Oncology Frontier: Besides the validated models of the MSKCC or the International Metastatic Renal Cell Carcinoma Database Consortium criteria， are there any serum tissue biomarkers or germ line genetic markers that are potentially associated with efficacy endpoints in first-line RCC patients treated using the anti-VEGF pathway?

《肿瘤瞭望》：除了MSKCC的和国际转移性肾细胞癌数据库联盟（IMDC）标准的验证模式外，是否存在其他血清/组织学生物标志物，或种系遗传标志物可作为预测RCC患者一线抗VEGF治疗的疗效指标？

Dr.Motzer: For the most part， the models that are based on pretreatment clinical features， the MSKCC model and the International model have been validated and they are used as standard of care for predicting prognosis and selecting treatment options. There haven’t been any validated biomarkers for renal cell carcinoma that are used in choosing treatment. It has been an area of unmet need that requires further study.

Motzer博士：在大多数情况下，这是基于预处理临床特征的模型，MSKCC模型和国际模型已被验证，并且作为标准用于判断预后和选择治疗方案。目前还没有有效的生物标志物被用于肾细胞癌的选择性治疗。对这一领域的研究尚不能满足临床需求，仍需进一步研究。

Recently， there has been some genetic mutations that have been identified that help to predict prognosis. For example， mutations in the VHL gene that characterize clear cell carcinoma of the kidney， predict a better outcome to the VEGF-targeted therapies. But essentially， all patients with clear cell carcinoma have mutations of the VHL gene. Some of the more recent chromatin modeling genetic alterations (like mutations of BAP1) have been associated with an adverse prognosis in patients with localized kidney tumors. We recently looked at patients with more advanced kidney tumors treated with everolimus or sunitinib and found that it correlated with progression-free survival in that setting. So there is a lot of work that needs to be done and there haven’t really been any validated markers for kidney cancer

最近，研究发现一些基因突变，有助于判断预后。例如，存在VHL基因突变的肾透明细胞癌，接受VEGF靶向治疗可以获得更好的效果。但实际上，所有肾透明细胞癌患者均发生了VHL基因突变。最新发现一些染色质建模的遗传改变（如BAP1基因突变）与局部肾脏肿瘤患者的不良预后有关。另外，我们观察用依维莫司或舒尼替尼治疗的更晚期的肾脏肿瘤患者，发现在这种情况下，其与无进展生存期相关。总之，还有很多工作需要做，现在还没有真正用于肾癌的有效标志物。

Oncology Frontier: There are several treatment choices for patients with advanced renal cell carcinoma but none of the available targeted drugs are significantly better than the others. Do you think the combination of two targeted therapies for vascular genesis would be better than one targeted therapy such as sunitinib or axitinib?

《肿瘤瞭望》：对于晚期肾细胞癌患者，您认为两种靶向药物联合使用与单用一种靶向药物相比，疗效如何？

Dr.Motzer: The types of medications we use to treat advanced clear cell carcinoma of the kidney fall into two families. One are the VEGF-targeted drugs (sunitinib， pazopanib， axitinib， sorafenib， and bevacizumab) and the other are the mTOR inhibitors (temsirolimus and everolimus). There have been attempts to combine VEGF and mTOR together， and to-date， they have not really been successful or pursued with registration strategies. Mostly， this is because of the toxicity that occurs with combining the two together. We have also tried to combine medicines that are VEGF-targeted agents together. The one combination that received the most attention was sunitinib plus bevacizumab. There was a lot of excitement around that combination several years back and a lot of potential， but we found that when those two drugs were combined they were intolerable because of severe hypertension and even some life threatening consequences.

Motzer博士：用于治疗晚期肾透明细胞癌的药物，我们将其分为两类，血管内皮生长因子靶向药物（舒尼替尼、培唑帕尼、阿西替尼、索拉非尼和贝伐珠单抗）和mTOR抑制剂（替西罗莫司和依维莫司）。曾有学者试图将VEGF和mTOR联合使用，但是至今，他们还没有真正成功。大多数情况下，是因为这两种靶向药物联合使用会引起细胞毒性反应。此外，我们也尝试将两种不同的血管内皮生长因子靶向药物联合使用，最受关注的一个组合是舒尼替尼联合贝伐珠单抗。回顾近几年的研究，我们获得了一些可喜的结果，但也发现，当这两种药物联合时，患者由于严重高血压、甚至一些危及生命的不良反应而无法耐受。

More recently， there is a new VEGF TKI， lenvatinib from Eisai， which is approved for the treatment of thyroid cancer. We performed a study where lenvatinib was combined with everolimus and compared to everolimus in that combination and as a monotherapy， and the combination looked better in terms of progression-free survival and overall survival compared to everolimus alone. That was really the first combination for which we some evidence that may be better than monotherapy.

最近，出现了一种新的VEGF TKI 靶向药lenvatinib，由Eisai提出的，已获批准用于甲状腺癌的治疗。我们进行了一项研究，比较lenvatinib联合依维莫司治疗与依维莫司单药治疗，结果发现，lenvatinib联合依维莫司治疗获得了更好的无进展生存期和总生存期。这是我们首个经研究证实的比单一疗法疗效更好的联合治疗方法。

Oncology Frontier: Therapeutic strategies targeting the ligand itself or its receptor have proven successful in mRCC， but complete remissions are rare and with time， patients invariably experience disease progression. Are there any novel VEGF-directed agents for the treatment of advanced renal cell carcinoma?

《肿瘤瞭望》：是否有新的血管内皮生长因子（VEGF）靶向药物用于晚期肾细胞癌的治疗？

Dr.Motzer: There are two novel VEGF-targeted drugs that are of high interest. One is lenvatinib， the VEGF-targeted drug made by Eisai. It is characterized by a high level of inhibition to VEGF receptor as well as fibroblast growth factor receptor (FGF). FGF is felt to be important in resistance to VEGF-targeted therapies. We think that that the two combined inhibitory properties of that drug may be helpful in overcoming VEGF resistance.

Motzer博士：有两种新的血管内皮生长因子靶向药物倍受关注。一种是lenvatinib，其特征是高水平地抑制血管内皮生长因子受体及成纤维细胞生长因子受体（FGF）。FGF被认为在抗血管内皮生长因子靶向治疗中发挥着重要的作用。我们认为，这一药物的两种抑制特征组合可能有利于克服VEGF耐药。

The other VEGF TKI that is on our radar screens is cabozantinib. This is a dual inhibitor of VEGF receptor and c-MET. Again， c-MET appears to be a pathway that tumors use to overcome VEGF resistance. Dual blockade of VEGF receptor and c-MET may be important in overcoming resistance. There is a pivotal trial of cabozantinib versus everolimus in second- or third-line therapy for patients who have progressed on pazopanib or sunitinib. The data from that is eagerly awaited and may result in the approval of cabozantinib in that setting.

另一种VEGF TKI是cabozantinib，是血管内皮生长因子受体和c-MET的双重抑制剂。c-Met似乎是肿瘤克服VEGF耐受的一个通路。血管内皮生长因子受体和c-Met的双重阻断可能是克服耐药研究的重要方向。