Medical Oncology and Immunotherapy, Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
Pulmonary and Thoracic Oncology, University of Lille, CHU de Lille, Lille, France.
Lancet Oncol. 2017 Sep;18(9):1261-1273. doi: 10.1016/S1470-2045(17)30446-1. Epub 2017 Jul 17.
New therapeutic strategies for malignant mesothelioma are urgently needed. In the DETERMINE study, we investigated the effects of the cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody tremelimumab in patients with previously treated advanced malignant mesothelioma.
DETERMINE was a double-blind, placebo-controlled, phase 2b trial done at 105 study centres across 19 countries in patients with unresectable pleural or peritoneal malignant mesothelioma who had progressed after one or two previous systemic treatments for advanced disease. Eligible patients were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and measurable disease as defined in the modified Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 for pleural mesothelioma or RECIST version 1.1 for peritoneal mesothelioma. Patients were randomly assigned (2:1) in blocks of three, stratified by European Organisation for Research and Treatment of Cancer status (low risk vs high risk), line of therapy (second line vs third line), and anatomic site (pleural vs peritoneal), by use of an interactive voice or web system, to receive intravenous tremelimumab (10 mg/kg) or placebo every 4 weeks for 7 doses and every 12 weeks thereafter until a treatment discontinuation criterion was met. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is ongoing but no longer recruiting participants, and is registered with ClinicalTrials.gov, number NCT01843374.
Between May 17, 2013, and Dec 4, 2014, 571 patients were randomly assigned to receive tremelimumab (n=382) or placebo (n=189), of whom 569 patients received treatment (two patients in the tremelimumab group were excluded from the safety population because they did not receive treatment). At the data cutoff date (Jan 24, 2016), 307 (80%) of 382 patients had died in the tremelimumab group and 154 (81%) of 189 patients had died in the placebo group. Median overall survival in the intention-to-treat population did not differ between the treatment groups: 7·7 months (95% CI 6·8-8·9) in the tremelimumab group and 7·3 months (5·9-8·7) in the placebo group (hazard ratio 0·92 [95% CI 0·76-1·12], p=0·41). Treatment-emergent adverse events of grade 3 or worse occurred in 246 (65%) of 380 patients in the tremelimumab group and 91 (48%) of 189 patients in the placebo group; the most common were dyspnoea (34 [9%] patients in the tremelimumab group vs 27 [14%] patients in the placebo group), diarrhoea (58 [15%] vs one [<1%]), and colitis (26 [7%] vs none). The most common serious adverse events were diarrhoea (69 [18%] patients in the tremelimumab group vs one [<1%] patient in the placebo group), dyspnoea (29 [8%] vs 24 [13%]), and colitis (24 [6%] vs none). Treatment-emergent events leading to death occurred in 36 (9%) of 380 patients in the tremelimumab group and 12 (6%) of 189 in the placebo group; those leading to the death of more than one patient were mesothelioma (three [1%] patients in the tremelimumab group vs two [1%] in the placebo group), dyspnoea (three [1%] vs two [1%]); respiratory failure (one [<1%] vs three [2%]), myocardial infarction (three [1%] vs none), lung infection (three [1%] patients vs none), cardiac failure (one [<1%] vs one [<1%]), and colitis (two [<1%] vs none). Treatment-related adverse events leading to death occurred in five (1%) patients in the tremelimumab group and none in the placebo group. The causes of death were lung infection in one patient, intestinal perforation and small intestinal obstruction in one patient; colitis in two patients, and neuritis and skin ulcer in one patient.
Tremelimumab did not significantly prolong overall survival compared with placebo in patients with previously treated malignant mesothelioma. The safety profile of tremelimumab was consistent with the known safety profile of CTLA-4 inhibitors. Investigations into whether immunotherapy combination regimens can provide greater efficacy than monotherapies in malignant mesothelioma are ongoing.
AstraZeneca.
恶性间皮瘤迫切需要新的治疗策略。在 DETERMINE 研究中，我们研究了细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）单克隆抗体 tremelimumab 对先前接受过治疗的晚期恶性间皮瘤患者的疗效。
DETERMINE 是一项在 19 个国家的 105 个研究中心进行的双盲、安慰剂对照、2b 期临床试验，纳入了先前接受过一次或两次晚期疾病全身治疗后进展的不可切除的胸膜或腹膜恶性间皮瘤患者。入选患者年龄在 18 岁及以上，东部肿瘤协作组体力状态为 0 或 1，根据改良实体瘤反应评价标准（RECIST）1.0 版用于胸膜间皮瘤或 RECIST 1.1 版用于腹膜间皮瘤定义为可测量疾病。患者按欧洲癌症研究和治疗组织（ECOG）状态（低危与高危）、治疗线数（二线与三线）和解剖部位（胸膜与腹膜）以 3 例为一组、2:1 的比例分层，通过交互式语音或网络系统随机分配接受静脉注射 tremelimumab（10mg/kg）或安慰剂，每 4 周 7 剂，此后每 12 周 1 剂，直至达到治疗终止标准。主要终点是在意向治疗人群中的总生存期。对至少接受过一剂研究药物的所有患者进行安全性评估。该试验正在进行中，但不再招募参与者，已在 ClinicalTrials.gov 注册，编号为 NCT01843374。
2013 年 5 月 17 日至 2014 年 12 月 4 日，571 例患者被随机分配接受 tremelimumab（n=382）或安慰剂（n=189），其中 569 例患者接受了治疗（tremelimumab 组中有 2 例患者因未接受治疗而被排除在安全性人群之外）。在数据截止日期（2016 年 1 月 24 日），tremelimumab 组 382 例患者中有 307 例（80%）死亡，安慰剂组 189 例患者中有 154 例（81%）死亡。意向治疗人群的中位总生存期在治疗组之间没有差异：tremelimumab 组为 7.7 个月（95%CI 6.8-8.9），安慰剂组为 7.3 个月（5.9-8.7）（风险比 0.92 [95%CI 0.76-1.12]，p=0.41）。tremelimumab 组 380 例患者中有 246 例（65%）和安慰剂组 189 例患者中有 91 例（48%）发生 3 级或更高级别的治疗相关不良事件；最常见的是呼吸困难（tremelimumab 组 34 例[9%]，安慰剂组 27 例[14%]）、腹泻（tremelimumab 组 58 例[15%]，安慰剂组 1 例[<1%]）和结肠炎（tremelimumab 组 26 例[7%]，安慰剂组无）。最常见的严重不良事件是腹泻（tremelimumab 组 69 例[18%]，安慰剂组 1 例[<1%]）、呼吸困难（tremelimumab 组 29 例[8%]，安慰剂组 24 例[13%]）和结肠炎（tremelimumab 组 24 例[6%]，安慰剂组无）。tremelimumab 组 380 例患者中有 36 例（9%）和安慰剂组 189 例患者中有 12 例（6%）发生治疗相关的导致死亡的事件；导致 1 例以上患者死亡的事件是间皮瘤（tremelimumab 组 3 例[1%]，安慰剂组 2 例[1%]）、呼吸困难（tremelimumab 组 3 例[1%]，安慰剂组 2 例[1%]）；呼吸衰竭（<1%vs 3%）、心肌梗死（tremelimumab 组 3 例[1%]，安慰剂组无）、肺部感染（tremelimumab 组 3 例[1%]，安慰剂组无）、心力衰竭（<1%vs 1%）和结肠炎（tremelimumab 组 2 例[1%]，安慰剂组无）。tremelimumab 组有 5 例（1%）患者发生与治疗相关的导致死亡的不良事件，安慰剂组无。死亡原因是肺部感染 1 例，肠穿孔和小肠梗阻 1 例；结肠炎 2 例，神经炎和皮肤溃疡 1 例。
与安慰剂相比，tremelimumab 并未显著延长先前治疗的恶性间皮瘤患者的总生存期。tremelimumab 的安全性与 CTLA-4 抑制剂的已知安全性一致。正在进行调查，以确定免疫疗法联合方案是否能比单药治疗在恶性间皮瘤中提供更大的疗效。
阿斯利康。
Zotero 插件