新药讨论：Regorafenib

Phase III Trial of Regorafenib in Metastatic Colorectal Cancer Meets Primary Endpoint of Improving Overall Survival
Trial stopped based on positive data from a pre-planned interim analysis
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Berlin, October 26, 2011 – Bayer HealthCare today announced positive results from its Phase III trial evaluating its investigational compound regorafenib (BAY 73-4506) for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed after approved standard therapies: The trial met its primary endpoint of statistically significantly improving overall survival. This is the result of a pre-planned interim analysis conducted by an independent Data Monitoring Committee (DMC) of the CORRECT (Patients with metastatic colorectal cancer treated with regorafenib or placebo after failure of standard therapy) trial. Per the recommendation of the DMC, the study has been unblinded and patients in the placebo arm will be offered treatment with regorafenib. In this trial, the safety and tolerability of regorafenib were generally as expected and did not show any new or unexpected toxicities. Data from the study are expected to be presented at a forthcoming scientific meeting.

8 [, ]+ X) e# F+ y“These data are significant because they demonstrate that regorafenib increases overall survival in patients with heavily pretreated mCRC, an area of high unmet medical need,” said Kemal Malik, MD, Head of Global Development and member of the Bayer HealthCare Executive Committee. “We are extremely encouraged by the result of this analysis and we are hopeful about the potential of regorafenib to fill this unmet treatment need.”
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# l5 K' K! |' ]  lBayer will continue discussions with health authorities worldwide, including the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) regarding next steps in filing for approval of regorafenib in the treatment of mCRC.
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9 G3 Y1 B% Q- m! {$ l5 C/ l9 RBayer recently entered into an agreement with Onyx Pharmaceuticals, Inc. under which Onyx will receive a royalty on any future global net sales of regorafenib in oncology.

About the CORRECT Study
# O1 K7 |0 k0 _: r) CThe CORRECT trial is an international, multicenter, randomized, double-blind, placebo-controlled study that enrolled 760 patients with mCRC whose disease has progressed after approved standard therapies. The study was conducted in North America, Europe, China, Japan and Australia.
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4 P4 ~' i% c- x9 d& \Patients were randomized to receive either regorafenib plus best supportive care (BSC) or placebo plus BSC. Treatment cycles consisted of 160 mg of regorafenib (or matching placebo) once daily for three weeks on / one week off plus BSC. The primary endpoint of this trial was overall survival. Secondary endpoints included progression-free survival, objective tumor response rate and disease control rate. The safety and tolerability of the two treatment groups were also compared.

About Regorafenib
& w0 u5 ]+ T0 {* w4 W+ ^Regorafenib is an investigational oral multi-kinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases (TK). Regorafenib inhibits angiogenic kinases like receptors for VEGF which play central roles in angiogenesis. It also inhibits various oncogenic kinases including RAF, RET as well as stromal kinases such as KIT and PDGFR, thereby helping to stop the proliferation of cancer cells. Regorafenib has shown antitumor activity in preclinical studies by inhibiting tumor growth in multiple xenograft models via antiangiogenic and antiproliferative mechanisms. Based on these results, regorafenib is currently being investigated in clinical trials for its potential to treat patients with various tumor types.
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Regorafenib is an investigational agent and is not approved by the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA) or other health authorities.

Regorafenib was granted orphan drug designation by the FDA for the treatment of patients with gastrointestinal stromal tumors (GIST). Orphan drug designation aims to encourage the development of drugs involved in the diagnosis, prevention or treatment of a medical condition affecting fewer than 200,000 people in the country.
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Regorafenib was granted Fast Track designation by the U.S. FDA for the treatment of patients with metastatic and/or unresectable GIST whose disease has progressed despite at least imatinib and sunitinib as prior treatments, as well as for the treatment of patients with mCRC who have progressed after approved standard therapies. Fast Track is a process designed to facilitate the development, and expedite the review of drugs to treat serious diseases and fill an unmet medical need.

* a8 A% r& P4 w! r3 F从报到来看Regorafenib很有希望成为首个转移性结直肠癌口服多靶点小分子抑制剂上市，三期的临床在中国的很多城市都有。
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clinicaltrials上的三期临床链接

http://clinicaltrials.gov/ct2/sh ... mp;show_locs=Y#locn

% i8 N+ [" b( [) @2 r' N" f+ q3 F中国参加临床实验的城市
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4 s& o. y, {+ q1 Y* SChina, Guangdong

Guangzhou, Guangdong, China, 510515  
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Guangzhou, Guangdong, China, 510060  
China, Jiangsu
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Nanjing, Jiangsu, China, 210009  

Nanjing, Jiangsu, China, 210002  
7 _# l# W: b7 H: wChina, Shandong
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Qingdao, Shandong, China, 266003  
China

Beijing, China, 100021  

- C3 [2 @2 T5 ~! W# ~5 VBeijing, China, 100071  

Changchun, China, 130021  
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9 ~  |, }2 [' XChongqing, China, 400042  

Chongqing, China, 400038  

Fuzhou, China, 350014  
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Fuzhou, China, 350025  
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% R$ U6 v- w- T. C: kHa'erbin, China, 150040  

  v2 B$ B  H4 w* ?5 M- XHanghzou, China, 310009  

Shanghai, China, 200001  

- c8 x. [1 C; `& _' ?Shanghai, China, 200030  

" m& o: N; I5 M" |Tianjin, China  

该实验已停止招募，重新开的临床请见临床专用贴。

2012 GI Cancers Symposium Preliminary Program Agenda

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2:30 PM — 4:00 PM  Oral Abstract Session: Cancers of the Colon and Rectum
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( S0 d; Y% J0 ~0 N8 L- Q! OResults of a phase III randomized, double-blind, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients with metastatic colorectal cancer (mCRC) who have progressed after standard therapies.

http://gicasym.org/MeetingProgram.aspx

期待ASCO的好结果。
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Regorafenib在mCRC方面的三期实验结果公布：

Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies.
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! P  [) L- b+ _4 b  f. EAbstract:
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1 F6 b* _5 `+ n3 sBackground: Regorafenib (BAY 73-4506) is an oral multikinase inhibitor of a broad range of angiogenic, oncogenic, and stromal kinases. The phase III CORRECT trial was conducted to evaluate efficacy and safety of regorafenib in pts with mCRC who had progressed after all approved standard therapies. Methods: Enrollment criteria included documented mCRC and progression during or ≤3 months after last standard therapy. Pts were randomized 2:1 to receive regorafenib (160 mg od po, 3 weeks on/1 week off) plus BSC, or placebo (PL) plus BSC. Pts continued on treatment until progression, death, or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), safety, and quality of life. Results: From May 2010 to March 2011, 760 pts were randomized (regorafenib: 505; PL: 255). Baseline characteristics were balanced between two arms. Preliminary results are available from a pre-planned formal interim analysis. The estimated hazard ratio (HR) for OS was 0.773 (95% CI: 0.635, 0.941; 1-sided p=0.0051). Median OS was 6.4 mos (95% CI: 5.9, 7.3) for regorafenib and 5.0 mos (95% CI: 4.4, 5.8) for PL. The estimated HR for PFS was 0.493 (95% CI: 0.418, 0.581; 1-sided p < 0.000001). Median PFS was 1.9 mos (95% CI: 1.88, 2.17) for regorafenib and 1.7 mos (95% CI: 1.68, 1.74) for PL. ORR was 1.6% for regorafenib and 0.4% for PL. DCR was 44% for regorafenib and 15% for PL (p < 0.000001). Since the prespecified OS efficacy boundary was crossed (nominal α: 0.0093), the Data Monitoring Committee recommended to unblind the study and pts on PL were allowed to cross over to regorafenib. The most frequent grade 3+ AEs in the regorafenib arm were hand-foot skin reaction (17%), fatigue (15%), diarrhea (8%), hyperbilirubinemia (8%), and hypertension (7%). Updated results will be presented. Conclusions: Statistically significant benefit in OS and PFS was observed for regorafenib over PL in pts with mCRC who have failed all approved standard therapies. No new or unexpected safety signal was found.

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: i9 Z0 K  y6 X2 ?7 }评：拜耳公布了Regorafenib在mCRC的三期临床数据。主要目标（OS）和次要目标 （PFS、ORR、DRC）均达到设计终点，拜耳因此将向FDA提出新药上市申请。
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6 |; j3 y! c6 {8 N1 [新药设计目标是让患者在所有标准治疗失败后仍然有一种选择。从目前已公布的数据来看，OS、PFS虽有提高达到了统计性差异但幅度并不大。不过从新药的表现来看，单药可对mCRC末期的患者的疾病进展起到一定控制作用。因此有理由相信新药在一线、二线仍有很大空间待挖掘。

6 M( Y9 ~/ s1 {7 fCORRECT Trial Results: Regorafenib Potential New Standard of Care for Refractory mCRC
Findings from the CORRECT trial indicate that regorafenib, an investigational, oral multi-kinase inhibitor, is the first and only agent in phase III analysis to significantly improve overall survival in patients with metastatic colorectal cancer (mCRC) who have failed all approved standard therapies (Abstract LBA385). Consequently, regorafenib could help address the high unmet clinical need faced by this patient population once the drug receives regulatory approval, according to principal investigator Axel Grothey, MD, of the Mayo Clinic in Minnesota.
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Interim analysis of data from the global, randomized, double-blind, placebo-controlled trial showed that the addition of regorafenib to best supportive care significantly prolonged median overall survival—the primary endpoint—from 5.0 to 6.4 months in 760 patients with documented mCRC and disease progression during or within 3 months after their last standard therapy (p = 0.0052, 1-sided). This translated into a 23% reduction in the risk of death with regorafenib.

- }1 ?1 T: U6 t& e5 a7 cRegorafenib also significantly prolonged median progression-free survival (PFS) from 1.7 months to 1.9 months when added to best supportive care (p < 0.000001, 1-sided). The 0.2-month difference in PFS belies the 51% reduction in the risk of disease progression with regorafenib. “The PFS curves shown here clearly [identify] that the median difference in PFS does not fully reflect the efficacy of this drug in this patient population,” Dr. Grothey commented.
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0 w' I8 V( [2 u; x* `2 sRegorafenib appeared to be well tolerated, with side effects considered manageable with dose reduction or supportive care. The most common adverse events of grade 3 or higher included hand-foot skin reaction (16.6%), fatigue (9.6%), diarrhea (7.2%), hypertension (7.2%), and rash/desquamation (5.8%). Approximately 8% of patients assigned to regorafenib permanently discontinued treatment due to adverse events, compared with 1% in the placebo arm.
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Findings from the CORRECT trial will be used to support the applications for regulatory approval of regorafenib in the United States and abroad.

新药Regorafenib在ASCO2012年胃肠道癌讨论会上大出风头，与会者认为新药有可能改变现有mCRC治疗规范，详见上述报道。
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# m/ z$ ]- W/ H. v" I3 B, X" C相关新闻网络链接：http://gicasym.org/Gastrointesti ... ailyNews/GI385.aspx

FDA批准Regorafenib治疗转移性结直肠癌

; ^! E* Z2 P, `9月27日，FDA批准了口服药物Regorafenib（Stivarga，拜耳）治疗转移性结直肠癌。Regorafenib是一种新型的多激酶抑制剂，阻断促进肿瘤生长的多种酶。
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) y5 N3 L6 @/ ?, f% Q: i7 M    FDA药物评价和研究中心血液和肿瘤学办公室主任Richard Pazdur博士在发布会上指出，Regorafenib是最近的结直肠癌治疗药物，被证明可以延长病人的生命，在过去两个月来是第二个被批准治疗结直肠癌的药物。8月份，阿柏西普（Zaltrap，赛诺菲 - 安万特）被FDA批准联合FOLFIRI应用。
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    Regorafenib被批准时同时带有黑框警告，指出可能有严重或致命性的肝毒性。

, E# R, d3 U! d7 U' {# y    在这项药物的关键性3期随机试验中，被称为CORRECT试验，Regorafenib组的中位总生存期为6.4个月，而安慰剂组为5.0个月。生存期增加了29%，最初是在2012的胃肠道肿瘤研讨会中报告，这是第一个小分子激酶抑制剂被证明对转移性结直肠癌有效。

& h5 g' P3 m4 D) a- s" {    在CORRECT研究中，除了标准治疗外，505名病人被随机分配口服Regorafenib 160mg，255名病人进入安慰剂组。患者持续治疗直到疾病进展，死亡或是出现不可耐受的毒性。
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    除了总生存期改善外，中位无进展生存期也得到改善（2.0 vs 1.7个月），HR为0.493（P<0.000001）。疾病控制率也同样如此（44% vs 15%，P<0.000001）。
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: H. a9 q3 _5 `1 y  ]9 P    最常见的3+级不良反应是手足皮肤反应（17%），疲劳（15%），腹泻（8%），高胆红素血症（8%），高血压（7%）。

烦恼啊。俺是本地鸟，看不懂洋鸟字啊，麻烦翻译下啦，哈哈

行者老金 发表于 2012-11-10 19:22

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& o! W5 t4 M/ h# J, ~$ b烦恼啊。俺是本地鸟，看不懂洋鸟字啊，麻烦翻译下啦，哈哈

) Q; T( V- R+ ~; s8 ]金哥，最新报道是中文啦。

是多靶点的抗血管生成类药物吧。

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抗VEGF比索拉强，不知副作用如何。
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Targets VEGFR1/2/3 PDGFRβ Kit RET Raf-1  
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