Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study.
Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study.
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杜瓦卢马布（Durvalumab）和非小细胞肺癌中的tremelimumab的安全性和抗肿瘤活性：多中心1B研究。
DOI：
10.1016/s1470-2045(15)00544-6
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发表时间：
2016-03
期刊：
影响因子：
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通讯作者：
Rizvi NA
中科院分区：
文献类型：
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作者：
Antonia S;Goldberg SB;Balmanoukian A;Chaft JE;Sanborn RE;Gupta A;Narwal R;Steele K;Gu Y;Karakunnel JJ;Rizvi NA
PD-L1和CTLA-4免疫检查点抑制抗肿瘤t细胞活性。与抗pd - l1抗体durvalumab和抗ctla -4抗体tremelimumab联合治疗可能比单独使用任何一种药物提供更大的抗肿瘤活性。我们的目的是评估durvalumab和tremelimumab在晚期鳞状或非鳞状非小细胞肺癌（NSCLC）患者中的疗效。我们在美国的五个癌症中心进行了一项多中心、非随机、开放标签的1b期研究。我们招募了immunotherapy-naïve年龄在18岁或以上的确诊局部晚期或转移性NSCLC患者。我们给患者durvalumab的剂量为每4周3mg /kg、10mg /kg、15mg /kg或20mg /kg，或每2周10mg /kg， tremelimumab的剂量为每4周1mg /kg、3mg /kg或10mg /kg，共6次给药，然后每12周给药3次。剂量递增阶段的主要终点是安全性。安全性分析是基于治疗后的人群。该研究的剂量扩展阶段正在进行中。本研究已在ClinicalTrials.gov注册，编号NCT02000947。2013年10月28日至2015年4月1日期间，102名患者入组进入剂量递增阶段并接受治疗。在本分析进行时（2015年6月1日），中位随访时间为18.8周（IQR 11-33）。在每4周接受durvalumab 20mg /kg和tremelimumab 3mg /kg的队列中，超过了最大耐受剂量，6例患者中有2例（30%）具有剂量限制性毒性（1例3级天冬氨酸转氨酶和丙氨酸转氨酶升高，1例4级脂肪酶升高）。最常见的与治疗相关的3级和4级不良事件是腹泻（11例[11%]）、结肠炎（9例[9%]）和脂肪酶升高（8例[8%]）。102例患者中有29例（28%）因治疗相关不良事件而停药。102例患者中37例（36%）发生与治疗相关的严重不良事件。22例患者在研究期间死亡，其中3例死亡与治疗有关。与治疗相关的死亡是由于重症肌无力（durvalumab每4周10 mg/kg加tremelimumab 1 mg/kg）、心包积液（durvalumab每4周20 mg/kg加tremelimumab 1 mg/kg）和神经肌肉疾病（durvalumab每4周20 mg/kg加tremelimumab 3 mg/kg）引起的并发症。在pd - l1阳性肿瘤患者和pd - l1阴性肿瘤患者中都注意到临床活性的证据。研究者报告证实，在联合tremelimumab 1 mg/kg队列中，26例患者中有6例（23%,95% CI 9-44）实现了客观反应，包括9例PD-L1阳性肿瘤患者中的2例（22%,95% CI 3-60）和14例PD-L1阴性肿瘤患者中的4例（29%,95% CI 8-58），包括未PD-L1染的患者（4例[40%，95% CI 12-74]）。Durvalumab 20mg /kg每4周加tremelimumab 1mg /kg显示出可控的耐受性，与PD-L1状态无关，具有抗肿瘤活性，并被选为正在进行的3期研究的剂量。这项研究由MedImmune赞助。
PD-L1 and CTLA-4 immune checkpoints inhibit antitumour T-cell activity. Combination treatment with the anti-PD-L1 antibody durvalumab and the anti-CTLA-4 antibody tremelimumab might provide greater antitumour activity than either drug alone. We aimed to assess durvalumab plus tremelimumab in patients with advanced squamous or non-squamous non-small cell lung cancer (NSCLC). We did a multicentre, non-randomised, open-label, phase 1b study at five cancer centres in the USA. We enrolled immunotherapy-naïve patients aged 18 years or older with confirmed locally advanced or metastatic NSCLC. We gave patients durvalumab in doses of 3 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg every 4 weeks, or 10 mg/kg every 2 weeks, and tremelimumab in doses of 1 mg/kg, 3 mg/kg, or 10 mg/kg every 4 weeks for six doses then every 12 weeks for three doses. The primary endpoint of the dose-escalation phase was safety. Safety analyses were based on the as-treated population. The dose-expansion phase of the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT02000947. Between Oct 28, 2013, and April 1, 2015, 102 patients were enrolled into the dose-escalation phase and received treatment. At the time of this analysis (June 1, 2015), median follow-up was 18.8 weeks (IQR 11–33). The maximum tolerated dose was exceeded in the cohort receiving durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg, with two (30%) of six patients having a dose-limiting toxicity (one grade 3 increased aspartate aminotransferase and alanine aminotransferase and one grade 4 increased lipase). The most frequent treatment-related grade 3 and 4 adverse events were diarrhoea (11 [11%]), colitis (nine [9%]), and increased lipase (eight [8%]). Discontinuations attributable to treatment-related adverse events occurred in 29 (28%) of 102 patients. Treatment-related serious adverse events occurred in 37 (36%) of 102 patients. 22 patients died during the study, and three deaths were related to treatment. The treatment-related deaths were due to complications arising from myasthenia gravis (durvalumab 10 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), pericardial effusion (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), and neuromuscular disorder (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg). Evidence of clinical activity was noted both in patients with PD-L1-positive tumours and in those with PD-L1-negative tumours. Investigator-reported confirmed objective responses were achieved by six (23%, 95% CI 9–44) of 26 patients in the combined tremelimumab 1 mg/kg cohort, comprising two (22%, 95% CI 3–60) of nine patients with PD-L1-positive tumours and four (29%, 95% CI 8–58) of 14 patients with PD-L1-negative tumours, including those with no PD-L1 staining (four [40%, 95% CI 12–74] of ten patients). Durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg showed a manageable tolerability profile, with antitumour activity irrespective of PD-L1 status, and was selected as the dose for phase 3 studies, which are ongoing. This study was sponsored by MedImmune.