Jean-Charles Soria教授介绍了ASCO会议上免疫治疗的热门研究。免疫疗法用于一线治疗的大型随机试验将于明年得出研究数据。在肺癌联合免疫治疗方面，2016年ASCO公布了最新的nivolumab （PD-1抑制剂）与ipililumab（CTLA-4抑制剂）联合治疗进展期非小细胞肺癌的Checkmate 012。

 

　　CheckMate 012旨在研究免疫药物的组合用于非小细胞肺癌一线治疗的安全性和有效性，ASCO 2016公布了I期试验的安全性和有效性数据（摘要编号3001）。nivolumab（3mg/kg）+Ipilimumab（1mg/kg)方案较其他方案在使肿瘤缩小方面有更强的效力，毒性比先前的报道要低。单用nivolumab有20%的反应率，nivolumab加ipilimumab的ORR是47%左右（Nivo 3mg/kg，2周+Ipi 1mg/kg 每12周）。当PD-L1表达≧1%，ORR为57%。在EGFR 突变阳性的ORR为50%。这是第一次发现免疫疗法在EGFR突变阳性患者中的治疗活性。nivolumab治疗EGFR突变阳性患者通常无效，但是Nivo+ Ipi联合治疗时，8例有了完全的治疗响应。我们需要对研究继续跟进。在EGFR突变阳性患者中，EGFR抑制剂仍然是标准疗法，这种情况的治疗反应率为80%，但Nivo+ Ipi的50%的反应率也不差。

 

　　本次会议有一项pembrolizumab联合各种标准化疗方案（卡铂/培美曲塞、卡铂/紫杉醇或其他含铂双药化疗方案）的I期研究数据，没有随机或对照组。这种方案耐受性似乎很好，治疗反应率达50%-70%。

 

　　根据一项CTLA-4抑制剂Tremelimumab在二、三线治疗恶性间皮瘤的随机、安慰剂对照研究，Tremelimumab相比安慰剂没有生存获益，Tremelimumab没能延长患者的PFS，这是一项CTLA-4抑制剂的阴性结果试验。

 

　　关于默克/辉瑞PD-1抑制剂avelumab，Raffit Hassan医生报道了75例患者的的研究数据，治疗反应率为14.9%，效果不如预期。nivolumab+ipilimumab、tremelimumab + durvalumab的研究正在进行，明年得出研究结果。

 

　　以下为《肿瘤瞭望》采访原文

 

　　Oncology Frontier: What are the hot topics at ASCO 2016 regarding immunotherapy in lung cancer?

 

　　《肿瘤瞭望》：请您谈一谈ASCO 2016肺癌免疫治疗的热点。

 

　　Dr Soria: Thank you for the opportunity to liaise with our Chinese colleagues. This year is perhaps an in-between year. The previous two years have been extremely exciting with game-changing data in lung cancer.

 

　　This year is probably the year before the big randomized trials in the frontline setting to be presented next year. This year in immunotherapy for lung cancer， we have some interesting data regarding the combination of two immune checkpoint blockers， nivolumab plus ipilimumab. This is phase I data in a limited number of patients， but this combination with decreased doses of ipilimumab at 3mg/kg and nivolumab at 1mg/kg has lower toxicity than previously reported (grade 3/4 adverse events around 39% compared to 20% grade 3/4 for nivolumab).   In terms of efficacy， it is clearly better. Nivolumab alone has a 20% response rate. Nivolumab plus ipilimumab is around 47%. These are good and interesting results. At the same time， it is the first time that we see activity in EGFR-mutated patients. Nivolumab has no activity in EGFR-mutations usually， but with Nivo + Ipi， eight patients reported full responses. These are small numbers but we need to follow that up. In EGFR mutations， oncogene deaddiction with EGFR inhibitors remains the standard as the response rate in that setting is 80%， but Nivo + Ipi giving 50% is not bad.

 

　　The second data we have in immunotherapy is the combination of pembrolizumab plus various regimens of chemotherapy， either carboplatin/pemetrexed or carboplatin/paclitaxel or another platinum doublet. This was phase I data， no randomization or comparison. Tolerability seemed good and response rates ranged from 50-70%.

 

　　Another topic of interest is the activity of immune checkpoint blockers in malignant mesothelioma. Tremelimumab， an anti-CTLA-4， was randomized against placebo in second- and third-line malignant mesothelioma. Unfortunately， there was no survival benefit， no progression-free survival benefit and a response rate of 4.5% versus 1% with placebo. So， a negative trial for CTLA-4. But we have some data regarding the PD-L1 inhibitor from Pfizer-Merck， the avelumab compound. Dr Raffit Hassan reported on 75 patients with a response rate of 14.9%. That was not as good as expected but a response none-the-less. Maybe mesothelioma is not an inflammatory tumor where we will see much response， so combinations like Nivo + Ipi and tremelimumab + durvalumab are ongoing and we will have to wait till next year for those.

 

　　Soria博士：免疫疗法用于一线治疗的大型随机试验将于明年得出研究数据。在肺癌双重免疫治疗方面，2016年ASCO公布了最新的nivolumab （PD-1抑制剂）与ipililumab（CTLA-4抑制剂）联合治疗进展期非小细胞肺癌的Checkmate 012。CheckMate 012旨在研究免疫药物的组合用于非小细胞肺癌一线治疗的安全性和有效性，ASCO 2016公布了I期试验的安全性和有效性数据（摘要编号3001）。nivolumab（3mg/kg）+Ipilimumab（1mg/kg)方案较其他方案在使肿瘤缩小方面有更强的效力，毒性比先前的报道要低。单用nivolumab有20%的反应率，nivolumab加ipilimumab的ORR是47%左右（Nivo 3mg/kg，2周+Ipi 1mg/kg 每12周）。当PD-L1表达≧1%，ORR为57%。在EGFR 突变阳性的ORR为50%。这是第一次发现免疫疗法在EGFR突变阳性患者中的治疗活性。nivolumab治疗EGFR突变阳性患者通常无效，但是Nivo+ Ipi联合治疗时，8例有了完全的治疗响应。我们需要对研究继续跟进。在EGFR突变阳性患者中，EGFR抑制剂仍然是标准疗法，这种情况的治疗反应率为80%，但Nivo+ Ipi的50%的反应率也不差。

 

　　本次会议有一项pembrolizumab联合各种标准化疗方案（卡铂/培美曲塞、卡铂/紫杉醇或其他含铂双药化疗方案）的I期研究数据，没有随机或对照组。这种方案耐受性似乎很好，治疗反应率达50%-70%。

 

　　根据一项CTLA-4抑制剂Tremelimumab在二、三线治疗恶性间皮瘤的随机、安慰剂对照研究，Tremelimumab相比安慰剂没有生存获益，Tremelimumab没能延长患者的PFS，这是一项CTLA-4抑制剂的阴性结果试验。

 

　　关于默克/辉瑞PD-1抑制剂avelumab，Raffit Hassan医生报道了75例间皮瘤患者的研究数据，治疗反应率为14.9%，效果不如预期。nivolumab+ipilimumab、tremelimumab + durvalumab的研究正在进行，明年得出研究结果。

 

　　Oncology Frontier: Could you outline the main points of your presentation on checkpoint inhibitors?

 

 

　　Dr Soria: I was asked to give a talk on now that we have immunotherapy in lung cancer， how do we choose? This is not an easy topic because there are only two registered compounds. Nivolumab is registered in the United States and Europe for second-line non-small cell lung cancer， squamous or non-squamous， independent of PD-L1 status. The other PD-1 compound that is registered is pembrolizumab， which is only approved in the US in the second-line setting with any histology but you need to be PD-L1-positive (at least 50% of the sets). It is an interesting situation where we have two approved compounds but three others that are in phase III. In phase III， we have two other PD-L1s， atezolizumab and durvalumab， and another PD-1， which is avelumab. My talk tried to provide some perspective to the clinicians regarding the difference between PD-1 and PD-L1. This is not Coca Cola versus Pepsi Cola. There are subtle differences. When you block PD-1， you will leave the PD-L1 B7-1 interaction. But when you block PD-L1， you will leave the PD-L2/PD-1 interaction. PD-1 and PD-L1 are not interexchangeable; they are different targets. I also highlighted to the audience that the different antibodies have different isotypes. All of the anti-PD-1 and anti-PD-L1 antibodies with the exception of avelumab have an Fc fragment that is IgG4 or genetically modified IgG1. That means it cannot bind the Fc-gamma receptor and therefore there is no antibody dependent cell death or antibody dependent cell phagocytosis. The only exception in that setting is avelumab， which has an IgG1-na?ve Fc fragment， and it can have ADCC and ADCP， which could be of interest where a PD-L1 is the target.

 

　　Soria博士：我在ASCO会议上作了一个关于免疫治疗的报告“我们应该如何选择免疫治疗（The Checkpoint Inhibitor For Your Patient Is）”。这不是一个容易讲解的话题，因为目前只上市了两种化合物。Nivolumab在美国和欧洲被审批上市，用于鳞状和非鳞状非小细胞肺癌二线治疗（不管患者的PD-L1状态如何）。另一个是PD-1化合物pembrolizumab，仅仅在美国被批准用于PD-L1-阳性（至少50%）非小细胞肺癌的二线治疗。还有三种药物处于III期临床研究阶段：PD-L1抗体atezolizumab和durvalumab、PD-1抑制剂avelumab。我在讲座中试图向临床医生解释PD-1和PD-L1之间微妙差异。这种差异不是可口可乐与百事可乐的差异。