Medical Oncology and Immunotherapy, Azienda Ospedaliera Universitaria Senese, Istituto Toscano Tumori, Siena, Italy.
Lancet Oncol. 2012 Sep;13(9):879-86. doi: 10.1016/S1470-2045(12)70324-8. Epub 2012 Aug 13.
Ipilimumab improves survival of patients with metastatic melanoma, many of whom develop brain metastases. Chemotherapy-induced release of tumour antigens might amplify ipilimumab's antitumour activity. We aimed to investigate the efficacy and safety of ipilimumab plus fotemustine in patients with metastatic melanoma with or without asymptomatic brain metastases.
In our open-label, single-arm phase 2 trial, we enrolled patients 18 years or older with measurable, locally advanced, unresectable stage III or stage IV melanoma between July 6, 2010, and April 14, 2011. Eligible patients had a life expectancy of 16 weeks or more and an Eastern Cooperative Oncology Group performance status of 1 or less, and could have received a maximum of one previous line of chemotherapy. Participants received induction treatment of 10 mg/kg intravenous ipilimumab every 3 weeks to a total of four doses, and 100 mg/m(2) intravenous fotemustine weekly for 3 weeks and then every 3 weeks from week 9 to week 24. Patients with a confirmed clinical response were eligible for maintenance treatment from week 24, with ipilimumab every 12 weeks and fotemustine every 3 weeks. The primary endpoint was the proportion of patients with immune-related disease control as established with immune-related response criteria. Analyses were done per protocol. This trial is registered with EudraCT, number 2010-019356-50, and with ClinicalTrials.gov, number NCT01654692.
86 patients were eligible for treatment, of whom 20 had asymptomatic brain metastases at baseline. 40 patients in the study population achieved disease control (46·5%, 95% CI 35·7-57·6), as did ten with brain metastases (50·0%, 27·2-72·8). 47 patients (55%) had grade 3 or 4 treatment-related adverse events, of which the most common was myelotoxicity (thrombocytopenia in 21 [24%] patients and neutropenia in 16 [19%]). The most common grade 3 or 4 immune-related adverse events were hepatic: 21 patients (24%) had grade 3 or 4 increases in concentrations of alanine aminotransferase or aspartate aminotransferase.
The combination of ipilimumab plus fotemustine has clinical activity in patients with metastatic melanoma, including those with brain metastases.
Bristol-Myers Squibb.
依匹单抗可改善转移性黑色素瘤患者的生存率，其中许多患者会出现脑转移。化疗诱导的肿瘤抗原释放可能会增强依匹单抗的抗肿瘤活性。我们旨在研究依匹单抗联合福莫司汀在有或无症状脑转移的转移性黑色素瘤患者中的疗效和安全性。
在我们的开放性、单臂 2 期试验中，我们招募了 2010 年 7 月 6 日至 2011 年 4 月 14 日期间年龄在 18 岁及以上、可测量的局部晚期、不可切除的 III 期或 IV 期黑色素瘤患者。符合条件的患者预期寿命在 16 周以上，东部合作肿瘤学组（ECOG）体能状态为 1 或更低，并且最多接受过一次前期化疗。参与者接受诱导治疗，每 3 周静脉注射 10mg/kg 依匹单抗，共 4 个剂量，100mg/m2 静脉注射福莫司汀每周 3 周，然后从第 9 周到第 24 周每 3 周 1 次。有明确临床反应的患者有资格从第 24 周开始进行维持治疗，每 12 周接受依匹单抗治疗，每 3 周接受福莫司汀治疗。主要终点是根据免疫相关反应标准确定的免疫相关疾病控制率。分析按照方案进行。本试验在 EudraCT 注册，编号为 2010-019356-50，并在 ClinicalTrials.gov 注册，编号为 NCT01654692。
86 名患者符合治疗条件，其中 20 名基线时有无症状脑转移。研究人群中有 40 名患者（46.5%，95%CI 35.7-57.6）达到疾病控制，10 名有脑转移的患者（50.0%，27.2-72.8）达到疾病控制。47 名患者（55%）发生 3 级或 4 级治疗相关不良事件，最常见的是骨髓毒性（血小板减少症 21 例[24%]，中性粒细胞减少症 16 例[19%]）。最常见的 3 级或 4 级免疫相关不良事件是肝毒性：21 名患者（24%）出现丙氨酸氨基转移酶或天冬氨酸氨基转移酶浓度 3 级或 4 级升高。
依匹单抗联合福莫司汀在转移性黑色素瘤患者中具有临床活性，包括有脑转移的患者。
百时美施贵宝公司。
