FDA受理百时美黑色素瘤药物Yervoy sBLA，或成20年来辅助治疗新选择

百时美施贵宝（BMS）近日宣布，FDA已接受并审查肿瘤免疫疗法Yervoy（ipilimumab，易普利姆）补充生物制品许可（sBLA），该sBLA寻求批准Yervoy作为一种辅助治疗药物，用于已完成手术切除伴有高复发风险的3阶段黑色素瘤患者。FDA已指定处方药用户收费法（PDUFA）目标日期为2015年10月28日。如果获批，Yervoy将成为近20年来用于3阶段黑色素瘤患者辅助治疗的首个新治疗选择。

Yervoy sBLA的提交，是基于一项随机双盲III期研究CA184-029 (EORTC 18071) 的积极数据。该项研究评估了Yervoy（10mg/kg剂量）作为一种辅助疗法用于已手术切除的高危III阶段黑色素瘤患者以预防或推迟病情复发的潜力。数据表明，在治疗的3年中，Yervoy治疗组有46.5%患者病情无复发，安慰剂组为34.8%（p=0.0013）；平均随访2.7年，Yervoy治疗组无复发生存期（RFS）为26.1个月，安慰剂组为17.1个月，达到了研究的主要终点。

目前，百时美也正在调查PD-1肿瘤免疫疗法Opdivo（nivolumab）与Yervoy组合疗法用于黑色素瘤的治疗。根据去年6月在美国临床肿瘤学会（ASCO）年会上公布的数据，Opdivo（1mg/kg）+Yervoy（3mg/kg）联合治疗组一年总生存率达到了94%，2年总生存率达到88%。这一剂量方案已用于正在开展的II期和III期研究。

黑色素瘤（melanoma）是一种高度恶性肿瘤，复发率和死亡率非常高。根据其原位特性（厚度、溃烂）、是否已扩散至淋巴结、远处转移程度，黑色素瘤可分为5级（0-4阶段）。3阶段黑色素瘤已到达区域性淋巴结，但尚未扩散到远端淋巴结或机体其他部位（转移），需要外科手术切除原发肿瘤及所涉及的淋巴结。3阶段黑色素瘤复发风险很高，总存活率一直很低；许多患者会在治疗后5年内复发，其中近90%复发病例发生于高复发风险人群。一旦病情复发，存活率将非常低，历史数据为11%-20%。

Yervoy是一种重组人单克隆抗体，能够有效阻断细胞毒性T淋巴细胞相关抗原4（CTLA-4）。CTLA-4是一种T细胞活化的负调控因子，Yervoy与CTLA-4结合后，能阻断CTLA-4与其配体CD80/CD86的相互作用。而阻断CTLA-4已被证明能够增强T细胞的活化和增殖。Yervoy在黑色素瘤患者中的疗效作用机制，是间接通过T细胞介导的抗肿瘤免疫反应。FDA于2011年3月批准Yervoy（3mg/kg）单药疗法用于不能手术切除或转移性黑色素瘤患者的治疗，目前该药已获全球40多个国家批准。

英文原文：U.S. Food and Drug Administration Accepts Supplemental Biologics License Application for Yervoy® (ipilimumab) as Adjuvant Treatment for Patients with Stage 3 Melanoma Who Are at High Risk of Recurrence

Yervoy has the potential to be the first new therapeutic approach approved as an adjuvant treatment for patients with stage 3 melanoma in almost two decades

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced that the U.S. Food and Drug Administration (FDA) has accepted for filing and review the supplemental Biologics License Application (sBLA) for Yervoy for the adjuvant treatment of patients with stage 3 melanoma who are at high risk of recurrence following complete surgical resection. The projected FDA action date is October 28, 2015.

For many stage 3 melanoma patients, there is a high risk of disease recurrence and there has been a low overall survival rate. By five years, the majority of patients experience disease recurrence, with nearly 90 percent in those considered at the highest risk. Once the disease returns, survival rates have been been very low historically, ranging from 11 to 20 percent.

“Four years ago, Yervoy was approved for the treatment of unresectable or metastatic melanoma, the most advanced form of the disease,” said Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb. “Today’s announcement is a reflection of our commitment to investigate our immuno-oncology treatments for patients across lines of therapy and stages of the disease.”

This filing acceptance is based on clinical data from a randomized, double-blind Phase III trial, CA184-029 (EORTC 18071), assessing the efficacy of Yervoy, at the investigational dose of 10 mg/kg, in preventing or delaying recurrence after complete resection of high-risk stage 3 melanoma.

About Melanoma

Melanoma is separated into five staging categories (stages 0-4) based on the in-situ feature, thickness and ulceration of the tumor, whether the cancer has spread to the lymph nodes, and how far the cancer has spread beyond lymph nodes. Stage 3 melanoma has reached the regional lymph nodes but has not yet spread to distant lymph nodes or to other parts of the body (metastasized), and requires surgical resection of the primary tumor as well as the involved lymph nodes.

About Yervoy

Yervoy, which is a recombinant, human monoclonal antibody, blocks the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activation. Yervoy binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of Yervoy’s effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses. On March 25, 2011, the FDA approved Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is now approved in more than 40 countries. There is a broad, ongoing development program in place for Yervoy spanning multiple tumor types. This includes Phase III trials in prostate and lung cancers.

Immuno-Oncology at Bristol-Myers Squibb

Surgery, radiation, cytotoxic or targeted therapies have represented the mainstay of cancer treatment over the last several decades, but long-term survival and a positive quality of life have remained elusive for many patients with advanced disease.

To address this unmet medical need, Bristol-Myers Squibb is leading advances in an innovative field of cancer research and treatment known as immuno-oncology, which involves agents whose primary mechanism is to work directly with the body’s immune system to fight cancer. The company is exploring a variety of compounds and immunotherapeutic approaches for patients with different types of cancer, including researching the potential of combining immuno-oncology agents that target different and complementary pathways in the treatment of cancer.

Bristol-Myers Squibb is committed to advancing the science of immuno-oncology, with the goal of changing survival expectations and the way patients live with cancer.