索拉非尼不能延长HER2阴性乳腺癌患者无进展生存期（RESILIENCE研究）

多吉美（Nexavar，通用名：sorafenib，索拉非尼）的一项III期研究(RESILIENCE)的数据。该项研究是一项随机、双盲、安慰剂对照III期研究，在537例既往对紫杉类药物（taxane）有抵抗或治疗失败、同时对蒽环类药物（anthracycline）有抵抗或治疗失败或不适于进一步的蒽环类药物治疗的局部晚期或转移性HER2阴性乳腺癌患者中开展，调查了Nexavar+卡培他滨（capecitabine）组合疗法的疗效和安全性。研究中，患者随机分配接受每日口服600mg Nexavar或安慰剂，同时在21天周期内接受14天每日2次1000mg/平方米 卡培他滨治疗。该项研究的主要终点是无进展生存期（PFS），次要终点包括：总生存期（OS），疾病进展时间，总缓解率，疾病控制率，缓解持续时间，患者报告的生活质量，安全性。

数据表明，该项研究未能达到无进展生存期（PFS）的主要终点。相关数据的初步审查表明，该项研究中所观察到的不良事件类型与既往Nexavar或卡培他滨已知不良事件类型一致。详细的疗效和安全性分析数据将提交至即将举行的科学会议。

拜耳执行委员会成员及全球发展部门主管Joerg Moeller博士称，该项研究未能达到无进展生存期主要终点，对此非常失望。但该项研究的结果并不影响目前多吉美（Nexavar）已获批的适应症，同时非常感谢参与该项研究的患者及相关研究人员。

MedSci小编：
MedSci小编检索了此前的文献，尤其是两个meta分析的结果。这两个meta分析均显示Sorafenib为基础的治疗方案能延长HER2患者的PFS和TTP，但不能延长OS。其中一个meta认为还有延长ORR，另一个meta则持否定意见。

但是，大规模的RCT则不支持这一结论。可见，Meta分析的结果，还需要采用RCT进一步验证。不过本研究在phase 2时取得不错的效果（Clin Cancer Res. 2013 May 15;19(10):2745-54），但这种疗效并没有被phase 3证实。在phase 2临床研究中，共招募160名患者，其中82.5%患者接收gemcitabine ，17.5%接收capecitabine。研究发现，与安慰剂相比，Sorafenib（基础化疗为gemcitabine/capecitabine）能显著延长患者的PFS，从2.7个月延长至3.4个月（HR = 0.65; 95% CI: 0.45-0.95; P = 0.02）,TTP结果十分近似，ORR为19.8%，安慰剂组为12.7%(P = 0.23)，中位生存期安慰剂组为11.4个月，sorafenib 组为13.4个月(HR = 1.01; 95% CI: 0.71-1.44; P = 0.95)。但是遗憾的是，在phase 2时，82.5%患者接收gemcitabine，但是在phase 3时则换成capecitabine，这也可能是结果不能被phase 3重复的原因之一。这个phase 3主要基于phase 2中capecitabine结果，认为capecitabine将患者的中位PFS从4.1个月延长至6.4 个月 (HR = 0.58; P = 0.001)，但是，这毕竟是亚组分析，而且仅仅是其中的17.5%人群，结果是相当不可靠的。以此进行phase 3研究，并不合时宜。

另外，进一步研究RESILIENCE的设计时，研究可能过度自信，这个研究的采用单侧α=0.005，power =98.9%，最终达到363个事件，最终招募约519位患者。这个研究α与β值的设置非常苛刻，但现实很残酷，小型试验证据本身并不可靠，加上亚组的结果，更令人质疑，而phase 3如果苛刻条件，想成功确实不易。这个研究设计值得后面研究者进行借鉴与参考。

研究方案：
Baselga J, Costa F, Gomez H, Hudis CA, Rapoport B, Roche H, Schwartzberg LS, Petrenciuc O, Shan M, Gradishar WJ.A phase 3 tRial comparing capecitabinE in combination with SorafenIb or pLacebo for treatment of locally advanced or metastatIc HER2-Negative breast CancEr (the RESILIENCE study): study protocol for a randomized controlled trial.Trials. 2013 Jul 22;14:228. （PDF (282K)）

相关研究：
Tan QX, Qin QH, Lian B, Yang WP, Wei CY.Sorafenib-based therapy in HER2-negative advanced breast cancer: Results from a retrospective pooled analysis of randomized controlled trials.Exp Ther Med. 2014 May;7(5):1420-1426.

Chen J, Tian CX, Yu M, Lv Q, Cheng NS, Wang Z, Wu X.Efficacy and Safety Profile of Combining Sorafenib with Chemotherapy in Patients with HER2-Negative Advanced Breast Cancer: A Meta-analysis.J Breast Cancer. 2014 Mar;17(1):61-8.

Schwartzberg LS, Tauer KW, Hermann RC, Makari-Judson G, Isaacs C, Beck JT, Kaklamani V, Stepanski EJ, Rugo HS, Wang W, Bell-McGuinn K, Kirshner JJ, Eisenberg P, Emanuelson R, Keaton M, Levine E, Medgyesy DC, Qamar R, Starr A, Ro SK, Lokker NA, Hudis CA.Sorafenib or placebo with either gemcitabine or capecitabine in patients with HER-2-negative advanced breast cancer that progressed during or after bevacizumab.Clin Cancer Res. 2013 May 15;19(10):2745-54


英文原文：Phase III Trial of Sorafenib in Combination with Capecitabine Does Not Meet Primary Endpoint in Patients with Advanced Breast Cancer

Berlin, July 25, 2014 - Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc., an Amgen subsidiary, today announced that an investigational Phase III trial of sorafenib (Nexavar®) tablets plus capecitabine in patients with advanced breast cancer did not meet its primary endpoint of improving progression-free survival (PFS).

The study, called RESILIENCE, evaluated the efficacy and safety of sorafenib in combination with capecitabine, an oral chemotherapeutic agent, compared to placebo plus capecitabine, in patients with HER2 negative breast cancer who are resistant to or have failed prior taxane, and are resistant to or have failed an anthracycline or for whom further anthracycline therapy is not indicated. Based on initial review of the data, the types of adverse events observed were generally comparable with those known for either sorafenib or capecitabine. Detailed efficacy and safety analyses from this study are expected to be presented at an upcoming scientific congress.

"We are disappointed that the trial did not show an improvement in progression-free survival in patients with advanced breast cancer," said Dr. Joerg Moeller, Member of the Bayer HealthCare Executive Committee and Head of Global Development. "While the primary endpoint of this trial was not met, the results do not affect the currently approved indications for Nexavar. We would like to thank the patients and the study investigators for their contributions and participation in this study."

Phase III Trial Design The RESILIENCE (Phase III TRial Comparing CapecitabinE in Combination with S orafenIb or PLacebo for Treatment of Locally Advanced or MetastatIc HER2- Negative Breast CancEr) trial is a randomized, double-blind, placebo-controlled Phase III study which enrolled 537 patients in more than 20 countries, including the United States, Europe, Japan and Australia. The study evaluated sorafenib in combination with capecitabine in patients with locally advanced or metastatic HER2 negative breast cancer who are resistant to or have failed prior taxane, and are resistant to or have failed an anthracycline or for whom further anthracycline therapy is not indicated.

The primary endpoint of the study was progression-free survival. Secondary endpoints included overall survival, time to progression, overall response rate, disease control rate, duration of response, patient reported quality of life and safety. Patients were randomized to receive 600 mg of oral sorafenib or matching placebo daily on a continuous schedule, in addition to 1000mg/m2 of capecitabine twice daily for 14 days of a 21 day cycle.

About Nexavar® (sorafenib)
Nexavar® (sorafenib), an oral anti-cancer therapy, is currently approved in more than 100 countries worldwide. In Europe, Nexavar is approved for the treatment of hepatocellular carcinoma (HCC); for the treatment of patients with advanced renal cell carcinoma (RCC) who have failed prior interferon-alpha or interleukin-2 based therapy or are considered unsuitable for such therapy; and for progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to radioactive iodine.

In preclinical studies, Nexavar has been shown to inhibit multiple kinases thought to be involved in both cell proliferation (growth) and angiogenesis (blood supply) - two important processes that enable cancer growth. These kinases include Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET.

Nexavar is also being evaluated by Bayer and Onyx, international study groups, government agencies and individual investigators in a range of other cancers.

Nexavar is co-developed by Onyx Pharmaceuticals, Inc., an Amgen subsidiary, and Bayer, except in Japan where Bayer manages all development. The companies co-promote Nexavar in the U.S. Outside of the U.S., excluding Japan, Bayer has exclusive marketing rights, and Bayer and Onyx share profits globally.

About Oncology at Bayer
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer now includes three oncology products and several other compounds in various stages of clinical development. Together, these products reflect the company's approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

About Bayer HealthCare
The Bayer Group is a global enterprise with core competencies in the fields of health care, agriculture and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR 18.9 billion (2013), is one of the world's leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare's aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 56,000 employees (Dec 31, 2013) and is represented in more than 100 countries. More information is available at www.healthcare.bayer.com.