2014年12月21日，美国FDA批准ramucirumab（将以品牌名Cyramza上市）治疗晚期胃癌或胃食管结合部腺癌。该药物是人源化血管内皮生长因子受体2(VEGFR-2)的IgG1 类抗体，用于治疗含氟尿嘧啶或铂类治疗后不可切除或转移性胃癌患者。 一项包含355 例不可切除或转移性胃癌或胃食管结合部腺癌患者的临床研究，对ramucirumab 的安全性和疗效进行了评估。其中2/3的患者应用ramucirumab，其余患者应用安慰剂。结果显示，ramucirumab 组和安慰剂组患者的中位总生存(OS)期分别为5.2 个月和3.8个月，此外，ramucirumab组患者的无进展生存(PFS)期也获延长。 另一项临床研究结果显示ramucirumab联合紫杉醇治疗较单用紫杉醇，患者的OS更优。ramucirumab常见的不良反应为腹泻和高血压。 FDA 通过优先程序对ramucirumab 进行了审评，并将其纳入孤儿药范畴。FDA的药品评估和研究中心血液学和肿瘤学产品办公室主任Pazdur 博士评论，“尽管过去的40年内美国胃癌发病率在下降，但患者仍然需要新的治疗选择，特别是对其他治疗不再有反应的人群。ramucirumab是一种治疗的新选择，可延长患者的生存，减缓肿瘤的生长。 注射用CYRAMZA (雷莫芦单抗[ramucirumab])，为静脉输注 初次批准：2014 商品名：Cyramza  通用名：ramucirumab  中文名：雷莫芦单抗 审批分类：优先审评+孤儿药 药企：Eli Lilly 适应证和用途 CYRAMZATM是一种人血管内皮生长因子受体2(VEGFR2)拮抗剂适用为胃癌的治疗。 ⑴ 晚期胃癌或胃-食管结合部腺癌，作为单药既往氟嘧啶-或含铂化疗后。 剂量和给药方法 ⑴ 给予8mg/kg静脉每2周。 ⑵ 只为静脉输注。不要静脉推注或丸注。 剂型和规格 ⑴ 100 mg/10mL(10mg每mL)溶液，单次-剂量小瓶 ⑵ 500 mg/50mL (10mg每mL)溶液，单次-剂量小瓶 禁忌证 无。 警告和注意事项 ⑴ 动脉血栓事件(ATEs)：在临床试验中曾报道严重，有时致命性ATEs。对严重ATEs终止CYRAMZA。 ⑵ 高血压：监视血压和治疗高血压。对严重高血压暂时不给CYRAMZA。对药物不能控制的高血压终止CYRAMZA。 ⑶ 输注相关反应：输注期间监视体征和症状。 ⑷ 胃肠道穿孔：终止CYRAMZA。 ⑸ 损害伤口愈合：手术前不给CYRAMZA。 ⑹ 有肝硬变患者中临床恶化：有Child-Pugh B或C肝硬化患者可能发生脑病，腹水，或肝肾综合征新发病或恶化。 ⑺ 可逆性后部白质脑病综合征: 终止CYRAMZA。 不良反应 CYRAMZA-治疗患者观察到发生率≥10%和高于安慰剂≥2%最常见不良反应为高血压和腹泻。 特殊人群中使用 ⑴ 妊娠：根据其作用机制，CYRAMZA可能致胎儿危害。 ⑵ 哺乳母亲：终止哺乳或终止CYRAMZA。 Lilly’s CYRAMZA™ (ramucirumab) Becomes First FDA-Approved Treatment for Advanced Gastric Cancer After Prior Chemotherapy INDIANAPOLIS, April 21, 2014 / PRNewswire / — Eli Lilly and Company (NYSE: LLY) announced today that the U.S. Food and Drug Administration (FDA) has approved CYRAMZA™ (pronounced "si – ram - ze") (ramucirumab) as a single-agent treatment for patients with advanced or metastatic gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. With this approval, CYRAMZA becomes the first FDA-approved treatment for patients in this setting. Read more Read more   “Lilly Oncology is committed to delivering innovative medicines that extend the lives of people with cancer,” said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. “Until now, there were no FDA-approved options for patients in this indication. We are pleased that the FDA has approved CYRAMZA for these patients. This is an aggressive disease that is difficult to treat, and the prognosis has typically been very poor.” The CYRAMZA (ramucirumab injection 10 mg/mL solution) approval is based on results of REGARD, a multicenter, randomized, placebo-controlled, double-blind trial of patients with locally advanced or metastatic gastric cancer including GEJ adenocarcinoma previously treated with fluoropyrimidine- or platinum-containing chemotherapy. It is the first Phase III trial to show improved overall survival and progression-free survival with a biologic agent in advanced gastric cancer after prior chemotherapy. Results demonstrated that CYRAMZA (8 mg/kg by infusion every two weeks) plus best supportive care (BSC), as compared to placebo plus BSC, increased the median overall survival of patients with advanced gastric cancer by 37 percent (median overall survival of 5.2 months [95% confidence interval (CI) 4.4, 5.7] vs. 3.8 months [95% CI 2.8, 4.7] for placebo, P=0.047, hazard ratio 0.78 [95% CI 0.60, 0.998]). Additionally, CYRAMZA significantly improved progression-free survival, demonstrating a 62 percent increase in median progression-free survival (2.1 months [95% CI 1.5, 2.7] vs. 1.3 months [95% CI 1.3, 1.4] for placebo, P<0.001, hazard ratio 0.48 [95% CI 0.38, 0.62]). The labeling for CYRAMZA contains a Boxed Warning regarding increased risk of hemorrhage, including severe and sometimes fatal events. CYRAMZA should be discontinued in patients who experience severe bleeding. The most commonly reported adverse reactions (all grades) in REGARD, occurring in at least 5 percent of patients receiving CYRAMZA and at a rate at least 2 percent higher than those receiving placebo, were hypertension (16% vs. 8%), diarrhea (14% vs. 9%), headache (9% vs. 3%), and hyponatremia (6% vs. 2%). The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs. 8.7% of patients who received placebo. Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In REGARD, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in the REGARD trial was 0.8% and the rate of infusion-related reactions was 0.4%. This is not a complete list of adverse reactions. For full safety information, see the Important Safety Information at the end of this press release and the full Prescribing Information. “There is a high unmet medical need in patients with this disease,” said Charles Fuchs, M.D., M.P.H., principal investigator of the REGARD trial and director, Gastrointestinal Malignancy Program, Dana-Farber Cancer Institute. “This approval represents a meaningful advance for patients and gives those of us who treat them an important new second-line treatment option.” “As someone who has experienced firsthand the limited options available to treat this devastating disease, I consider this approval to be much needed. This is a significant moment for many patients and their families,” said Debbie Zelman, president and founder of a leading international patient advocacy organization, Debbie’s Dream Foundation, which is dedicated to raising awareness about gastric cancer, advancing funding for research, and providing education and support to those affected by the disease. Zelman founded the organization following her own gastric cancer diagnosis. Lilly Oncology and Debbie’s Dream Foundation have established a partnership to improve patient and caregiver awareness of and access to gastric cancer resources. CYRAMZA is a vascular endothelial growth factor (VEGF) Receptor 2 antagonist that specifically binds VEGF Receptor 2 and blocks binding of VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D. VEGF Receptor 2 is an important mediator in the VEGF pathway.i,ii In an in vivo animal model, ramucirumab inhibited angiogenesis. Angiogenesis is a process by which new blood vessels form to supply blood to normal healthy tissues as well as tumors, enabling the cancer to grow. FDA approval of CYRAMZA marks a pivotal regulatory milestone in Lilly’s research and development program for the molecule, which it acquired when it purchased ImClone Systems in 2008. CYRAMZA has been granted Orphan Drug Designation by the FDA for this indication. Orphan drug status is given in the U.S. by the FDA’s Office of Orphan Products Development (OOPD) to medicines that show promise for the treatment of rare diseases. Lilly expects to make CYRAMZA available in the coming weeks and is committed to offering patient assistance programs for eligible patients receiving CYRAMZA treatment. Patients, physicians, pharmacists or other healthcare professionals with additional questions about CYRAMZA should contact The Lilly Answer Center at 1-800-LillyRx or visit www.Lilly.com. About Angiogenesis Angiogenesis is the process of making new blood vessels. This process involves the migration, growth, and differentiation of endothelial cells, which line the inside wall of blood vessels. Chemical signals in the body stimulate the repair of damaged blood vessels and formation of new blood vessels during this process. In a person with cancer, angiogenesis creates new blood vessels that give a tumor its own blood supply, allowing it to grow and spread. Some tumors create proteins called VEGF. These proteins attach to the VEGF receptors of blood vessel cells causing new blood vessels to form around the tumors, enabling growth. Blocking the VEGF protein from linking to the blood vessels helps to inhibit tumor growth by slowing angiogenesis and the blood supply that feeds tumors. Of the three known VEGF receptors, VEGF Receptor 2 is linked most closely to VEGF-induced tumor angiogenesis.iii About CYRAMZA™ (ramucirumab) CYRAMZA (pronounced si – ram - ze) as a single agent is the first and only treatment approved for patients with advanced gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma who have progressed after prior fluoropyrimidine- or platinum-containing chemotherapy. CYRAMZA inhibited angiogenesis in an in vivo animal model. CYRAMZA is a VEGF Receptor 2 antagonist that specifically binds and blocks activation of VEGF Receptor 2 and blocks binding of VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D. About REGARD REGARD is a global, randomized, double-blinded, placebo-controlled Phase III study of CYRAMZA and BSC compared to placebo and BSC as treatment in patients with locally advanced or metastatic gastric cancer including gastroesophageal junction adenocarcinoma following progression after initial fluoropyrimidine- or platinum-containing chemotherapy. In total, 355 patients were randomized in 29 countries. The major efficacy outcome measure (i.e., primary endpoint) of the REGARD trial was overall survival and the supportive efficacy outcome measure (i.e., secondary endpoint) was progression-free survival. About Gastric Cancer Gastric (stomach) cancer is a major health problem. It is the fifth most common cancer in the world and is the third-leading cause of cancer death. There were nearly one million new cases worldwide in 2012 (631,000 men, 320,000 women) with approximately 723,000 deaths (469,000 men, 254,000 women).iv Stomach cancer is more prevalent in countries outside the U.S. and EU.v In the U.S., it is estimated that approximately 22,000 people will be diagnosed with gastric cancer in 2014.vi Gastric cancer is a disease in which cancer cells form in the stomach. It develops slowly, usually over many years, and often goes undetected.vii As stomach cancer advances, it can travel through the bloodstream and spread to organs such as the liver, lungs and bones.viii The most common type of stomach cancer is called adenocarcinoma, which starts from one of the common cell types found in the lining of the stomach.ix Lilly PatientOne The Lilly PatientOne program addresses financial and coverage issues for qualified uninsured, underinsured and insured patients who are prescribed a Lilly Oncology product. Lilly PatientOne provides reimbursement assistance for eligible patients who are prescribed a Lilly Oncology product, such as information about coding and billing, prior authorization, benefits investigation, and denied claim appeals, as well as operating a patient assistance program. To learn more, visit www.LillyPatientOne.com or call 1-866-4PatOne (1-866-472-8663). Indication for CYRAMZA CYRAMZA as a single agent is indicated for the treatment of patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Warnings and Precautions Hemorrhage •CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, which evaluated CYRAMZA as a single agent in ad-vanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gas-tric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events •Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension •An increased incidence of severe hypertension occurred in patients receiving CY-RAMZA as a single agent (8%) as compared to placebo (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions •Prior to the institution of premedication recommendations across clinical trials of CY-RAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), in-cluding 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hy-poxia, and paresthesia. In severe cases, symptoms included bronchospasm, supra-ventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations •CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CY-RAMZA as a single agent in clinical trials experienced gastrointestinal perforation. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal per-foration. Impaired Wound Healing •CYRAMZA has not been studied in patients with serious or nonhealing wounds. CY-RAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Child-Pugh B or C Cirrhosis •Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) •RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Con-firm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who de-velop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death. Most Common Adverse Reactions •The most commonly reported adverse reactions (all grades) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in Study 1 were hypertension (16% vs 8%), diarrhea (14% vs 9%), headache (9% vs 3%), and hyponatremia (6% vs 2%). •The most common serious adverse events with CYRAMZA in Study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo. •Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%). •Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients includ-ed proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed pro-teinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%. •As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) CYRAMZA-treated patients with post-baseline serum samples tested positive for anti-ramucirumab antibodies using an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting anti-ramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies. Drug Interactions •No formal drug interaction studies have been conducted. Use in Specific Populations •Pregnancy Category C: Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant, including use of adequate contraception, while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Animal models link angiogenesis, VEGF and VEGF Re-ceptor 2 to critical aspects of female reproduction, embryofetal development, and post-natal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes preg-nant while taking this drug, apprise the patient of the potential hazard to a fetus. •Nursing Mothers: It is recommended to discontinue nursing or discontinue CYRAMZA due to the potential risks to the nursing infant. •Females of Reproductive Potential: Advise females of reproductive potential that CY-RAMZA may impair fertility. Please see full Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage at http://pi.lilly.com/us/cyramza-pi.pdf. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c6080942-dee6-423e-b688-1272c2ae90d4 包装规格[注：以下产品不同上市国家和不同价格，采购以咨询为准] 美国包装 CYRAMZA 10MG/ML 10ML PF SDV 1/EA  RAMUCIRUMAB     00002-7669-01  CYRAMZA 10MG/ML 50ML PF SDV 1/EA  RAMUCIRUMAB     00002-7678-01  欧洲包装： CYRAMZA 10MG/ML 10ML PF SDV 1/EA  RAMUCIRUMAB CYRAMZA 10MG/ML 50ML PF SDV 1/EA  RAMUCIRUMAB 欧盟批准礼来RAMUCIRUMAB(CYRAMZA(R))用于化疗经治的晚期胃癌 ——欧盟首次批准专门用于胃癌二线的治疗 2014年12月29日欧盟已批准Ramucirumab(CYRAMZA®)上市，联合紫杉醇用于治疗化疗经治的成人晚期胃癌或胃食管连接部(GEJ)腺癌以及作为单药用于不适合联合紫杉醇的同类患者。这是Ramucirumab在欧盟获得的首次适应症注册批准。 “今天标志着欧盟境内晚期胃癌治疗的一个重要里程碑，患者和医务人员现在拥有了一种批准专门用于这种难治性疾病二线治疗的药物，”礼来制药抗肿瘤事业部产品研发和医学事务高级副总裁Richard Gaynor博士表示：“我们很骄傲能兑现我们支持癌症患者及其医护人员这一承诺。” 此次欧盟上市批准是基于两项全球、随机、双盲、安慰剂对照III期研究的结果：RAINBOW和REGARD。RAINBOW评估了Ramucirumab联合紫杉醇（一种化疗药物）用于化疗经治的晚期胃癌或GEJ腺癌，而REGARD则评估了Ramucirumab作为单药用于同样的患者。 欧洲药品管理局孤儿药品委员会（COMP）授予Ramucirumab为孤儿药，用于欧盟境内胃癌患者的治疗。孤儿药地位授予那些用于治疗罕见疾病，疗效显著好于现有治疗方法的药物。 关于RAINBOW试验 RAINBOW是一项全球、随机、双盲、安慰剂对照III期研究，在含氟嘧啶和含铂初始化疗方案难治或上述方案使用后疾病进展的晚期（局部晚期、不可切除或转移性）胃癌（包括GEJ腺癌）患者中比较Ramucirumab联合紫杉醇和安慰剂联合紫杉醇。共有来自27个国家的665位患者进行了随机分组，RAINBOW 试验的主要疗效结果测量指标（即主要终点）为总生存期，支持性疗效结果测量指标（即次要终点）为无进展生存期。 关于 REGARD 试验 REGARD是一项全球、随机、双盲、安慰剂对照III期研究，在含氟嘧啶和含铂初始化疗方案使用后疾病进展的局部晚期或转移性胃癌（包括GEJ腺癌）患者中比较 Ramucirumab联合最佳支持治疗（BSC）和安慰剂联合BSC。共有来自29个国家的355位患者进行了随机分组，REGARD试验的主要疗效结果测量指标为总生存期，而支持性疗效结果测量指标为无进展生存期。 关于胃癌 胃癌在全球最常见的癌症中占第五位，同时也是全球第三大癌症相关死亡原因。2012年全球新发病例近一百万（631，000男性病例，320，000女性病例），约723，000死亡病例（469，000男性病例，254，000女性病例）。胃癌更常见于欧美以外的国家。欧洲胃癌罕见；据估计，2012年法国、德国、意大利、西班牙和英国新发胃癌总例数约为50000。 胃癌是一种在胃部形成了癌细胞的疾病。这种疾病发展缓慢，通常需要很多年方可形成且经常不能检出。随着胃癌的进展，它能够随血流游走，扩散到诸如肝脏、肺和骨骼等器官。 最常见的胃癌类型是腺癌，它起源于胃粘膜中一种常见细胞。 关于 Ramucirumab 在欧盟，Ramucirumab(CYRAMZA®) 已经获得上市批准，与紫杉醇联合用于化疗经治成人晚期胃癌或胃食管连接部（GEJ）腺癌，并可作为单药用于不适合联合紫杉醇的同类患者。Ramucirumab在美国已获得批准用于化疗经治的晚期或转移性胃癌或GEJ腺癌患者。 Ramucirumab 是一种抗血管生成药物，在体内动物模型中可抑制血管生成。Ramucirumab 是一种 VEGF 受体2拮抗剂，通过特异性结合 VEGF受体2，阻止 VEGF受体配体VEGF-A、VEGF-C和VEGF-D的结合，来阻止VEGF受体2的激活。而 VEGF 介导的血管生成和多种疾病的发病机制相关，其中就包括了晚期胃癌。