克服靶向药物治疗耐药的关键是“对患者进行活检采样”以 明确耐药分子机制

　　“克服非小细胞肺癌（NSCLC）靶向治疗耐药”是目前的研究热点之一。若患者出现靶向药物耐药时（比如靶向治疗后疾病进展），克服耐药的关键是“对患者进行活检采样”，通过组织活检明确获得性耐药的分子机制，并以此指导下一步治疗。比如，EGFR突变阳性的患者群体中，约50%人群的获得性耐药分子机制为T790M突变，目前已有第三代EGFR抑制剂专门治疗这类患者。如果T790M突变者接受第三代抑制剂治疗后疾病再次进展，目前的通常做法是再次活组织切片检查，以明确获得性耐药的新机制，并以此制定肺癌新疗法。

　　目前NSCLC软脑膜转移（LM）还没有疗效很好的方案

　　目前还不清楚NSCLC软脑膜转移最好的治疗方法是什么。第二代ALK抑制剂ceritinib、alectinib和X396中枢神经系统（CNS）药物渗透的研究数据良好。随着疾病进展，大约50%靶向治疗的患者会发生脑部转移。几年前有一些研究数据显示：脉冲式给药增加厄洛替尼剂量对NSCLC软脑膜转移或CNS疾病有效，厄洛替尼每周一次给药1500 mg（而非150 mg）提高了治疗有效率。目前NSCLC软脑膜转移还没有疗效良好的方案，而放射治疗是目前的标准治疗，但这种疗法的预后较差。

　　NCCN非小细胞肺癌的指南更新： nivolumab三线治疗鳞状细胞肺癌

　　对于获得性耐药ALK阳性非小细胞肺癌，比较新的推荐药物是色瑞替尼（Ceritinib），而先前治疗选项是克里唑蒂尼（crizotinib）。2015年3月9日，NCCN发布了2015年第5版非小细胞肺癌诊疗指南。新版NCCN指南增加了nivolumab作为鳞状细胞肺癌三线治疗及以后治疗的选项（图1）。NCCN指南依据新疗法、新药物的研究数据持续更新，目前几乎是一月更新一版。指南首次迭代没有其他重大的治疗推荐变化，在七月份NCCN年度会议（NCCN Annual Congress）上，专家组会讨论一些NCCN指南具体细节。

　　图1. nivolumab被推荐治疗鳞状细胞肺癌

访谈原文

　　Oncology Frontier: How do we overcome the problem of drug resistance in the treatment of non-small cell lung cancer?

　　《肿瘤瞭望》：应该怎么克服非小细胞肺癌（NSCLC）靶向治疗耐药？

　　Dr Horn: This is an issue we are all trying to deal with. One of the key issues is biopsying patients when they are on targeted therapies， for example， and their disease is progressing. Through the biopsies， we are able to see the mechanism of acquired resistance to the targeted therapies and that is helping us guide future therapies. An example is in the EGFR mutation-positive patient population， we know that about 50% of those patients will have T790M as their mechanism of acquired resistance. Now we have third-generation EGFR inhibitors that are specifically targeting those patient populations. What everyone is doing， including at Vanderbilt University， is that when these patients are progressing on the third-generation inhibitors， we are doing additional biopsies so we can look for new mechanisms of acquired resistance and develop new therapies for lung cancer patients.

　　Horn博士：“克服NSCLC靶向治疗耐药”是目前的研究热点之一。若患者出现靶向药物耐药时（比如靶向治疗后疾病进展），克服耐药的关键是“对患者进行活检采样”，通过组织活检明确获得性耐药的分子机制，并以此指导下一步治疗。比如，EGFR突变阳性的患者群体中，约50%人群获得性耐药分子机制为T790M突变，目前已有第三代EGFR抑制剂专门治疗这类患者人群。如果T790M突变者接受第三代抑制剂治疗后疾病再次进展，目前的通常做法是（包括在范德比尔特大学）再次行活组织切片检查，以明确获得性耐药的新机制，并以此制定肺癌新疗法。

　　Oncology Frontier: What is the optimal therapy for leptomeningeal disease in non-small cell lung cancer patients?

　　《肿瘤瞭望》：如何治疗NSCLC软脑膜转移（LM）？

　　Dr Horn: We don’t know what the best treatments are for patients with leptomeningeal disease. There is very exciting data with a second-generation ALK inhibitor with ceritinib， alectinib and X396 where we are seeing CNS penetration. But we know that about 50% of patients on targeted therapies will develop brain metastases as their site of progression. There was some data several years ago showing pulse doses of high-dose erlotinib given at 1500mg rather than 150 mg once a week could help in patients with leptomeningeal disease or CNS disease， but we still don’t have great treatment options for these patients and right now， radiation treatment is standard of care. Unfortunately， we know from many of these patients that the prognosis is poor.

　　Horn博士：目前还不清楚NSCLC软脑膜转移最好的治疗方法是什么。第二代ALK抑制剂ceritinib、alectinib和X396中枢神经系统（CNS）药物渗透的研究数据良好。但随着疾病进展，大约50%靶向治疗的患者会发生脑部转移。几年前有一些研究数据显示：脉冲式给药增加厄洛替尼剂量对NSCLC软脑膜转移或CNS疾病有效，厄洛替尼每周一次给药1500 mg（而非150 mg）提高了有效率。目前NSCLC软脑膜转移还没有疗效良好的方案，而放射治疗是目前的标准治疗，但这种疗法的预后较差。

　　Oncology Frontier: As a member of the NCCN lung cancer guidelines panel， could you comment on the recently updated guidelines that relate to non-small cell lung cancer?

　　《肿瘤瞭望》：作为NCCN肺癌指南小组的成员，请您谈一谈NCCN非小细胞肺癌的指南更新情况？

　　Dr Horn: The guidelines seem to be changing on a monthly basis. Ceritinib was added as an option for patients with acquired resistance to crizotinib for ALK-positive non-small cell lung cancer patients. We will likely be adding nivolumab as third-line treatment and beyond for patients with squamous cell lung cancer. As new treatments emerge and new drugs are developed， the guidelines will continue to be updated. There were no other major changes in terms of therapeutic options at the first iteration， but to put it into perspective of where we are， it is 2015 and they are already on their fifth amendment to the guidelines. So the updates are constant as new data becomes available. We have our annual meeting in July when we really work through some of the specific details for the NCCN Guidelines.

　　Horn博士：目前的指南几乎一月一更新。对于获得性耐药ALK阳性非小细胞肺癌，比较新的推荐药物是色瑞替尼（Ceritinib），而先前治疗选项是克里唑蒂尼（crizotinib）。2015年3月9日，NCCN发布了2015年第5版非小细胞肺癌诊疗指南。新版NCCN指南增加了nivolumab作为鳞状细胞肺癌三线治疗及以后治疗的选项。NCCN指南依据新疗法、新药物的研究数据持续更新。指南首次迭代没有其他重大的治疗推荐变化，在七月份NCCN年度会议（NCCN Annual Congress）上，专家组会讨论一些NCCN指南具体细节。