University of Washington, Seattle, WA 98109, USA.
Lancet Oncol. 2012 May;13(5):459-65. doi: 10.1016/S1470-2045(12)70090-6. Epub 2012 Mar 27.
Brain metastases commonly develop in patients with melanoma and are a frequent cause of death of patients with this disease. Ipilimumab improves survival in patients with advanced melanoma. We aimed to investigate the safety and activity of this drug specifically in patients with brain metastases.
Between July 31, 2008, and June 3, 2009, we enrolled patients with melanoma and brain metastases from ten US centres who were older than 16 years into two parallel cohorts. Patients in cohort A were neurologically asymptomatic and were not receiving corticosteroid treatment at study entry; those in cohort B were symptomatic and on a stable dose of corticosteroids. Patients were to receive four doses of 10 mg/kg intravenous ipilimumab, one every 3 weeks. Individuals who were clinically stable at week 24 were eligible to receive 10 mg/kg intravenous ipilimumab every 12 weeks. The primary endpoint was the proportion of patients with disease control, defined as complete response, partial response, or stable disease after 12 weeks, assessed with modified WHO criteria. Analyses of safety and efficacy included all treated patients. This trial is registered with ClinicalTrials.gov, number NCT00623766.
We enrolled 72 patients: 51 into cohort A and 21 into cohort B. After 12 weeks, nine patients in cohort A exhibited disease control (18%, 95% CI 8-31), as did one patient in cohort B (5%, 0·1-24). When the brain alone was assessed, 12 patients in cohort A (24%, 13-38) and two in cohort B (10%, 1-30) achieved disease control. We noted disease control outside of the brain in 14 patients (27%, 16-42) in cohort A and in one individual (5%, 0·1-24) in cohort B. The most common grade 3 adverse events in cohort A were diarrhoea (six patients [12%]) and fatigue (six [12%]); in cohort B, they were dehydration (two individuals [10%]), hyperglycaemia (two [10%]), and increased concentrations of serum aspartate aminotransferase (two [10%]). One patient in each cohort had grade 4 confusion. The most common grade 3 immune-related adverse events were diarrhoea (six patients [12%]) and rash (one [2%]) in cohort A, and rash (one individual [5%]) and increased concentrations of serum aspartate aminotransferase (two [10%]) in cohort B. One patient in cohort A died of drug-related complications of immune-related colitis.
Ipilimumab has activity in some patients with advanced melanoma and brain metastases, particularly when metastases are small and asymptomatic. The drug has no unexpected toxic effects in this population.
Bristol-Myers Squibb.
脑转移在黑色素瘤患者中很常见，是导致此类疾病患者死亡的常见原因。依匹单抗可改善晚期黑色素瘤患者的生存率。我们旨在研究该药在脑转移患者中的安全性和疗效。
在 2008 年 7 月 31 日至 2009 年 6 月 3 日期间，我们从美国 10 个中心招募了患有脑转移的黑色素瘤患者，这些患者年龄均在 16 岁以上，分为两组平行队列。队列 A 的患者没有神经症状，在研究入组时未接受皮质类固醇治疗；队列 B 的患者有症状且正在接受稳定剂量的皮质类固醇治疗。所有患者均接受四剂 10mg/kg 静脉注射依匹单抗，每 3 周 1 次。在第 24 周时，如果临床状况稳定，有资格接受每 12 周静脉注射 10mg/kg 依匹单抗。主要终点是根据改良 WHO 标准，在 12 周后疾病控制的患者比例，定义为完全缓解、部分缓解或疾病稳定。安全性和疗效分析包括所有接受治疗的患者。本试验在 ClinicalTrials.gov 注册，编号为 NCT00623766。
我们共纳入了 72 名患者：51 名患者入组队列 A，21 名患者入组队列 B。12 周后，队列 A 中有 9 名患者（18%，95%CI 8-31）出现疾病控制，队列 B 中有 1 名患者（5%，0.1-24）出现疾病控制。当仅评估脑转移时，队列 A 中有 12 名患者（24%，13-38）和队列 B 中有 2 名患者（10%，1-30）达到疾病控制。我们还观察到队列 A 中有 14 名患者（27%，16-42）和队列 B 中有 1 名患者（5%，0.1-24）出现脑外疾病控制。队列 A 中最常见的 3 级不良事件为腹泻（6 名患者[12%]）和疲劳（6 名患者[12%]）；队列 B 中最常见的 3 级不良事件为脱水（2 名患者[10%]）、高血糖（2 名患者[10%]）和血清天冬氨酸转氨酶浓度升高（2 名患者[10%]）。两个队列中各有 1 名患者出现 4 级意识混乱。队列 A 中最常见的 3 级免疫相关不良事件为腹泻（6 名患者[12%]）和皮疹（1 名患者[2%]），队列 B 中最常见的免疫相关不良事件为皮疹（1 名患者[5%]）和血清天冬氨酸转氨酶浓度升高（2 名患者[10%]）。队列 A 中有 1 名患者因药物相关免疫性肠炎并发症而死亡。
依匹单抗在某些患有晚期黑色素瘤和脑转移的患者中具有活性，特别是当转移灶较小且无症状时。该药在该人群中无意外的毒性作用。
百时美施贵宝公司。
