在美国临床肿瘤学会（ASCO）年会的脑转移瘤的多学科管理专场，克利夫兰诊所（Cleveland Clinic）的肿瘤学家Manmeet Singh Ahluwalia，MD作报告“Targeted Therapy in Brain Metastases: Ready for Prime Time?（脑转移瘤的靶向治疗的黄金时代是否来临 ）”。

　　Ahluwalia教授：脑转移瘤是临床上常见的问题。最常见的三种易发生脑转移的癌症是肺癌、乳腺癌和黑色素瘤。据估计，美国每年有20-30万的脑转移患者。在美国肺癌脑转移最常见，约50%的脑转移瘤患者有肺源性。许多脑转移患者有驱动基因突变，例如，10%的白人患者有表皮生长因子受体（EGFR）突变，而东亚人群高达35%。靶向药物改变了这些患者的治疗模式。

　　美国FDA批准了一些脑转移靶向疗法（包括吉非替尼、厄洛替尼、阿法替尼、osimertinib）。第三代EGFR-TKI如osimertinib较第一代TKI能更好地透过血脑屏障。今年ASCO会议展示了osimertinib令人振奋的研究数据。同样，ALK基因突变在肺癌患者有5%的发生率。FDA批准的药物有克唑替尼和二代ALK抑制剂ceritinib和alectinib。初步研究发现ceritinib和alectinib的反应率约为40%-60%，优于只有5-10%有效率的最佳化疗方案（血脑屏障穿透能力不好）。

　　过去脑转移患者的治疗选择是手术切除或放疗（全脑照射、立体定向放射外科或其他）。近期有一些试验将放疗/局部放疗联合靶向药物进行研究。也有一些专门针对脑转移瘤的新药，比如ASCO会议展示的新型靶向紫杉醇衍生物ANG1005。ANG1005的初步研究结果显示，ANG1005使70%的患者获得临床获益，患者总生存期为35周。HER-2阳性脑转移瘤患者可使用该药物。

　　我的研究小组对比了ALK或EGFR突变脑转移瘤患者和野生型患者的治疗结果。我们发现。 EGFR 突变肺癌患者的总生存率已经提高，约为20个月，野生型是9-12个月。ALK阳性患者的OS提高更显著，总生存超过4年，过去ALK阳性患者的总生存预期是6-12月。

　　许多免疫疗法治疗脑转移瘤的疗效可与全身治疗相媲美。因此，相比化疗，我们要增加靶向和免疫治疗的应用。局部放疗和全脑放疗仍有用。专家们发现脑转移瘤多学科治疗能达到最好的效果。

　　总之，靶向治疗提高了部分携带可治疗驱动基因突变的肿瘤患者的生存率（非小细胞肺癌、乳腺癌和黑色素瘤）。对于脑转移的患者，这些药物不仅可控制颅内肿瘤，也有助于全身治疗。特别是EGFR突变的脑转移瘤患者，一些靶向新靶点的药物显示出可喜成果。在过去的几年里，我们对脑转移的分子驱动基因、血-脑屏障和中枢神经系统药物渗透性的了解大幅增加。我们对生物综合治疗认识的提高以及创新药物开发可改进脑转移瘤治疗策略。未来靶向治疗会在脑转移瘤患者中扮演越来越重要的角色。

　　基于最近研究结果，我们已经确定了脑转移患者的新治疗模式。我们主张个体化治疗，根据脑转移的多少、引发脑转移瘤的癌症类型（肺癌、乳腺癌、黑色素瘤）、基因检测结果，多学科治疗团队（放射肿瘤学家、医疗肿瘤学家和神经神经外科医生等）为患者制定合适的治疗方案，根据靶向突变的基因检测结果选择靶向治疗药物。免疫疗法越来越多地被用于脑转移瘤治疗，有研究显示，PD-1/CTLA-4抗体药物治疗脑转移瘤的缓解率 与其他部位肿瘤的治疗效果相似。

访谈原文

　　Oncology Frontier: Could you please talk about the role of targeted therapy in Brain Metastase?

　　《肿瘤瞭望》：请您谈一谈靶向药物在脑转移瘤中的治疗作用。

　　Dr Ahluwalia: Brain metastases are a common clinical problem that we see every day when we treat patients with cancer. The incidence of brain metastases is increasing every day due to the increased use of imaging， increased participation in clinical trials， as well as patients doing better with their systemic cancers. As patients live longer， they develop brain metastases because the central nervous system is a sanctuary site. It is estimated that 200-300 thousand patients will develop brain metastases in the United States each year. The three most common cancers that go to the brain are lung cancer， breast cancer and melanoma. Lung cancer is the most common cause of brain metastases in the United States and around 50% of patients with brain metastases have a lung origin. A number of these patients have mutations that are now accessible with novel drugs that can get to the brain， and as a result， are changing the treatment paradigm of this patient population. For example， EGFR mutation is seen in 10% of the Caucasian population， but can occur in up to 35% of the East Asian population.

　　There are a number of targeted therapies that are FDA approved for this patient profile. They include gefitinib， erlotinib， afatinib and more recently osimertinib. The new generation compounds like osimertinib have better blood-brain penetration compared to the earlier generation drugs like erlotinib or gefitinib. There has been some exciting data with these drugs that has been presented at ASCO this year showing intriguing results in patients with EGFR mutations. Similarly， 5% of patients with lung cancer harbor ALK mutations. There are a number of compounds that are FDA approved for this patient population including crizotinib and the new generation drugs， ceritinib and alectinib. The response rates seen with ceritinib and alectinib in initial studies are around 40-60%. These are very impressive results compared to prior chemotherapies， which did not have a good blood-brain penetration， of around 5-10% at best for most regimens.

　　As our patients are living longer， it is more important to redefine how we treat these patients. Traditionally， patients with brain metastases were treated with radiation-based techniques or surgical resections. Radiation techniques included whole-brain irradiation， stereotactic radiosurgery or other focused forms of radiation. These days， there are a number of ongoing trials combining radiation or focused forms of radiation with some of the novel drugs I mentioned earlier. There are also drugs being designed that actually reach the brain. One example is ANG1005， which is being presented here at ASCO. This is a drug where three molecules of paclitaxel are covalently linked to Angiopep， which is a peptide that helps it get across the blood-brain barrier using the LRP-1 transport system. Initial results with this drug show a clinical benefit is seen in 70% of patients treated. Overall survival in this patient population is 35 weeks， which compares favorably with similar patients with this profile. Patients with HER2-positive disease are treated with this compound.

　　There is another presentation that our group has been involved with concerning the outcomes in patients with brain metastases harboring ALK or EGFR mutations compared to those with wild type. What we found is that lung cancer patients who have EGFR mutations have an improved overall survival. In our group， the overall survival in this patient population was around twenty months compared to 9-12 months in those with wild type lung cancer mutations. These results are even more impressive in the ALK-positive patients where we are seeing survival exceeding four years. Traditionally， someone who has lung cancer brain metastases was expected to live six to twelve months.

　　What is also very interesting is the use of immunotherapy in treating patients with brain metastases. A number of drugs are showing efficacy in brain metastases comparable to what has been seen elsewhere in the body. So we are redefining how we treat patients with brain metastases with the increased use of targeted therapies and immunotherapy compared to the prior use of chemotherapy. There will still be an ongoing role for focused forms of radiation and whole-brain radiation in the management of this patient population. I chaired a session yesterday in which it was outlined that the multidisciplinary management of patients with brain metastases gives the best outcomes for this patient population.

　　Ahluwalia教授：脑转移瘤是临床上常见的问题。最常见的三种易发生脑转移的癌症是肺癌、乳腺癌和黑色素瘤。据估计，美国每年有20-30万的脑转移患者。在美国肺癌脑转移最常见，约50%的脑转移瘤患者有肺源性。许多脑转移患者有驱动基因突变，例如，10%的白人患者有表皮生长因子受体（EGFR）突变，而东亚人群高达35%。靶向药物改变了这些患者的治疗模式。美国FDA批准了一些脑转移靶向疗法（包括吉非替尼、厄洛替尼、阿法替尼、osimertinib）。第三代EGFR-TKI如osimertinib较第一代TKI能更好地透过血脑屏障。今年ASCO会议展示了Osimertinib令人振奋的研究数据。同样，ALK基因突变在肺癌患者有5%的发生率。FDA批准的药物有克唑替尼和二代ALK抑制剂ceritinib和alectinib。初步研究发现ceritinib和alectinib的反应率约为40%-60%，优于只有5-10%有效率的最佳化疗方案（血脑屏障穿透能力不好）。

　　过去脑转移患者的治疗选择是手术切除或放疗（全脑照射，立体定向放射外科或其他）。近期有一些试验将放疗/局部放疗联合靶向药物进行研究。也有一些专门针对脑转移瘤的新药，比如ASCO会议展示的新型靶向紫杉醇衍生物ANG1005。一种可靶向低密度脂蛋白受体相关蛋白-1（LRP-1）的19个氨基酸的肽Angiopep-2与3分子紫杉醇结合构成ANG1005，ANG1005与LRP-1结合作用后可以促使受体介导的药物通过跨细胞转运进入脑组织中。ANG1005的初步研究结果显示，ANG1005使70%的患者获得临床获益，患者总生存期为35周。HER-2阳性脑转移瘤患者可使用该药物。

　　我的研究小组对比了ALK或EGFR突变肺癌脑转移瘤患者和野生型患者的治疗结果。我们发现。 EGFR 突变肺癌患者的总生存率已经提高，约为20个月，野生型是9-12个月。ALK阳性患者的OS提高更显著，总生存超过4年，过去ALK阳性患者的总生存预期是6-12月。

　　许多免疫疗法治疗脑转移瘤的疗效可与全身治疗相媲美。因此，相比化疗，我们要增加靶向和免疫治疗的应用。局部放疗和全脑放疗仍有用。专家们发现脑转移瘤多学科治疗能达到最好的效果。

　　Oncology Frontier: According to ASCO 2016， Is there any progress that may change practice in the treatment of Brain Metastases from NSCLC?

　　《肿瘤瞭望》：ASCO会议展示了哪些可改变肺癌脑转移瘤临床实践的进展？

　　Dr Ahluwalia: Based on the results of some of the recent studies that have been presented elsewhere and at ASCO， we have been determining the new treatment paradigms for patients with brain metastases. We need to recognize that each patient is unique. We need to look at how functional the patient is， how many brain metastases they have， the type of cancer causing the brain metastases (lung cancer， breast cancer or melanoma)， and accordingly， in consultation with radiation oncologists， medical oncologists and neurosurgeons， adopt an appropriate treatment plan for that patient. We are in the era of precision medicine where genomic profiling is routinely available for most patients at rates that are affordable. We need to see if someone has an actionable mutation and if so， use a targeted agent to help treat that patient. Immunotherapies are increasingly being used in the management of this patient population. Studies have shown that the response rates in brain metastases are very similar to what are seen in the rest of the body with the use of anti-PD-1 agents， as well as anti-CTLA-4 agents in melanoma.

　　Ahluwalia:教授：基于最近研究结果，我们已经确定了脑转移患者的新治疗模式。我们主张个体化治疗，根据脑转移的多少、引发脑转移瘤的癌症类型（肺癌、乳腺癌、黑色素瘤）、基因检测结果，多学科治疗团队（放射肿瘤学家、医疗肿瘤学家和神经外科医生等）为患者制定合适的治疗方案，根据靶向突变的基因检测结果选择靶向治疗药物。免疫疗法越来越多地被用于脑转移瘤治疗，有研究显示，PD-1/CTLA-4抗体药物治疗脑转移瘤的缓解率与其他部位肿瘤的治疗效果相媲美。