Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA.
Cleveland Clinic, Cleveland, OH, USA.
Lancet Oncol. 2018 May;19(5):694-704. doi: 10.1016/S1470-2045(18)30148-7. Epub 2018 Apr 5.
Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and many of those who do initially respond then develop resistance to treatment. Agonists that target the shared interleukin-2 (IL-2) and IL-15Rβγ pathway have induced complete and durable responses in some cancers, but no studies have been done to assess the safety or efficacy of these agonists in combination with anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and activity of this drug combination in patients with NSCLC.
In this non-randomised, open-label, phase 1b trial, we enrolled patients (aged ≥18 years) with previously treated histologically or cytologically confirmed stage IIIB or IV NSCLC from three academic hospitals in the USA. Key eligibility criteria included measurable disease, eligibility to receive anti-PD-1 immunotherapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the anti-PD-1 monoclonal antibody nivolumab intravenously at 3 mg/kg (then 240 mg when US Food and Drug Administration [FDA]-approved dosing changed) every 14 days (either as new treatment or continued treatment at the time of disease progression) and the IL-15 superagonist ALT-803 subcutaneously once per week on weeks 1-5 of four 6-week cycles for 6 months. ALT-803 was administered at one of four escalating dose concentrations: 6, 10, 15, or 20 μg/kg. The primary endpoint was to define safety and tolerability and to establish a recommended phase 2 dose of ALT-803 in combination with nivolumab. Analyses were per-protocol and included any patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02523469; phase 2 enrolment of patients is ongoing.
Between Jan 18, 2016, and June 28, 2017, 23 patients were enrolled and 21 were treated at four dose levels of ALT-803 in combination with nivolumab. Two patients did not receive treatment because of the development of inter-current illness during enrolment, one patient due to leucopenia and one patient due to pulmonary dysfunction. No dose-limiting toxicities were recorded and the maximum tolerated dose was not reached. The most common adverse events were injection-site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most common grade 3 adverse events, occurring in two patients each, were lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one patient. No grade 4 or 5 adverse events were recorded. The recommended phase 2 dose of ALT-803 is 20 μg/kg given once per week subcutaneously in combination with 240 mg intravenous nivolumab every 2 weeks.
ALT-803 in combination with nivolumab can be safely administered in an outpatient setting. The promising clinical activity observed with the addition of ALT-803 to the regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease shows evidence of anti-tumour activity for a new class of agents in NSCLC.
Altor BioScience (a NantWorks company), National Institutes of Health, and Medical University of South Carolina Hollings Cancer Center.
免疫疗法联合 PD-1 或 PD-L1 阻断在未经选择的非小细胞肺癌（NSCLC）患者中约有 80%无法诱导应答，而那些最初有应答的患者中有许多随后对治疗产生耐药。靶向共同的白细胞介素-2（IL-2）和 IL-15Rβγ途径的激动剂在一些癌症中已诱导出完全和持久的应答，但尚无研究评估这些激动剂与抗 PD-1 免疫疗法联合使用的安全性或疗效。我们旨在确定该药物组合在 NSCLC 患者中的安全性、耐受性和活性。
这是一项非随机、开放标签、1b 期临床试验，我们招募了来自美国三家学术医院的先前治疗过的组织学或细胞学确认的 IIIB 期或 IV 期 NSCLC 患者（年龄≥18 岁）。主要入选标准包括可测量的疾病、有资格接受抗 PD-1 免疫治疗和东部肿瘤协作组（Eastern Cooperative Oncology Group）表现状态 0 或 1。患者接受静脉注射 3mg/kg 的抗 PD-1 单克隆抗体纳武利尤单抗（当美国食品和药物管理局[FDA]批准的剂量改变时，随后为 240mg），每 14 天一次（作为新治疗或疾病进展时继续治疗），每周一次皮下给予 IL-15 超激动剂 ALT-803，持续 6 个月，共 6 周。ALT-803 以四种递增剂量浓度之一给药：6、10、15 或 20μg/kg。主要终点是确定安全性和耐受性，并确定 ALT-803 与纳武利尤单抗联合用药的推荐 2 期剂量。分析是基于方案的，包括接受至少一剂研究治疗的任何患者。该试验在 ClinicalTrials.gov 注册，编号为 NCT02523469；正在招募 2 期患者。
在 2016 年 1 月 18 日至 2017 年 6 月 28 日期间，有 23 名患者入组，21 名患者在 ALT-803 的四个剂量水平下与纳武利尤单抗联合治疗。有两名患者因在入组期间发生并发疾病而未接受治疗，一名患者因白细胞减少症，另一名患者因肺功能障碍。未记录到剂量限制性毒性，未达到最大耐受剂量。最常见的不良反应是注射部位反应（21 名患者中有 19 名[90%]）和流感样症状（15 名[71%]）。最常见的 3 级不良事件，各有两名患者发生，为淋巴细胞减少症和疲劳。一名患者发生 3 级心肌梗死。未记录到 4 级或 5 级不良事件。ALT-803 的推荐 2 期剂量为每周皮下给予 20μg/kg，每 2 周静脉给予 240mg 纳武利尤单抗。
ALT-803 联合纳武利尤单抗可在门诊环境中安全给药。在 PD-1 单克隆抗体复发和难治性疾病患者中加入 ALT-803 后观察到的有希望的临床活性表明，新一类药物在 NSCLC 中具有抗肿瘤活性。
Altor BioScience（NantWorks 公司）、美国国立卫生研究院和南卡罗来纳医科大学霍林斯癌症中心。
