《柳叶刀》:白介素-15激动剂联合免疫治疗靶向非小细胞肺癌

免疫治疗与阻断PD-1或PD-L1在80%非选择性的非小细胞肺癌患者(NSCLC)中尚无疗效,有些患者在最初起效后又产生耐药。靶向白细胞介素-2(IL-2)和IL-15Rβγ信号通路的激动剂(ALT - 803)使多种癌症得到完全和持久的缓解。但还没有研究评估与抗PD-1免疫治疗联合这些激动剂的安全性和有效性。本研究希望确定非小细胞肺癌患者联合用药的安全性、耐受性和药物活性。


在这一非随机、开放、1b期试验中,研究者登记了患者(年龄大于18岁)之前在美国的三家学术医院接受过组织学或细胞学确认的IIIB期或IV期NSCLC。关键的入组标准包括可测量的疾病,接受抗PD -1免疫治疗的资格,以及东部合作肿瘤学组0或1的表现状态。病人接受抗PD-1单克隆抗体nivolumab静脉注射3毫克/公斤(240毫克当美国食品和药物管理局(FDA)批准的剂量改变)每14天(作为新的治疗或继续治疗疾病进展的时候)和IL-15超级激动剂ALT - 803每周的周1 – 5皮下注射,四个六周周期持续6个月。ALT-803是在4个不断升高的剂量浓度中进行的,分别为:6、10、15或20 g/kg。主要终点是确定安全性和耐受性,并在与nivolumab结合的情况下建立推荐的第2期ALT-803。任何接受至少一剂研究治疗的病人纳入分析。


研究结果显示,在2016年1月18日至2017年6月28日期间,23名患者和21名患者接受了4剂ALT-803和nivolumab的联合治疗。有两名患者由于在注册期间出现了目前的疾病,一名患者因白细胞减少,另一名患者因肺功能障碍而未接受治疗。未记录剂量限制毒性,未达到最大耐受剂量。最常见的不良反应是注射部位反应(在21例患者中有19例[90%])和流感样症状(15例[71%])。最常见的3级不良事件发生在两个病人身上,分别是淋巴细胞减少和疲劳。一名患者发生3级心肌梗塞。没有记录4级或5级不良事件。推荐的第二阶段的ALT - 803是20μg /公斤,结合240毫克每星期一次皮下注射静脉nivolumab每2周。


该研究显示,ALT-803与nivolumab结合可以在门诊环境中安全地使用。在PD-1单克隆抗体复发和难治性疾病患者的治疗方案中加入ALT-803的临床活性,显示了NSCLC中一类新型药物的抗肿瘤活性的证据。


原文摘要


Background

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.


Methods

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, numberNCT02523469; phase 2 enrolment of patients is ongoing.


Findings

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.


Interpretation

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.




Reference: ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial


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