Medical Oncology and Immunotherapy, Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
Euganea Medica Radiology Center, Padua, Italy.
Lancet Respir Med. 2018 Jun;6(6):451-460. doi: 10.1016/S2213-2600(18)30151-6. Epub 2018 May 15.
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.
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.
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.
The combination of tremelimumab and durvalumab appeared active, with a good safety profile in patients with mesothelioma, warranting further exploration.
Network Italiano per la Bioterapia dei Tumori Foundation, Associazione Italiana per la Ricerca sul Cancro, AstraZeneca, and Istituto Toscano Tumori.
抗 CTLA-4 单克隆抗体 Tremelimumab 最初在间皮瘤患者中单独使用时表现出良好的活性，但在 DETERMINE 研究中，与安慰剂相比，它并没有改善一线或二线化疗失败的患者的总生存期。我们旨在研究一线或二线 Tremelimumab 联合抗 PD-L1 单克隆抗体 durvalumab 治疗恶性间皮瘤患者的疗效和安全性。
在这项开放标签、非随机、2 期试验中，无法切除的胸膜或腹膜间皮瘤患者接受静脉注射 Tremelimumab（1mg/kg 体重）和 durvalumab（20mg/kg 体重），每 4 周 4 剂，随后以相同剂量和方案静脉注射 durvalumab 维持治疗 9 剂。主要终点是根据免疫相关改良实体瘤反应评估标准（RECIST；用于胸膜间皮瘤）或免疫相关 RECIST 版本 1.1（用于腹膜间皮瘤）评估的免疫相关客观缓解患者比例。主要分析为意向治疗，而安全性分析包括至少接受一剂研究药物的患者。该试验在欧洲临床试验数据库注册，编号为 2015-001995-23，在 ClinicalTrials.gov 注册，编号为 NCT02588131，正在进行中，但不再招募患者。
从 2015 年 10 月 30 日至 2016 年 10 月 12 日，共纳入 40 例间皮瘤患者，每位患者均接受了至少一剂 Tremelimumab 和 durvalumab 治疗。中位随访时间为 19.2 个月（IQR 13.8-20.5）。40 例患者中有 11 例（28%）出现免疫相关客观缓解（均为部分缓解；在 10 例患者中得到确认），中位缓解持续时间为 16.1 个月（IQR 11.5-20.5）。26 例（65%）患者出现免疫相关疾病控制，25 例（63%）患者疾病控制。中位免疫相关无进展生存期为 8.0 个月（95%CI 6.7-9.3），中位无进展生存期为 5.7 个月（1.7-9.7），中位总生存期为 16.6 个月（13.1-20.1）。基线肿瘤 PD-L1 表达与免疫相关客观缓解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 例（75%）患者发生任何等级的治疗相关不良事件，其中 7 例（18%）发生 3-4 级治疗相关不良事件。治疗相关毒性通常是可管理和可逆的，符合方案指南。
Tremelimumab 和 durvalumab 联合治疗在间皮瘤患者中表现出活性，安全性良好，值得进一步研究。
意大利肿瘤生物治疗网络基金会、意大利癌症研究协会、阿斯利康和托斯卡纳肿瘤研究所。
