Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study
Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study
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DOI：
10.1016/s2213-2600(18)30151-6
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发表时间：
2018-06-01
影响因子：
76.2
通讯作者：
Maio, Michele
中科院分区：
文献类型：
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作者：
Calabro, Luana;Morra, Aldo;Maio, Michele
背景：Tremlimumab是一种抗CTLA4的单抗，最初单独用于间皮瘤患者时显示出良好的活性，但在Decision研究中，与安慰剂相比，它并不能改善一线或二线化疗失败的患者的总体存活率。我们旨在研究一线或二线雷米单抗联合抗PD-L1单抗杜伐单抗治疗恶性间皮瘤的疗效和安全性。方法在这项开放的、非随机的2期试验中，不能切除的胸膜或腹膜间皮瘤患者每4周静脉注射雷利单抗(1 mg/kg体重)和杜瓦单抗(20 mg/kg体重)，共4剂，然后维持静脉注射相同剂量的杜瓦单抗，共9剂。主要终点是根据实体肿瘤免疫相关改良反应评估标准(RECIST；对于胸膜间皮瘤)或免疫相关RECIST 1.1版(对于腹膜间皮瘤)具有免疫相关客观反应的患者的比例。初步分析是根据治疗意图进行的，而安全性分析包括接受至少一剂研究药物的患者。这项试验在欧洲临床试验数据库注册，编号2015-001995-23，在ClinicalTrials.gov注册，编号NCT02588131，正在进行中，但不再招募患者。研究发现，从2015年10月30日到2016年10月12日，40名间皮瘤患者入选，分别接受至少一剂雷米单抗和杜伐单抗治疗。对患者进行了中位数为19次的随访。2个月(IQR 13.8比20。5)。40例患者中有11例(28%)有免疫相关的客观应答(全部部分应答；10例确诊)，中位应答持续时间为16。1个月(IQR 11.5比20。5)。26例(65%)患者有免疫相关疾病控制，25例(63%)有疾病控制。免疫相关无进展生存率的中位数为8。0个月(95%可信区间6。7比9。3)，中位无进展生存期为5。7个月(1.7比9。7)，中位总生存期为16。6个月(13.1比20。1)。基线肿瘤PD-L1表达与免疫相关客观反应或免疫相关疾病控制、免疫相关无进展生存期或总生存期的患者比例无关。30名患者(75%)经历了任何级别的治疗相关不良事件，其中7名(18%)发生了3-4级治疗相关不良事件。根据方案指南，与治疗相关的毒性通常是可控和可逆的。解释说，雷米单抗和杜伐单抗的联合使用似乎是有效的，在间皮瘤患者中具有良好的安全性，值得进一步探索。
Background Tremelimumab, an anti-CTLA4 monoclonal antibody, initially showed good activity when used alone in patients with mesothelioma, but did not improve the overall survival of patients who failed on first-line or second-line chemotherapy compared with placebo in the DETERMINE study. We aimed to investigate the efficacy and safety of first-line or second-line tremelimumab combined with durvalumab, an anti-PD-L1 monoclonal antibody, in patients with malignant mesothelioma.Methods In this open-label, non-randomised, phase 2 trial, patients with unresectable pleural or peritoneal mesothelioma received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. The primary endpoint was the proportion of patients with an immune-related objective response according to the immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST; for pleural mesothelioma) or immune-related RECIST version 1.1 (for peritoneal mesothelioma). The primary analysis was done by intention to treat, whereas the safety analysis included patients who received at least one dose of study drug. This trial is registered with the European Clinical Trials Database, number 2015-001995-23, and ClinicalTrials.gov, number NCT02588131, and is ongoing but no longer recruiting patients.Findings From Oct 30, 2015, to Oct 12, 2016, 40 patients with mesothelioma were enrolled and received at least one dose each of tremelimumab and durvalumab. Patients were followed-up for a median of 19 . 2 months (IQR 13 . 8-20 . 5). 11 (28%) of 40 patients had an immune-related objective response (all partial responses; confirmed in ten patients), with a median response duration of 16 . 1 months (IQR 11 . 5-20 . 5). 26 (65%) patients had immune-related disease control and 25 (63%) had disease control. Median immune-related progression-free survival was 8 . 0 months (95% CI 6 . 7-9 . 3), median progression-free survival was 5 . 7 months (1 . 7-9 . 7), and median overall survival was 16 . 6 months (13 . 1-20 . 1). Baseline tumour PD-L1 expression did not correlate with the proportion of patients who had an immune-related objective response or immune-related disease control, with immune-related progression-free survival, or with overall survival. 30 (75%) patients experienced treatment-related adverse events of any grade, of whom seven (18%) had grade 3-4 treatment-related adverse events. Treatment-related toxicity was generally manageable and reversible with protocol guidelines.Interpretation The combination of tremelimumab and durvalumab appeared active, with a good safety profile in patients with mesothelioma, warranting further exploration.