在进行中，但已关闭招募。
2014 年 7 月 29 日至 2017 年 2 月 21 日，我们治疗了 73 例患者：38 例患者在剂量递增第 1 部分，35 例患者在剂量扩展第 2 部分。没有剂量限制毒性，也没有在第 1 部分中确定最大耐受剂量。基于安全性和临床活性，我们选择 3.40mg/kg 作为推荐的 2 期剂量。角膜事件很常见（第 1 部分 38 例患者中有 20 例[53%]，第 2 部分 35 例患者中有 22 例[63%]）；大多数（第 1 部分 18 例[47%]，第 2 部分 19 例[54%]）为 1 级或 2 级，导致第 1 部分中有 2 例治疗中断，第 2 部分中无中断。最常见的 3 级或 4 级事件是血小板减少症（第 1 部分 38 例患者中有 13 例[34%]，第 2 部分 35 例患者中有 12 例[34%]）和贫血（第 1 部分 6 例[16%]，第 2 部分 5 例[14%]）。有 12 例与治疗相关的严重不良事件，无治疗相关死亡。在第 2 部分中，35 例患者中有 21 例（60.0%；95%CI 42.1-76.1）获得了总体反应。
在确定的推荐的 2 期剂量下，GSK2857916 在接受过多重预处理的患者中具有良好的耐受性和良好的临床活性，表明这可能是治疗复发性或难治性多发性骨髓瘤的一种很有前途的候选药物。
葛兰素史克。
