《肿瘤瞭望》：免疫治疗能否成为早期NSCLC的标准疗法？

　　Peters:教授：这是一个很好的问题，目前还没有答案。在 IV期NSCLC患者中，一些免疫治疗的药物（比如Pembrolizumab和Nivolumab）的随机试验已经证明，免疫疗法能够取代化疗作为二线治疗。在早期的NSCLC患者中应用免疫治疗有以下两种情况。

　　①免疫疗法用于I期和II期肺癌术后的辅助治疗（术后化疗然后免疫治疗）。目前有三项正在开展辅助临床试验进行验证，需要5-7年才能有结果。我们对这种治疗策略很乐观，但是还需要研究结果证明。而局限之处是，肺癌术后须先进行辅助化疗，然后给予免疫治疗。辅助化疗是否影响免疫治疗的效果？加入免疫治疗是否提高治愈率？我们目前还不知道。

　　②III期肺癌患者的免疫治疗，对于III期肺癌，长期放化疗可控的病例大概不到30%，复发率很高。III期肺癌免疫治疗达到研究终点更容易，因为无病生存期（PFS）较短。在III期肺癌治疗中，免疫治疗也正作为被巩固治疗（而不是辅助治疗）被检验。 三项不同的试验的治疗方案是“同步放化疗±抗PD-1 /抗PD-L1治疗（选用的药物是Nivolumab，pembrolizumab和durvalumab）”，试验的主要终点是PFS、OS、或者PFS和OS，明年或2018年会出试验结果。我们应该知道的是，不止是I期或IV期患者，对于III期患者，强烈激活肺癌患者免疫系统可能会有非常好的治疗效果，也可能有不利的影响（包括对健康肺功能的影响或晚期毒性），所以我们需要等待阳性试验结果的验证。

　　《肿瘤瞭望》：请您谈一谈免疫疗法的联合治疗策略

　　Peters教授：免疫治疗的联合治疗策略包括：①免疫疗法与放射治疗相结合可使抗原释放，即使是IV期NSCLC患者，较强的放射治疗与免疫治疗相结合能更好地激活免疫系统，这方面的研究正在进行。我们需要探索促进肿瘤相关抗原释放的最适宜的放射剂量。

　　②不同免疫检查点抑制剂的联合。我们目前有CTLA-4抑制剂、PD-1/PD-L1抑制剂，将来会有针对TIM3、 LAG3靶点抑制剂、 IDO抑制剂。同时抑制多个通路可能是提高治疗反应的最佳策略，我认为这是未来的研究方向。

　　③免疫治疗与化疗联合有很大争议。首先我不认为化疗时进行免疫治疗激活T细胞是好主意，不认为这种方案会很有效。更重要的是，我认为免疫疗法是一种让患者能有较好的生活质量，从而有机会继续治疗的策略。在我的研究中心，我一般不会采用免疫治疗联合化疗的战略。

　　《肿瘤瞭望》：ELCC 2016发布哪些重要的免疫治疗研究

　　Peters教授：本次会议发布了多项免疫治疗组合疗法的研究。会议发布Osimertinib（AZD9291）联合PD-L1抑制剂Durvalumab治疗EGFR突变的非小细胞肺癌的研究结果（136O. Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: Results from the TATTON phase Ib trial ）。出乎意外，两药使用产生无法耐受的毒性。免疫检查点抑制剂与阿法替尼和厄洛替尼联用是没有任何问题的，但PD-L1抑制剂Durvalumab联合Osimertinib（AZD9291）却产生很大毒性。因此在使用免疫疗法时应谨慎，因为免疫治疗对我们的身体的影响是无法预计或预期的，这项试验给我们上了一课，在没有获得安全性数据之前不能开展III期试验。

　　一项研究提示，吉非替尼与免疫检查抑制剂Durvalumab联合的耐受性良好，该方案对于经选择患者是可行的（但不一定是所有患者）[57O. Efficacy， safety and tolerability of MEDI4736 (durvalumab [D])， a human IgG1 anti-programmed cell death-ligand-1 (PD-L1) antibody， combined with gefitinib (G): A phase I expansion in TKI-naive patients (pts) with EGFR mutant NSCLC。]

　　本次会议还发布了CheckMate 017的长期数据。研究已经显示免疫治疗有较好的耐受性，但我们总是希望一些患者表现出长期获益。不同于化疗，免疫治疗反应可能会持续数年，根据CheckMate 017的长期数据结果，我们可以期待免疫治疗的前景。

　　Oncology Frontier: Immunotherapy is an emerging standard care in stage IV lung cancer ，but can we make it a standard in early stage disease as well?

　　Dr Peters: It’s a very good question. The answer is not yet. In stage IV， different molecules (the most advanced are probably pembrolizumab and nivolumab) have been shown in randomized trials to be able to replace chemotherapy as second-line therapy. In early disease， there are maybe two scenarios. The first scenario is adjuvant post-surgery i.e. stage I and II. This is being tested now in three adjuvant clinical trials and they will take 5-7 years for results to be available. Until then， we remain very optimistic but it needs to be proven and we have to wait for those results. The main limitation in that setting is that you would have to use adjuvant chemo and then give immunotherapy. Does the adjuvant chemo actually impact on the activity of the immunotherapy and does the addition of immunotherapy increase cure rates? We don’t currently know. The other scenario is stage III and this is easier to study， because in stage III， whatever you do， probably less than 30% of cases are controllable in the long term by radiochemotherapy. There are lots of relapses so the endpoint is easier to meet because the PFS is shorter. In this setting， it is also now being tested as a consolidation (rather than an adjuvant) therapy. Nivolumab， pembrolizumab and durvalumab are in three different trials where radiochemo is given and then the anti-PD-1/anti-PD-L1 is either given or not. The primary endpoint in these trials is PFS， OS or both. These trial results will be available faster， either in the next year or 2018. Until then， we still don’t know. It is something to keep in mind that maybe not in stage I or stage IV but in stage III， when you activate the immune system very strongly， it may have a very positive impact on the tumor. On the other hand， it may have a detrimental impact in general on the health of the lung function or a late toxicity， so we have to make sure we end up with positive trials that do not have additional detrimental outcomes.

　　Oncology Frontier: How to improve the standard of care for NSCLC by combining Immunotherapy and other strategies?  <http://www.baidu.com/link?url=euTbMLEvM3emGMmzmImsLz0Sbdnx8bifxfD3vfuxFIFABQxzGZ_dPF8w0xsFiX1y2qFFUuENefXN4CI4sDn456tDsDqZHOM_syxXcta-6iPYetMZ9GuTaGS4AQ67a-FiBQZOTc1aZ_zttKrSclMwj_>

　　Dr Peters: Of course， they can be combined with other strategies. They can be combined with radiotherapy. There are lots of thoughts regarding the application of radiotherapy allowing an antigen release. So even in a stage IV lesion， applying a strong radiotherapy to the lesion in conjunction with immunotherapy would better activate the immune system. This is being studied and I can see promise with that. We need to know what fractionation of radiotherapy will be best， possibly a high dose or even a very low dose to just have enough a sufficient antigen release. The second modality is combining checkpoints with checkpoints. We have CTLA-4 and PD-1/PD-L1 as well as others in the pipeline. The immune response will be inhibited at not just one checkpoint but by several checkpoints in a tumor. Inhibiting more than one of these may be the best way to improve the response. At the moment we are looking at CTLA-4 and PD-1/PD-L1 but in the future there will be TIM3， LAG3 and IDO inhibitors and a whole field in development with the potential for combinations. I strongly believe this will be the way of the future. The last heavily debated combination is with chemotherapy. Firstly， I don’t think it is a good idea to give concomitant immunotherapy to activate T-cells when giving chemotherapy， as I can’t see that it will be very efficient. More importantly， I think immunotherapy is a way to help our patients by having results from chemotherapy and having a new strategy to move forward with which preserves quality of life and so on. I am not convinced it is a priority of immunotherapy to be combined with chemo， but rather a means to find new directions to act. In my center， I try to stay away from this strategy.

　　Oncology Frontier: ELCC 2016 released the results of a number of studies on immunotherapy， which studies do you think have a major impact on clinical practice?

　　Dr Peters: It’s all about the combinations. The major impact is that we are not able to do anything we like with the immune compounds. I mentioned stage III radiation therapy of the lung and the risks you take， and at this conference data was presented on combining durvalumab， one of the best anti-PD-1 compounds， with osimertinib， the best drug for EGFR inhibition. Used together there is an intolerable amount of toxicity， which was completely unexpected. You can combine immune checkpoints with afatinib and erlotinib without any problems， but in combination with osimertinib， it doesn’t work. This means that we need to be very careful with immunotherapy because there may be some reactivity on the part of our bodies that cannot be preplanned for or expected. This is a very good lesson that we need to proceed very carefully and not enter phase III trials without first having safety data. Secondly， we have seen data of combinations with gefitinib which is not toxic and shows it is feasible to combine immunotherapy with checkpoints in selected patients (but not necessarily all-comers). Lastly， there are long-term outcomes. I look forward to the long-term data of CheckMate 017. It is fine to see data that immunotherapies are well-tolerated and so on， but we always hope that some patients show long-term benefits. The response to immunotherapy might last for years which we would never see with chemo alone and the long-term data allows us to see whether this is a reality or just a dream. This data will be presented here.