诺华公布Afinitor乳腺癌BOLERO-2次要终点数据

关键词： 诺华 Afinitor 乳腺癌 mTOR抑制剂

                               
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2014年3月20日讯 /生物谷BIOON/ --诺华（Novartis）3月19日在第9届欧洲乳腺癌会议（EBCC-9）上公布了抗癌药Afinitor乳腺癌III期BOLERO-2研究的次要终点数据。

BOLERO-2研究涉及全球195个位点超过700例患者。研究中，患者随机（2:1）接受依维莫司片（Afinitor，10mg/天）或安慰剂持续疗法，同时接受依西美坦（exemestane，25mg/天）治疗。主要终点是疾病无进展生存期（PFS），次要终点包括总生存期（OS）、总缓解率、不良事件发生率、患者自报的预后和临床获益率。

研究数据表明，联合治疗组平均总生存期为31个月，依西美坦单药治疗组平均总生存期为26个月，差异4.4个月（HR=0.89,p=0.1426），未达统计学显著性阈值。这是目前为止在既往接受过非甾体类芳香化酶抑制剂（NSAI）治疗的HR+/HER2-晚期乳腺癌患者群体中开展的III期临床试验中，所取得的最长的总生存期数据。

此前，所公布的BOLERO-2研究疾病无进展生存期（PFS）数据，Afinitor+依西美坦联合治疗组为7.8个月，依西美坦单药治疗组为3.2个月（HR=0.45,p＜0.0001）。

关于Afinitor：

Afinitor是首个也是唯一一个获批用于HR+/HER2-乳腺癌的mTOR抑制剂，目前已获80多个国家批准，联合依西美坦（exemestane）用于激素受体阳性（HR+）及人表皮生长因子受体2阴性（HER2-）晚期乳腺癌（HR+型晚期乳腺癌）的治疗，适用人群为接受非甾体芳香化酶抑制剂类药物治疗后复发或进展型、且无内脏疾病症状的绝经后妇女患者。

Afinitor靶向于PI3K/AKT/mTOR信号通路，该通路在多种类型肿瘤中处于过度激活（hyperactived）状态。mTOR是一种蛋白，是细胞分裂、血管生长、细胞代谢中的一种重要调节因子。已有数据证实，阻断mTOR是一种行之有效的方法，能够使现有晚期乳腺癌疗法的临床利益最大化。

HR+/HER2-晚期乳腺癌是乳腺癌中的最常见类型，约70%的侵入性乳腺癌在确诊时为HR+。（生物谷Bioon.com）

英文原文：Novartis reports data at EBCC-9 for secondary survival endpoint of Afinitor trial in HR+/HER2- advanced breast cancer

Basel, March 19, 2014 - Results from the secondary endpoint of the Phase III BOLERO-2 (Breast cancer trials of OraL EveROlimus-2) study of Afinitor® (everolimus) trial were presented today at the 9th European Breast Cancer Conference (EBCC-9) in Glasgow, Scotland.

A median overall survival duration of 31 months was seen in the combination arm versus 26.6 months for those on exemestane monotherapy, a difference of 4.4 months (hazard ratio=0.89 [95% CI: 0.73 to 1.10]; p=0.1426)[1],[2]. This secondary endpoint did not reach the threshold of statistical significance[1]. The median overall survival is the longest reported to date in a Phase III hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer trial following prior treatment with a non-steroidal aromatase inhibitor (NSAI)[2].

"The BOLERO-2 trial shows that treatment with Afinitor in combination with exemestane works against multiple target pathways to slow the progression of hormone receptor-positive advanced breast cancer, even among patients who have progressed while on or within 12 months of completing adjuvant non-steroidal aromatase inhibitor therapy," said Gabriel Hortobagyi, MD, professor, Breast Medical Oncology, The University of Texas MD Anderson Cancer Center. "This dual approach both extends the benefits of endocrine therapy while delaying the time until the patient needs chemotherapy, which can have an important impact on patients living with this disease."

The final overall survival results were assessed as part of a prospectively planned secondary endpoint analysis. Previously reported progression-free survival (PFS) results found that treatment with everolimus plus exemestane more than doubled median PFS to 7.8 months, compared to 3.2 months with exemestane alone, meeting the study's primary endpoint (hazard ratio=0.45 [95% Cl: 0.38 to 0.54]; p<0.0001), confirmed by central assessment (11 months versus 4.1 months PFS)[3]. The most common adverse reactions (incidence >= 30%) were stomatitis, infections, rash, fatigue, diarrhea and decreased appetite[2],[3]. The most common grade 3-4 adverse reactions (incidence >= 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis and diarrhea[2],[3].

"These data, along with experience from more than 18 months of real-world use, add to the growing body of evidence regarding the use of Afinitor plus exemestane in patients with hormone receptor-positive, HER2 negative advanced breast cancer after they progress on a non-steroidal aromatase inhibitor," said Alessandro Riva, MD, President Novartis Oncology ad interim and Global Head, Oncology Development and Medical Affairs. "We continue to research the role of Afinitor in advanced breast cancer and are committed to developing other novel therapies, such as those targeting the PI3K/AKT/mTOR and CDK 4/6 pathways."

Everolimus is the first and only mTOR inhibitor approved for the treatment of HR+/HER2- advanced breast cancer[2],[4]. mTOR is a protein that acts as an important regulator of cell division, blood vessel growth and cell metabolism[4]. Everolimus targets the PI3K/AKT/mTOR pathway, which is hyperactivated in many types of cancers[5]. Additional data presented at the meeting provide continued evidence on the important role of dual hormone receptor and mTOR inhibition in the treatment of HR+/HER2- advanced breast cancer upon NSAI failure[2].

Everolimus is approved as Afinitor in more than 80 countries to treat women with HR+/HER2- advanced breast cancer, including the most recent approval in Japan this week[2]. The specific indications vary by country.

Study design
BOLERO-2 involved more than 700 patients at more than 195 sites worldwide. Patients in the trial were randomized (2:1) to receive continuous therapy with everolimus 10 mg/day orally or placebo, plus oral exemestane 25 mg/day[5]. Patients who had received more than one prior chemotherapy regimen for advanced breast cancer were excluded from enrollment[5]. The primary endpoint was PFS[5]. Secondary endpoints included overall survival, overall response rate, incidence of adverse events, patient reported outcomes and clinical benefit rate[5].

About advanced breast cancer
Advanced breast cancer comprises metastatic breast cancer (stage IV) and locally advanced breast cancer (stage III)[6]. Metastatic breast cancer is the most serious form of the disease and occurs when the cancer has spread to other parts of the body, such as the brain, bones or liver[6]. Locally advanced breast cancer occurs when the cancer has spread to lymph nodes and/or other tissue in the area of the breast, but not to distant sites in the body[6].

It is estimated that women with metastatic breast cancer have a life expectancy of approximately 18-36 months after diagnosis and median survival for women with stage III disease is less than five years[7],[8]. Hyperactivation of the PI3K/AKT/mTOR pathway has been associated with disease progression in women with advanced breast cancer[4].

Approximately 70% of all invasive breast cancers are positive for HR expression at the time of diagnosis[9]. HR+ advanced breast cancer is the most common type of advanced breast cancer, with an estimated 220,000 women diagnosed globally each year[2],[10]. HR+ advanced breast cancer is characterized by hormone receptor-positive tumors, a group of cancers that express receptors for certain hormones such as estrogen and progesterone[11]. Cancer cell growth can be driven by these hormones[11].

About Afinitor® (everolimus)
Everolimus is approved as Afinitor® in the European Union for the treatment of hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor (NSAI). In the United States, Afinitor is approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2 negative (advanced HR+/HER2-) breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole.

Afinitor (everolimus) tablets is approved in more than 100 countries, including the United States and throughout the European Union, in the oncology settings of advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy, and in the United States and European Union for locally advanced, metastatic or unresectable progressive neuroendocrine tumors of pancreatic origin.

Everolimus is also available from Novartis for use in certain non-oncology patient populations under the brand names Afinitor® or Votubia®, Certican® and Zortress® and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Indications vary by country and not all indications are available in every country. The safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywhere else in the world.

About the Novartis breast cancer pipeline
Novartis is currently investigating PI3K inhibitors buparlisib (BKM120) and BYL719, and CDK 4/6 inhibitor LEE011, in the treatment of drug-resistant breast cancer in combination with other targeted therapies[2].

The PI3K/AKT/mTOR pathway regulates cell metabolism, proliferation and survival, and abnormal activation of this pathway has been shown to be important in initiation and maintenance of human tumors[4]. Cyclin-dependent kinases (CDKs) drive cell cycle progression and control transcriptional processes, and the deregulation of multiple CDK proteins, including CDK 4 and 6, occur commonly in cancer[12]. Targeting these pathways could arrest tumor growth and induce cell death in cancers that are resistant to currently available therapies[2],[4],[12].

Because they are investigational compounds, the safety and effiicacy profile of BKM120, BYL719 and LEE011 have not yet been established[2]. Access to these investigational compounds is available only through carefully controlled and monitored clinical trials designed to better understand their potential benefits and risks. Because of the uncertainty of clinical trials, there is no guarantee that BKM120, BYL719 and LEE011 will ever be commercially available anywhere in the world.