肾细胞癌潜在药物信息汇总+搜集（欢迎憨叔老马平安啊多提意见，药名就行！我去查！）

爸爸是肾透明细胞癌，主流的各种肾癌靶向药（索坦，索拉菲尼，阿西替尼。。）似乎都有点用，但时间似乎都没有很久，而且一直受胸水困扰，似乎胸膜上的特别难控制。。以后我要努力搜索有关肾细胞癌的临床试验，希望能帮助爸爸树立更多的信心，也能帮助更多的人，大家有什么新的消息也欢迎在这里更新，另外对于副作用可能搜集的不全，如果有决定试药的大家再讨论。愿上帝保佑大家。
爸爸，希望你看到这个帖子更坚强，还有好多药物可以试呢，我会陪着你努力的，你也要加油！！！妈妈也要坚强！！！

（后面的药我本来在第二楼写的更详细的，可是不知道何原因总是被管理员删掉，我就简略都写在这一楼了，附上英文网站链接，大家可以自己去看，管理员你要是看我不顺眼把这个贴删了好了，我马上就博士资格考了还努力发这个帖子也很不容易好吗！！！我只是想跟大家分享交流啊！！！）

首先是批准的药物，从liu-viktor 的帖子粘过来，请别介意哈，给个链接

http://www.yuaigongwu.com/forum.php?mod=viewthread&tid=8182

美国ＦＤＡ批准的７种肾癌靶向药物                                                        
        汉语名        曾用名        英文名           商品名              批准时间          类型        
７        阿西替尼                axitini              Inlyta                       2012        多靶点药物        VEGF抑制剂
６        帕唑帕尼                pazopanib             Votrient        2009        多靶点药物        VEGF抑制剂
５        贝伐单抗        阿瓦斯丁        Bevacizumab Avastin        2009        单靶点药物        VEGF抑制剂
4        依维莫司                everolimus　 Certican        2009         单靶点药物        mTOR抑制剂
３        替西罗莫 驮瑞塞尔        temsirolimus   Torisel                         2007        单靶点药物        mTOR抑制剂
２        舒尼替尼        索坦        sunitinib               Sutent               2006          多靶点药物        VEGF抑制剂
１        索拉非尼        多吉美        Sorafenib      Nexavar              2005           多靶点药物         VEGF抑制剂

XL184，Cabozatinib

我也发过XL184的临床试验，这个吸引我的地方是对治疗后的病人也有很好的效果，因为多了C-MET靶点吧。
http://www.yuaigongwu.com/forum.php?mod=viewthread&tid=8903

Cabozantinib（ XL184）为针对MET 及VEGFR2 的靶向药物。有基础研究发现，抗血管生成靶向药物耐药可能与MET激活有关，通过抑制MET 通路可能能够克服抗VEGF 治疗所造成的获得性耐药。本届大会发言报告了一项XL184 用于治疗复发难治性晚期肾癌的临床研究，共入组25 例患者。这些患者既往接受过多种靶向药物治疗，给予口服XL184 140mgqd，同时联合罗格列酮治疗。客观有效率达28%，疾病控制率达80%，仅4% 的患者出现原发耐药治疗，大部分患者的肿瘤获得缩小，16 周的疾病控制率为72%，全部患者的中位PFS为14.7 个月，中位随访14.7 个月后中位总生存时间仍未达到。不良反应主要为疲乏、腹泻等，与其他靶向药物的不良反应类似。上述研究的结果取得如此令人惊喜的效果，可能有望进行晚期肾癌的一线药物治疗临床试验。


多韦替尼

还有老马发过新药多韦替尼的实验，这个也是对多种治疗后的病人有很好的效果，我觉得是因为FGFR靶点吧，搜索网络可以看到很多肾癌病人都有FGFR的高表达，这觉得是个换药的好路子。另外我找到一篇12年的文献，有兴趣英文好的可以读读，有关肾癌的治疗耐药研究什么的。http://cdn.intechopen.com/pdfs/2 ... giogenic_agents.pdf

老马的链接，我把肾癌的部分粘在这里，老马别介意哈，我引用文献了的，就是没paraphrase。。
http://www.yuaigongwu.com/thread-10203-1-1.html

结果：20名三线治疗后的肾细胞癌病人入组，16名至少接受过一次抗血管生成药治疗，11名至少接受过1次mTOR抑制剂治疗，12名至少接受过一次免疫治疗。500mg组（吃5天停2天）有15名病人，600mg组（吃5天停2天）有5名病人。3名病人出现剂量限制性毒性：1名出现2级心动过缓（500mg）；1名出现4级高血压危象（600mg），1名出现3级乏力、2级疲劳和呕吐（600mg）。最常见的副作用包括疲劳（77%），腹泻（70%），呕吐（70%）和乏力（50%），其中大部分为轻度副作用（1级或者2级），3级副作用小于5%（除了乏力，15%）只有1名病人出现4级高血压危象。2名病人有效缓解（500mg），12名病人肿瘤稳定，包括2名病人肿瘤稳定超过1年（500mg）。
结论：多维替尼最大剂量为500mg吃5天停2天，该方案对于三线治疗后的肾细胞癌病人有抗肿瘤活性。

PS：BIBF1120也有肾癌的实验进行，早期实验有不到十个肾癌，一个CR一个PR，其他也很多SD，如果有大样本就更好了，证明FGFR靠谱。 http://clincancerres.aacrjournal ... CR-09-0694.full.pdf

瑞格非尼

憨叔跟我提过这个药，我一查果然有临床试验，憨叔果然知识渊博。这个药物的临床试验数据喜忧参半，反应率似乎非常的高，很多人能达到partial response，但是毒性似乎也很高，尤其是肝脏毒性，所以如果试药应该要密切观察。现在批准的是转移性结直肠癌。 另外这个实验是对没经过治疗的病人，所以我的兴趣没有以上两个药大。

http://www.peerviewpress.com/reg ... presented-ecco-esmo
提到PR是40%，SD是42%！！！总共80%多的反应率！！！但是但是！！！但是毒性很值得注意，另一个帖子http://www.ncbi.nlm.nih.gov/pubmed/22959186 说有5个人肾功能衰竭，但不知道什么时候的事，是不是短期吃会好一点？还有两个人死亡。就先放在这吧。。目前没有进一步的临床试验了，是索拉菲尼的同门，所以估计他们没啥动力再做临床试验，而且我爸爸不会吃的，因为索拉菲尼对他没效。。。他比较喜欢索坦的公司。。我继续找。。。

雷利度胺
http://www.ncbi.nlm.nih.gov/pubmed/18525302

40个病人入组，1个CR，3个PR，21个SD。25个病人6个月内出现进展，6个人6-12个月进展，9个人12个月以上进展。副作用可耐受。



Gemcitabine + Capecitabine 吉西他滨+卡培他滨
http://jco.ascopubs.org/content/29/8/e203.full
这个帖子总结了几个临床试验，介绍了两个CR的病人，都是免疫治疗活着靶向治疗失败，病情进展，几个临床试验我还没查，等有空更新上来，不过这个帖子提到 Response rates have ranged from 8.4% to 16%, stable disease rates from 48% to 67%, and median progression-free survival from 4.6 to 7.6 months.
反应率从8.4%到16%不等（我觉得挺高的了），SD从48%到67%不等。（我觉得也挺高的了哈）。然后中位无进展生存期4.6到7.6个月不等（作为靶向疗法外的疗法我觉得也挺高的了哈），而且似乎耐受不错的。

linifanib (ABT-869)
http://www.ncbi.nlm.nih.gov/pubmed/22078932
53名索坦耐药病人入组，13.2%的ORR，中位PFS是5.4个月，OS14.5个月。副反应主要是腹泻疲乏和高血压，可耐受。

BNC105/BNC105P
现在在进行的二期临床是联合依维莫司，还没有具体的结果 http://clinicaltrials.gov/show/NCT01034631
之前的一期试验有个短暂的介绍
http://www.4-traders.com/BIONOMI ... D-AT-ASCO-16921260/
跟依维莫司联合，12个人8个达到SD，中位治疗时间是11个周期（11个月？），最长的18个月。

这是一种血管破坏剂，针对的是已形成的血管而不是新生血管，所以应该也是种不同过的靶向药。临床前数据表明该候选药具有双重作用机制。它能破坏肿瘤血管，在体外对癌细胞具有直接毒性。它还能特异性地以较高的浓度在肿瘤内存留较长时间，可能也有利。

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~雷利度胺~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

40个病人入组，1个CR，3个PR，21个SD。25个病人6个月内出现进展，6个人6-12个月进展，9个人12个月以上进展。副作用可耐受。

http://www.ncbi.nlm.nih.gov/pubmed/18525302
Abstract
PURPOSE:
Treatments for refractory metastatic renal cell cancer (RCC) are limited. Oral lenalidomide, a thalidomide-based drug having enhanced immunomodulatory and antiangiogenic properties and reduced toxicity, was evaluated for safety and efficacy in this setting.
METHODS:
In an open-label, single-center phase II trial, adults (> or =18 years old) with newly diagnosed RCC seen at our institution between December 2003 and April 2004 were recruited to receive at least three 28-day cycles (21 days on drug and 7 days off) of oral lenalidomide (25 mg/d). The dose was reduced as needed in cases of toxicity. The primary endpoint was tumor response rate. Secondary endpoints were time to tumor progression, response duration, 6-month and 12-month progression-free survival, overall survival, and safety.
RESULTS:
Thirty-nine of 40 patients (97%) were evaluable for response. Many in the evaluable population [63 (38-73) years; male, 73% (29/39)]; Zubrod performance status < or =1, 97% (38/39) had the clear cell histotype [85% (33/39)], had undergone previous immunotherapy or chemotherapy [59% (23/39)]; and had > or =2 metastatic sites [69% (27/39)]. Most [92% (36/39)] completed at least 3 treatment cycles (12 weeks). A complete response was observed in 1 patient (3%), partial response in 3 (8%), stable disease in 21 (53%), and progressive or unknown-status disease in 15 (38%). Time to tumor progression was < or =6 months in 24 patients (62%), 6 to 12 months in 6 (15%), and >12 months in 9 (23%). Median response duration was 6 (2-22) months and median overall survival was 17 months (0.80-39.6). The most common treatment-related adverse event was grade < or =2 fatigue [60% (24/40)]. The most common laboratory abnormalities were grade > or =3 neutropenia [50% (20/40)] and thrombocytopenia [28% (11/40)].
CONCLUSION:
Lenalidomide is a safe and effective therapy for refractory metastatic RCC. Further studies of lenalidomide in this setting are warranted.

~~~~~~~~~~~~~~~~~~~~Gemcitabine + Capecitabine 吉西他滨+卡培他滨~~~~~~~~~~~~~~~

这个帖子总结了几个临床试验，介绍了两个CR的病人，都是免疫治疗活着靶向治疗失败，病情进展，几个临床试验我还没查，等有空更新上来，不过这个帖子提到 Response rates have ranged from 8.4% to 16%, stable disease rates from 48% to 67%, and median progression-free survival from 4.6 to 7.6 months.
反应率从8.4%到16%不等（我觉得挺高的了），SD从48%到67%不等。（我觉得也挺高的了哈）。然后中位无进展生存期4.6到7.6个月不等（作为靶向疗法外的疗法我觉得也挺高的了哈），而且似乎耐受不错的。


http://jco.ascopubs.org/content/29/8/e203.full

Targeted therapy is the current standard of care for the systemic treatment of metastatic RCC. The multitargeted tyrosine kinase inhibitors sunitinib and pazopanib as well as the combination of bevacizumab plus interferon alfa are the accepted first-line therapies for patients with metastatic clear cell RCC at good to intermediate risk.1–4 The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is the accepted first-line therapy for patients with advanced poor-risk RCC.5 Sorafenib, sunitinib, and pazopanib are accepted second-line therapies after cytokine failure; the mTOR inhibitor everolimus is the approved treatment after sorafenib and/or sunitinib failure.6,7 Approximately 20% of patients with metastatic RCC have primary resistance to anti–vascular endothelial growth factor (VEGF) therapies. Furthermore, there is no established third-line therapy for patients who develop progressive disease after VEGF- and mTOR-targeted therapies or for patients who are intolerant of these targeted agents. Metastatic RCC has traditionally been considered unresponsive to cytotoxic chemotherapy.8 The combination of gemcitabine and capecitabine has been studied in several case series and four single-arm phase II trials in patients with metastatic RCC refractory to immunotherapy and, to a lesser extent, refractory to targeted therapy. Response rates have ranged from 8.4% to 16%, stable disease rates from 48% to 67%, and median progression-free survival from 4.6 to 7.6 months.9–12

We report two patients with metastatic RCC who achieved durable remissions after treatment with the chemotherapy regimen of gemcitabine and capecitabine after failure of targeted therapies. One patient has been in remission more than 6 years since rapid disease progression while receiving high-dose IL-2 and sorafenib. The second patient demonstrated a second tumor response on rechallenge with this chemotherapy regimen after rapid disease progression while receiving two prior anti-VEGF therapies (bevacizumab and sunitinib). The mechanisms of resistance of RCC to anti-VEGF agents and mTOR inhibitors are poorly understood. Clinicopathologic studies have demonstrated that higher tissue levels of phosphorylated Akt in nephrectomy specimens from patients with metastatic RCC subsequently treated with sorafenib are associated with shorter progression-free survival.13 A study evaluating nephrectomy specimens from patients with metastatic RCC who received bevacizumab-based therapy before nephrectomy demonstrated that critical components of the PI3-kinase pathway are upregulated in individuals with shorter progression-free survival.14 Although these data do not prove a direct mechanistic association between PI3-kinase pathway upregulation and poor clinical outcome in patients treated with antiangiogenic agents, they provide hypothesis-generating studies for testing.

Gemcitabine (2′,2′-difluorodeoxycytidine, LY188011, dFdCyd) is a pyrimidine antimetabolite. Cell-cycle kinetic studies with gemcitabine have shown specificity for proliferation in the S phase of the cell cycle, with no effect on progress through the early G1, G2, or M phase.15 We postulate that c-Myc activation may provide a specific vulnerability to this class of agents by driving cells to accumulate higher levels of abnormal DNA in the presence of gemcitabine, generating in effect a synthetic lethal phenotype. Evan et al16 reviewed mechanisms by which increased DNA damage in conjunction with c-Myc activation could lead to susceptibilities to DNA-damaging processes. In patients with rapidly progressing disease with high cell-cycle activity, RCC tumors may be more susceptible to cytotoxic chemotherapy. A DNA analog like gemcitabine, in the background of the pre-existing gross chromosomal abnormalities seen in RCC, may be sufficient to drive a c-Myc–dominant tumor—the DNA repair mechanisms of which are down-regulated—into apoptosis.17,18 The combination of gemcitabine and capecitabine is an effective and well-tolerated regimen, with the potential for achieving durable remissions in metastatic RCC. We believe this regimen should be evaluated in the treatment paradigm of metastatic RCC refractory to targeted therapies.

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~雷利度胺~~~~~~~~~~~~~~~~~~~~~~

40个病人入组，1个CR，3个PR，21个SD。25个病人6个月内出现进展，6个人6-12个月进展，9个人12个月以上进展。副作用可耐受。

http://www.ncbi.nlm.nih.gov/pubmed/18525302
Abstract
PURPOSE:
Treatments for refractory metastatic renal cell cancer (RCC) are limited. Oral lenalidomide, a thalidomide-based drug having enhanced immunomodulatory and antiangiogenic properties and reduced toxicity, was evaluated for safety and efficacy in this setting.
METHODS:
In an open-label, single-center phase II trial, adults (> or =18 years old) with newly diagnosed RCC seen at our institution between December 2003 and April 2004 were recruited to receive at least three 28-day cycles (21 days on drug and 7 days off) of oral lenalidomide (25 mg/d). The dose was reduced as needed in cases of toxicity. The primary endpoint was tumor response rate. Secondary endpoints were time to tumor progression, response duration, 6-month and 12-month progression-free survival, overall survival, and safety.
RESULTS:
Thirty-nine of 40 patients (97%) were evaluable for response. Many in the evaluable population [63 (38-73) years; male, 73% (29/39)]; Zubrod performance status < or =1, 97% (38/39) had the clear cell histotype [85% (33/39)], had undergone previous immunotherapy or chemotherapy [59% (23/39)]; and had > or =2 metastatic sites [69% (27/39)]. Most [92% (36/39)] completed at least 3 treatment cycles (12 weeks). A complete response was observed in 1 patient (3%), partial response in 3 (8%), stable disease in 21 (53%), and progressive or unknown-status disease in 15 (38%). Time to tumor progression was < or =6 months in 24 patients (62%), 6 to 12 months in 6 (15%), and >12 months in 9 (23%). Median response duration was 6 (2-22) months and median overall survival was 17 months (0.80-39.6). The most common treatment-related adverse event was grade < or =2 fatigue [60% (24/40)]. The most common laboratory abnormalities were grade > or =3 neutropenia [50% (20/40)] and thrombocytopenia [28% (11/40)].
CONCLUSION:
Lenalidomide is a safe and effective therapy for refractory metastatic RCC. Further studies of lenalidomide in this setting are warranted.

~~~~~~~~~~~~~~~~~~~~~~~~Gemcitabine + Capecitabine 吉西他滨+卡培他滨~~~~~~~~~~~~~~~~~~~~~~

这个帖子总结了几个临床试验，介绍了两个CR的病人，都是免疫治疗活着靶向治疗失败，病情进展，几个临床试验我还没查，等有空更新上来，不过这个帖子提到 Response rates have ranged from 8.4% to 16%, stable disease rates from 48% to 67%, and median progression-free survival from 4.6 to 7.6 months.
反应率从8.4%到16%不等（我觉得挺高的了），SD从48%到67%不等。（我觉得也挺高的了哈）。然后中位无进展生存期4.6到7.6个月不等（作为靶向疗法外的疗法我觉得也挺高的了哈），而且似乎耐受不错的。


http://jco.ascopubs.org/content/29/8/e203.full

Targeted therapy is the current standard of care for the systemic treatment of metastatic RCC. The multitargeted tyrosine kinase inhibitors sunitinib and pazopanib as well as the combination of bevacizumab plus interferon alfa are the accepted first-line therapies for patients with metastatic clear cell RCC at good to intermediate risk.1–4 The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is the accepted first-line therapy for patients with advanced poor-risk RCC.5 Sorafenib, sunitinib, and pazopanib are accepted second-line therapies after cytokine failure; the mTOR inhibitor everolimus is the approved treatment after sorafenib and/or sunitinib failure.6,7 Approximately 20% of patients with metastatic RCC have primary resistance to anti–vascular endothelial growth factor (VEGF) therapies. Furthermore, there is no established third-line therapy for patients who develop progressive disease after VEGF- and mTOR-targeted therapies or for patients who are intolerant of these targeted agents. Metastatic RCC has traditionally been considered unresponsive to cytotoxic chemotherapy.8 The combination of gemcitabine and capecitabine has been studied in several case series and four single-arm phase II trials in patients with metastatic RCC refractory to immunotherapy and, to a lesser extent, refractory to targeted therapy. Response rates have ranged from 8.4% to 16%, stable disease rates from 48% to 67%, and median progression-free survival from 4.6 to 7.6 months.9–12

We report two patients with metastatic RCC who achieved durable remissions after treatment with the chemotherapy regimen of gemcitabine and capecitabine after failure of targeted therapies. One patient has been in remission more than 6 years since rapid disease progression while receiving high-dose IL-2 and sorafenib. The second patient demonstrated a second tumor response on rechallenge with this chemotherapy regimen after rapid disease progression while receiving two prior anti-VEGF therapies (bevacizumab and sunitinib). The mechanisms of resistance of RCC to anti-VEGF agents and mTOR inhibitors are poorly understood. Clinicopathologic studies have demonstrated that higher tissue levels of phosphorylated Akt in nephrectomy specimens from patients with metastatic RCC subsequently treated with sorafenib are associated with shorter progression-free survival.13 A study evaluating nephrectomy specimens from patients with metastatic RCC who received bevacizumab-based therapy before nephrectomy demonstrated that critical components of the PI3-kinase pathway are upregulated in individuals with shorter progression-free survival.14 Although these data do not prove a direct mechanistic association between PI3-kinase pathway upregulation and poor clinical outcome in patients treated with antiangiogenic agents, they provide hypothesis-generating studies for testing.

Gemcitabine (2′,2′-difluorodeoxycytidine, LY188011, dFdCyd) is a pyrimidine antimetabolite. Cell-cycle kinetic studies with gemcitabine have shown specificity for proliferation in the S phase of the cell cycle, with no effect on progress through the early G1, G2, or M phase.15 We postulate that c-Myc activation may provide a specific vulnerability to this class of agents by driving cells to accumulate higher levels of abnormal DNA in the presence of gemcitabine, generating in effect a synthetic lethal phenotype. Evan et al16 reviewed mechanisms by which increased DNA damage in conjunction with c-Myc activation could lead to susceptibilities to DNA-damaging processes. In patients with rapidly progressing disease with high cell-cycle activity, RCC tumors may be more susceptible to cytotoxic chemotherapy. A DNA analog like gemcitabine, in the background of the pre-existing gross chromosomal abnormalities seen in RCC, may be sufficient to drive a c-Myc–dominant tumor—the DNA repair mechanisms of which are down-regulated—into apoptosis.17,18 The combination of gemcitabine and capecitabine is an effective and well-tolerated regimen, with the potential for achieving durable remissions in metastatic RCC. We believe this regimen should be evaluated in the treatment paradigm of metastatic RCC refractory to targeted therapies.

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~雷利度胺~~~~~~~~~~~~~~~~~~~~~~

40个病人入组，1个CR，3个PR，21个SD。25个病人6个月内出现进展，6个人6-12个月进展，9个人12个月以上进展。副作用可耐受。

http://www.ncbi.nlm.nih.gov/pubmed/18525302
Abstract
PURPOSE:
Treatments for refractory metastatic renal cell cancer (RCC) are limited. Oral lenalidomide, a thalidomide-based drug having enhanced immunomodulatory and antiangiogenic properties and reduced toxicity, was evaluated for safety and efficacy in this setting.
METHODS:
In an open-label, single-center phase II trial, adults (> or =18 years old) with newly diagnosed RCC seen at our institution between December 2003 and April 2004 were recruited to receive at least three 28-day cycles (21 days on drug and 7 days off) of oral lenalidomide (25 mg/d). The dose was reduced as needed in cases of toxicity. The primary endpoint was tumor response rate. Secondary endpoints were time to tumor progression, response duration, 6-month and 12-month progression-free survival, overall survival, and safety.
RESULTS:
Thirty-nine of 40 patients (97%) were evaluable for response. Many in the evaluable population [63 (38-73) years; male, 73% (29/39)]; Zubrod performance status < or =1, 97% (38/39) had the clear cell histotype [85% (33/39)], had undergone previous immunotherapy or chemotherapy [59% (23/39)]; and had > or =2 metastatic sites [69% (27/39)]. Most [92% (36/39)] completed at least 3 treatment cycles (12 weeks). A complete response was observed in 1 patient (3%), partial response in 3 (8%), stable disease in 21 (53%), and progressive or unknown-status disease in 15 (38%). Time to tumor progression was < or =6 months in 24 patients (62%), 6 to 12 months in 6 (15%), and >12 months in 9 (23%). Median response duration was 6 (2-22) months and median overall survival was 17 months (0.80-39.6). The most common treatment-related adverse event was grade < or =2 fatigue [60% (24/40)]. The most common laboratory abnormalities were grade > or =3 neutropenia [50% (20/40)] and thrombocytopenia [28% (11/40)].
CONCLUSION:
Lenalidomide is a safe and effective therapy for refractory metastatic RCC. Further studies of lenalidomide in this setting are warranted.

~~~~~~~~~~~~~~~~~~~~~~~~Gemcitabine + Capecitabine 吉西他滨+卡培他滨~~~~~~~~~~~~~~~~~~~~~~

这个帖子总结了几个临床试验，介绍了两个CR的病人，都是免疫治疗活着靶向治疗失败，病情进展，几个临床试验我还没查，等有空更新上来，不过这个帖子提到 Response rates have ranged from 8.4% to 16%, stable disease rates from 48% to 67%, and median progression-free survival from 4.6 to 7.6 months.
反应率从8.4%到16%不等（我觉得挺高的了），SD从48%到67%不等。（我觉得也挺高的了哈）。然后中位无进展生存期4.6到7.6个月不等（作为靶向疗法外的疗法我觉得也挺高的了哈），而且似乎耐受不错的。


http://jco.ascopubs.org/content/29/8/e203.full

Targeted therapy is the current standard of care for the systemic treatment of metastatic RCC. The multitargeted tyrosine kinase inhibitors sunitinib and pazopanib as well as the combination of bevacizumab plus interferon alfa are the accepted first-line therapies for patients with metastatic clear cell RCC at good to intermediate risk.1–4 The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is the accepted first-line therapy for patients with advanced poor-risk RCC.5 Sorafenib, sunitinib, and pazopanib are accepted second-line therapies after cytokine failure; the mTOR inhibitor everolimus is the approved treatment after sorafenib and/or sunitinib failure.6,7 Approximately 20% of patients with metastatic RCC have primary resistance to anti–vascular endothelial growth factor (VEGF) therapies. Furthermore, there is no established third-line therapy for patients who develop progressive disease after VEGF- and mTOR-targeted therapies or for patients who are intolerant of these targeted agents. Metastatic RCC has traditionally been considered unresponsive to cytotoxic chemotherapy.8 The combination of gemcitabine and capecitabine has been studied in several case series and four single-arm phase II trials in patients with metastatic RCC refractory to immunotherapy and, to a lesser extent, refractory to targeted therapy. Response rates have ranged from 8.4% to 16%, stable disease rates from 48% to 67%, and median progression-free survival from 4.6 to 7.6 months.9–12

We report two patients with metastatic RCC who achieved durable remissions after treatment with the chemotherapy regimen of gemcitabine and capecitabine after failure of targeted therapies. One patient has been in remission more than 6 years since rapid disease progression while receiving high-dose IL-2 and sorafenib. The second patient demonstrated a second tumor response on rechallenge with this chemotherapy regimen after rapid disease progression while receiving two prior anti-VEGF therapies (bevacizumab and sunitinib). The mechanisms of resistance of RCC to anti-VEGF agents and mTOR inhibitors are poorly understood. Clinicopathologic studies have demonstrated that higher tissue levels of phosphorylated Akt in nephrectomy specimens from patients with metastatic RCC subsequently treated with sorafenib are associated with shorter progression-free survival.13 A study evaluating nephrectomy specimens from patients with metastatic RCC who received bevacizumab-based therapy before nephrectomy demonstrated that critical components of the PI3-kinase pathway are upregulated in individuals with shorter progression-free survival.14 Although these data do not prove a direct mechanistic association between PI3-kinase pathway upregulation and poor clinical outcome in patients treated with antiangiogenic agents, they provide hypothesis-generating studies for testing.

Gemcitabine (2′,2′-difluorodeoxycytidine, LY188011, dFdCyd) is a pyrimidine antimetabolite. Cell-cycle kinetic studies with gemcitabine have shown specificity for proliferation in the S phase of the cell cycle, with no effect on progress through the early G1, G2, or M phase.15 We postulate that c-Myc activation may provide a specific vulnerability to this class of agents by driving cells to accumulate higher levels of abnormal DNA in the presence of gemcitabine, generating in effect a synthetic lethal phenotype. Evan et al16 reviewed mechanisms by which increased DNA damage in conjunction with c-Myc activation could lead to susceptibilities to DNA-damaging processes. In patients with rapidly progressing disease with high cell-cycle activity, RCC tumors may be more susceptible to cytotoxic chemotherapy. A DNA analog like gemcitabine, in the background of the pre-existing gross chromosomal abnormalities seen in RCC, may be sufficient to drive a c-Myc–dominant tumor—the DNA repair mechanisms of which are down-regulated—into apoptosis.17,18 The combination of gemcitabine and capecitabine is an effective and well-tolerated regimen, with the potential for achieving durable remissions in metastatic RCC. We believe this regimen should be evaluated in the treatment paradigm of metastatic RCC refractory to targeted therapies.

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~雷利度胺~~~~~~~~~~~~~~~~~~~~~~

40个病人入组，1个CR，3个PR，21个SD。25个病人6个月内出现进展，6个人6-12个月进展，9个人12个月以上进展。副作用可耐受。

http://www.ncbi.nlm.nih.gov/pubmed/18525302
Abstract
PURPOSE:
Treatments for refractory metastatic renal cell cancer (RCC) are limited. Oral lenalidomide, a thalidomide-based drug having enhanced immunomodulatory and antiangiogenic properties and reduced toxicity, was evaluated for safety and efficacy in this setting.
METHODS:
In an open-label, single-center phase II trial, adults (> or =18 years old) with newly diagnosed RCC seen at our institution between December 2003 and April 2004 were recruited to receive at least three 28-day cycles (21 days on drug and 7 days off) of oral lenalidomide (25 mg/d). The dose was reduced as needed in cases of toxicity. The primary endpoint was tumor response rate. Secondary endpoints were time to tumor progression, response duration, 6-month and 12-month progression-free survival, overall survival, and safety.
RESULTS:
Thirty-nine of 40 patients (97%) were evaluable for response. Many in the evaluable population [63 (38-73) years; male, 73% (29/39)]; Zubrod performance status < or =1, 97% (38/39) had the clear cell histotype [85% (33/39)], had undergone previous immunotherapy or chemotherapy [59% (23/39)]; and had > or =2 metastatic sites [69% (27/39)]. Most [92% (36/39)] completed at least 3 treatment cycles (12 weeks). A complete response was observed in 1 patient (3%), partial response in 3 (8%), stable disease in 21 (53%), and progressive or unknown-status disease in 15 (38%). Time to tumor progression was < or =6 months in 24 patients (62%), 6 to 12 months in 6 (15%), and >12 months in 9 (23%). Median response duration was 6 (2-22) months and median overall survival was 17 months (0.80-39.6). The most common treatment-related adverse event was grade < or =2 fatigue [60% (24/40)]. The most common laboratory abnormalities were grade > or =3 neutropenia [50% (20/40)] and thrombocytopenia [28% (11/40)].
CONCLUSION:
Lenalidomide is a safe and effective therapy for refractory metastatic RCC. Further studies of lenalidomide in this setting are warranted.

~~~~~~~~~~~~~~~~~~~~~~~~Gemcitabine + Capecitabine 吉西他滨+卡培他滨~~~~~~~~~~~~~~~~~~~~~~

这个帖子总结了几个临床试验，介绍了两个CR的病人，都是免疫治疗活着靶向治疗失败，病情进展，几个临床试验我还没查，等有空更新上来，不过这个帖子提到 Response rates have ranged from 8.4% to 16%, stable disease rates from 48% to 67%, and median progression-free survival from 4.6 to 7.6 months.
反应率从8.4%到16%不等（我觉得挺高的了），SD从48%到67%不等。（我觉得也挺高的了哈）。然后中位无进展生存期4.6到7.6个月不等（作为靶向疗法外的疗法我觉得也挺高的了哈），而且似乎耐受不错的。


http://jco.ascopubs.org/content/29/8/e203.full

Targeted therapy is the current standard of care for the systemic treatment of metastatic RCC. The multitargeted tyrosine kinase inhibitors sunitinib and pazopanib as well as the combination of bevacizumab plus interferon alfa are the accepted first-line therapies for patients with metastatic clear cell RCC at good to intermediate risk.1–4 The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is the accepted first-line therapy for patients with advanced poor-risk RCC.5 Sorafenib, sunitinib, and pazopanib are accepted second-line therapies after cytokine failure; the mTOR inhibitor everolimus is the approved treatment after sorafenib and/or sunitinib failure.6,7 Approximately 20% of patients with metastatic RCC have primary resistance to anti–vascular endothelial growth factor (VEGF) therapies. Furthermore, there is no established third-line therapy for patients who develop progressive disease after VEGF- and mTOR-targeted therapies or for patients who are intolerant of these targeted agents. Metastatic RCC has traditionally been considered unresponsive to cytotoxic chemotherapy.8 The combination of gemcitabine and capecitabine has been studied in several case series and four single-arm phase II trials in patients with metastatic RCC refractory to immunotherapy and, to a lesser extent, refractory to targeted therapy. Response rates have ranged from 8.4% to 16%, stable disease rates from 48% to 67%, and median progression-free survival from 4.6 to 7.6 months.9–12

We report two patients with metastatic RCC who achieved durable remissions after treatment with the chemotherapy regimen of gemcitabine and capecitabine after failure of targeted therapies. One patient has been in remission more than 6 years since rapid disease progression while receiving high-dose IL-2 and sorafenib. The second patient demonstrated a second tumor response on rechallenge with this chemotherapy regimen after rapid disease progression while receiving two prior anti-VEGF therapies (bevacizumab and sunitinib). The mechanisms of resistance of RCC to anti-VEGF agents and mTOR inhibitors are poorly understood. Clinicopathologic studies have demonstrated that higher tissue levels of phosphorylated Akt in nephrectomy specimens from patients with metastatic RCC subsequently treated with sorafenib are associated with shorter progression-free survival.13 A study evaluating nephrectomy specimens from patients with metastatic RCC who received bevacizumab-based therapy before nephrectomy demonstrated that critical components of the PI3-kinase pathway are upregulated in individuals with shorter progression-free survival.14 Although these data do not prove a direct mechanistic association between PI3-kinase pathway upregulation and poor clinical outcome in patients treated with antiangiogenic agents, they provide hypothesis-generating studies for testing.

Gemcitabine (2′,2′-difluorodeoxycytidine, LY188011, dFdCyd) is a pyrimidine antimetabolite. Cell-cycle kinetic studies with gemcitabine have shown specificity for proliferation in the S phase of the cell cycle, with no effect on progress through the early G1, G2, or M phase.15 We postulate that c-Myc activation may provide a specific vulnerability to this class of agents by driving cells to accumulate higher levels of abnormal DNA in the presence of gemcitabine, generating in effect a synthetic lethal phenotype. Evan et al16 reviewed mechanisms by which increased DNA damage in conjunction with c-Myc activation could lead to susceptibilities to DNA-damaging processes. In patients with rapidly progressing disease with high cell-cycle activity, RCC tumors may be more susceptible to cytotoxic chemotherapy. A DNA analog like gemcitabine, in the background of the pre-existing gross chromosomal abnormalities seen in RCC, may be sufficient to drive a c-Myc–dominant tumor—the DNA repair mechanisms of which are down-regulated—into apoptosis.17,18 The combination of gemcitabine and capecitabine is an effective and well-tolerated regimen, with the potential for achieving durable remissions in metastatic RCC. We believe this regimen should be evaluated in the treatment paradigm of metastatic RCC refractory to targeted therapies.

这楼更新一些疫苗的信息，暂时不能试药，只能给点希望和斗志！

目前比较有希望的是Immatic的IMA901

还有 Bristol-Myers Squibb的 MDX1106/nivolumab
见到美国论坛上挺多参加临床试验的人说效果非常好，有个报道说对肺癌也有用，贴过来 http://www.medscape.com/viewarticle/806705 129个病人入组，反应率20%到25%

我又找到一个Immunicum AB的INTUVAX
http://globenewswire.com/news-re ... -kidney-cancer.html

12个肾癌病人入组，至今9个已经接受治疗，至今全部活着（2012初开始的实验，今年五月的报道，不过起始治疗时间大家都不一样），目前没有人需要更换其他的治疗。两个起始状况很差的病人至今平均已经活了11个月（还活着），其中一个人已经pfs达到八个月。而且没见什么明显的副作用。可以见到肿瘤附近明显的CD8 + T cells聚集，正常细胞没有。

这个药MPDL3280A对黑色素，肺癌，肾癌等等似乎都有用，是针对PD-l1的，据报道说实验数据比nivolumab安全些，而且对之前的免疫治疗失败的还能起效，包括一些测试PD-l1阴性的人。包括各种癌症的实验中五分之一的病人起效，而且一旦起效是长效反应。最高起效是黑色素和肺癌，所以应该比这个数字高。

http://news.yale.edu/2013/05/31/ ... -down-immune-system

谢谢辛勤的楼主。
奇怪怎么有几楼被删除了？

qingyang 发表于 2013-8-4 11:18

                               
登录/注册后可看大图

谢谢辛勤的楼主。
奇怪怎么有几楼被删除了？

不知道啊，可能是因为英文有些多吧，只能都简略放到一楼了，发了好几次，郁闷啊。。

这个好，记一下

谢谢楼主，你不是一个人在战斗，我们都在加油