——Ramucirumab(CYRAMZA®)注射剂已被欧盟首次批准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50,000。 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。 目前正在进行或计划进行一些研究来探索 Ramucirumab 作为单药以及联合其它抗癌药物治疗多种肿瘤。 Cyramza 10mg/ml concentrate for solution for infusion 1. Name of the medicinal product Cyramza 10 mg/ml concentrate for solution for infusion 2. Qualitative and quantitative composition One ml of concentrate for solution for infusion contains 10 mg ramucirumab. Each 10 ml vial contains 100 mg of ramucirumab. Each 50 ml vial contains 500 mg of ramucirumab. Ramucirumab is a human IgG1 monoclonal antibody produced in murine (NS0) cells by recombinant DNA technology. Excipient with known effect: Each 10 ml vial contains approximately 17 mg sodium. Each 50 ml vial contains approximately 85 mg sodium. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Concentrate for solution for infusion (sterile concentrate). The concentrate is a clear to slightly opalescent and colourless to slightly yellow solution, pH 6.0. 4. Clinical particulars 4.1 Therapeutic indications Cyramza in combination with paclitaxel is indicated for the treatment of adult patients with advanced gastric cancer or gastro-oesophageal junction adenocarcinoma with disease progression after prior platinum and fluoropyrimidine chemotherapy (see section 5.1). Cyramza monotherapy is indicated for the treatment of adult patients with advanced gastric cancer or gastro-oesophageal junction adenocarcinoma with disease progression after prior platinum or fluoropyrimidine chemotherapy, for whom treatment in combination with paclitaxel is not appropriate (see section 5.1). 4.2 Posology and method of administration Ramucirumab therapy must be initiated and supervised by physicians experienced in oncology. Posology Gastric cancer and gastro-oesophageal junction (GEJ) adenocarcinoma Cyramza in combination with paclitaxel The recommended dose of ramucirumab is 8 mg/kg on days 1 and 15 of a 28 day cycle, prior to paclitaxel infusion. The recommended dose of paclitaxel is 80 mg/m2 administered by intravenous infusion over approximately 60 minutes on days 1, 8 and 15 of a 28 day cycle. Prior to each paclitaxel infusion, patients should have a complete blood count and blood chemistry performed to evaluate hepatic function. Criteria to be met prior to each paclitaxel infusion are provided in Table 1. Table 1: Criteria to be met prior to each paclitaxel administration Criteria Neutrophils Day 1: ≥1.5 x 109/L Days 8 and 15: ≥1.0 x 109/L Platelets Day 1: ≥100 x 109/L Days 8 and 15: ≥75 x 109/L Bilirubin <1.5 x upper limit of normal value (ULN) Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) No liver metastases: ALT/AST ≤3 x ULN Liver metastases: ALT/AST ≤5 x ULN Cyramza as a single agent The recommended dose of ramucirumab as a single agent is 8 mg/kg every 2 weeks. Duration of treatment It is recommended that treatment be continued until disease progression or until unacceptable toxicity has occurred. Premedication Premedication is recommended with a histamine H1 antagonist (for example diphenhydramine) prior to infusion of ramucirumab. If a patient experiences a Grade 1 or 2 infusion-related reaction (as per the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]), premedication must be given for all subsequent infusions. If a patient experiences a second Grade 1 or 2 infusion-related reaction (IRR) administer dexamethasone (or equivalent); then, for subsequent infusions, premedicate with the following or equivalent medicinal products: an intravenous histamine H1 antagonist (for example diphenhydramine hydrochloride), paracetamol and dexamethasone. See paclitaxel prescribing information for premedication requirements and additional information. Posology adjustments for ramucirumab Infusion-related reactions The infusion rate of ramucirumab should be reduced by 50 % for the duration of the infusion and all subsequent infusions if the patient experiences a grade 1 or 2 IRR. Ramucirumab should be immediately and permanently discontinued in the event of a grade 3 or 4 IRR (see section 4.4). Hypertension The blood pressure of patients should be monitored prior to each ramucirumab administration and treated as clinically indicated. Ramucirumab therapy should be temporarily discontinued in the event of severe hypertension, until controlled with medical management. If there is medically significant hypertension that cannot be controlled safely with antihypertensive therapy, ramucirumab therapy should be permanently discontinued (see section 4.4). Proteinuria Patients should be monitored for the development, or worsening of proteinuria during ramucirumab therapy. If the urine protein is ≥2+ on a dipstick, a 24 hour urine collection should be performed. Ramucirumab therapy should be temporarily discontinued if the urine protein level is ≥2 g/24 hours. Once the urine protein level returns to <2 g/24 hours, treatment should be resumed at a reduced dose level (6 mg/kg every 2 weeks). A second dose reduction (to 5 mg/kg every 2 weeks) is recommended if a urine protein level ≥2 g/24 hours reoccurs. Ramucirumab therapy should be permanently discontinued if the urine protein level is >3 g/24 hours or in the event of nephrotic syndrome. Elective surgery or impaired wound healing Ramucirumab therapy should be temporarily discontinued for at least 4 weeks prior to elective surgery. Ramucirumab therapy should be temporarily discontinued if there are wound healing complications, until the wound is fully healed (see section 4.4). Ramucirumab therapy should be permanently discontinued in the event of: Severe arterial thromboembolic events (see section 4.4). Gastrointestinal perforations (see section 4.4). Severe bleeding: NCI CTCAE Grade 3 or 4 bleeding (see section 4.4). Spontaneous development of fistula (see section 4.4). Paclitaxel dose adjustments Paclitaxel dose reductions may be applied based upon the grade of toxicity experienced by the patient. For NCI CTCAE Grade 4 haematological toxicity or Grade 3 paclitaxel-related non-haematological toxicity, it is recommended to reduce the paclitaxel dose by 10 mg/m2 for all following cycles. A second reduction of 10 mg/m2 is recommended if these toxicities persist or reoccur. Special populations Elderly patients In the pivotal studies there has been no indication that patients 65 years of age or older are at increased risk of adverse events compared to patients younger than 65 years old. No dose reductions are recommended. Patients with renal impairment There have been no formal studies with Cyramza in patients with renal impairment. Clinical data suggest that no dose adjustments are required in patients with mild or moderate renal impairment. There are no data regarding ramucirumab administration in patients with severe renal impairment (calculated creatinine clearance <30 ml/min) (see section 5.2). No dose reductions are recommended. Patients with hepatic impairment There have been no formal studies with Cyramza in patients with hepatic impairment. There are no data regarding ramucirumab administration in patients with moderate or severe hepatic impairment (see section 5.2). No dose reductions are recommended. Paediatric population The safety and efficacy of Cyramza in children and adolescents (<18 years) has not been established. No data are available. There is no relevant use of ramucirumab in the paediatric population in the advanced gastric cancer or gastro-oesophageal indication. Method of administration After dilution, Cyramza is administered as an intravenous infusion over approximately 60 minutes. It should not be administered as an intravenous bolus or push. To achieve the required infusion duration of approximately 60 minutes, the maximum infusion rate of 25 mg/minute should not be exceeded, instead the infusion duration should be increased. The patient should be monitored during infusion for signs of infusion-related reactions (see section 4.4) and the availability of appropriate resuscitation equipment should be ensured. For instructions on dilution of the medicinal product before administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Arterial thromboembolic events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia have been reported in clinical studies. Ramucirumab should be permanently discontinued in patients who experience a severe ATE (see section 4.2). Gastrointestinal perforations Ramucirumab is an antiangiogenic therapy and has the potential to increase the risk of gastrointestinal perforations. Ramucirumab should be permanently discontinued in patients who experience gastrointestinal perforations (see section 4.2). Severe bleeding Ramucirumab is an antiangiogenic therapy and has the potential to increase the risk of severe bleeding. Ramucirumab should be permanently discontinued in patients who experience Grade 3 or 4 bleeding (see section 4.2). Blood counts and coagulation parameters should be monitored in patients with conditions predisposing to bleeding, and in those treated with anticoagulants or other concomitant medicinal products that increase the risk of bleeding. Severe gastrointestinal haemorrhage, including fatal events, were reported in patients with gastric cancer treated with ramucirumab in combination with paclitaxel. Infusion-related reactions Infusion-related reactions were reported in clinical studies with ramucirumab. The majority of events occurred during or following a first or second ramucirumab infusion. Patients should be monitored during the infusion for signs of hypersensitivity. Symptoms included rigors/tremors, back-pain/spasms, chest pain and/or tightness, chills, flushing, dyspnoea, wheezing, hypoxia, and paraesthesia. In severe cases symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Ramucirumab should be immediately and permanently discontinued in patients who experience a Grade 3 or 4 IRR (see section 4.2). Hypertension An increased incidence of severe hypertension was reported in patients receiving ramucirumab as compared to placebo. In most cases hypertension was managed using standard antihypertensive treatment. Patients with uncontrolled hypertension were excluded from the trials: ramucirumab treatment should not be initiated in such patients until and unless their pre-existing hypertension is controlled. Patients who are treated with ramucirumab should have their blood pressure monitored. Ramucirumab should be temporarily discontinued for severe hypertension until controlled with medical management. Ramucirumab should be permanently discontinued if medically significant hypertension cannot be controlled with antihypertensive therapy (see section 4.2). Impaired wound healing The impact of ramucirumab has not been evaluated in patients with serious or non-healing wounds. In a study conducted in animals, ramucirumab did not impair wound healing. However, since ramucirumab is an antiangiogenic therapy and may have the potential to adversely affect wound healing, ramucirumab treatment should be withheld for at least 4 weeks prior to scheduled surgery. The decision to resume ramucirumab following surgical intervention should be based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, ramucirumab should be discontinued until the wound is fully healed (see section 4.2). Hepatic impairment Ramucirumab should be used with caution in patients with severe liver cirrhosis (Child-Pugh B or C), cirrhosis with hepatic encephalopathy, clinically significant ascites due to cirrhosis, or hepatorenal syndrome. In these patients, ramucirumab should only be used if the potential benefits of treatment are judged to outweigh the potential risk of progressive hepatic failure. Fistula Patients may be at increased risk for the development of fistula when treated with Cyramza. Ramucirumab treatment should be discontinued in patients who develop fistula (see section 4.2). Proteinuria An increased incidence of proteinuria was reported in patients receiving ramucirumab as compared to placebo. Patients should be monitored for the development or worsening of proteinuria during ramucirumab therapy. If the urine protein is ≥2+ on a dipstick, a 24 hour urine collection should be performed. Ramucirumab therapy should be temporarily discontinued if the urine protein level is ≥2 g/24 hours. Once the urine protein level returns to <2 g/24 hours, treatment should be resumed at a reduced dose level. A second dose reduction is recommended if a urine protein level ≥2 g/24 hours reoccurs. Ramucirumab therapy should be permanently discontinued if the urine protein level is >3 g/24 hours or in the event of nephrotic syndrome (see section 4.2). Renal impairment There are no safety data available for patients with severe renal impairment (calculated creatinine clearance < 30 ml/min) treated with ramucirumab (see sections 4.2 and 5.2). Sodium restricted diet Each 10 ml vial contains approximately 17 mg sodium and each 50 ml vial contains approximately 85 mg sodium. To be taken into account for patients on a sodium restricted diet. 4.5 Interaction with other medicinal products and other forms of interaction No drug-drug interactions were observed between ramucirumab and paclitaxel. The pharmacokinetics of paclitaxel were not affected when co-administered with ramucirumab and the pharmacokinetics of ramucirumab were not affected when co-administered with paclitaxel. 4.6 Fertility, pregnancy and lactation Women of childbearing potential/Contraception in females Women of childbearing potential should be advised to avoid becoming pregnant while on Cyramza and should be informed of the potential hazard to the pregnancy and foetus. Women of childbearing potential should use effective contraception during and up to 3 months after the last dose of ramucirumab treatment. Pregnancy There are no data from the use of ramucirumab in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). As angiogenesis is critical to maintenance of pregnancy and to foetal development, the inhibition of angiogenesis following ramucirumab administration may result in adverse effects on pregnancy, including the foetus. Cyramza should only be used if the potential benefit to the mother justifies the potential risk during pregnancy. If the patient becomes pregnant while being treated with ramucirumab, she should be informed of the potential risk to the maintenance of pregnancy and the risk to the foetus. Cyramza is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding It is unknown whether ramucirumab is excreted in human milk. Excretion in milk and oral absorption is expected to be low. As a risk to newborns/infants cannot be excluded, breast-feeding should be discontinued during treatment with Cyramza and for at least 3 months after the last dose. Fertility There are no data on the effect of ramucirumab on human fertility. Female fertility is likely to be compromised during treatment with ramcuirumab based on studies in animals (see section 5.3). 4.7 Effects on ability to drive and use machines Cyramza has no known influence on the ability to drive and use machines. If patients experience symptoms affecting their ability to concentrate and react, it is recommended that they do not drive or use machines until the effect subsides. 4.8 Undesirable effects Summary of the safety profile The most serious adverse reactions associated with ramucirumab treatment (as a single agent or in combination with cytotoxic chemotherapy) were: Gastrointestinal perforation (see section 4.4) Severe gastrointestinal haemorrhage (see section 4.4) Arterial thromboembolic events (see section 4.4) The most common adverse reactions observed in ramucirumab-treated patients are: fatigue/asthenia, neutropenia, leukopenia, diarrhoea, epistaxis, and hypertension. Tabulated list of adverse reactions Adverse Drug Reactions (ADRs) which were reported in patients with advanced gastric cancer are listed below by MedDRA body system organ class, frequency and grade of severity. The following convention has been used for classification of frequency: Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000) Within each frequency grouping, ADRs are presented in order of decreasing seriousness. Ramucirumab in combination with paclitaxel The following table provides the frequency and severity of ADRs based on results from RAINBOW, a phase 3 study in adult patients with advanced gastric cancer randomised to treatment with ramucirumab in combination with paclitaxel or placebo plus paclitaxel. Table 2 ADRs reported in ≥ 5 % of ramucirumab treated patients in RAINBOW System organ class Frequency ADR Cyramza plus paclitaxel (N=327) Placebo plus paclitaxel (N=329) All grades toxicity (%) Grade ≥3 toxicity (%) All grades toxicity (%) Grade ≥3 toxicity (%) Blood and lymphatic system disorders Very common Neutropenia 54.4 40.7 31.0 18.8 Very common Leukopenia 33.9 17.4 21.0 6.7 Very common Thrombocytopenia 13.1 1.5 6.1 1.8 Metabolism and nutrition disorders Very common Hypoalbuminaemia 11.0 1.2 4.9 0.9 Vascular disorder Very common Hypertensiona 25.1 14.7 5.8 2.7 Respiratory, thoracic, and mediastinal disorders Very common Epistaxis 30.6 0.0 7.0 0.0 Gastrointestinal disorders Very common Gastrointestinal haemorrhage eventsb 10.1 3.7 6.1 1.5 Very common Stomatitis 19.6 0.6 7.3 0.6 Very common Diarrhoea 32.4 3.7 23.1 1.5 Renal and urinary disorders Very common Proteinuria 16.8 1.2 6.1 0.0 General disorders and administration site disorders Very common Fatigue/Asthenia 56.9 11.9 43.8 5.5 Very common Peripheral oedema 25.1 1.5 13.7 0.6 a Includes hypertensive cardiomyopathy. b MedDRA preferred terms included anal haemorrhage, diarrhoea haemorrhage, gastric haemorrhage, gastrointestinal haemorrhage, haematemesis, haematochezia, haemorrhoidal haemorrhage, Mallory-Weiss syndrome, melaena, oesophageal haemorrhage, rectal haemorrhage, and upper gastrointestinal haemorrhage. Clinically relevant ADRs reported in ≥ 1% and < 5% of the ramucirumab plus paclitaxel-treated patients in RAINBOW were gastrointestinal perforation (1.2% ramucirumab plus paclitaxel versus 0.3% for placebo plus paclitaxel) and sepsis (3.1% ramucirumab plus paclitaxel versus 1.8% placebo plus paclitaxel). Ramucirumab as a single agent The following table provides the frequency and severity of the ADRs based on results from REGARD, a phase 3 study in adult patients with advanced gastric cancer randomised to treatment with single-agent ramucirumab plus Best Supportive Care (BSC) or placebo plus BSC. Table 3 ADRs reported in ≥ 5 % of ramucirumab treated patients in REGARD System organ class Frequency ADRa,b Cyramza (N=236) Placebo (N=115) All gradesc toxicity (%) Grade 3-4 toxicity (%) All grades toxicity (%) Grade 3-4 toxicity (%) Metabolism and nutrition disorders Common Hypokalaemiad 5.9 2.1 5.2 0.9 Common Hyponatraemia 5.5 3.4 1.7 0.9 Nervous system disorders Common Headache 9.3 0.0 3.5 0.0 Vascular disorders Very common Hypertensione 16.1 7.6 7.8 2.6 Gastrointestinal disorders Very common Abdominal painf 28.8 5.9 27.8 2.6 Very common Diarrhoea 14.4 0.8 8.7 1.7 a MedDRA preferred term (Version 15.0) b There were no Grade 5 ADRs for Cyramza. There was one Grade 4 ADR of hypokalaemia and one of hyponatraemia. c Refer to NCI CTCAE Criteria (Version 4.0) for each Grade of toxicity. d MedDRA preferred terms included are: blood potassium decreased and hypokalaemia. e MedDRA preferred terms included are: blood pressure increased and hypertension. f MedDRA preferred terms included are: abdominal pain, abdominal pain lower, abdominal pain upper, and hepatic pain. Clinically relevant ADRs reported in ≥ 1% and < 5% of the ramucirumab treated patients in REGARD were: neutropenia, arterial thromboembolic events (see sections 4.2 and 4.4), intestinal obstruction, epistaxis, and rash. Clinically relevant reactions (including Grade ≥ 3) associated with antiangiogenic therapy observed in ramucirumab-treated patients across clinical studies were: gastrointestinal perforations, infusion-related reactions and proteinuria (see sections 4.2 and 4.4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517; Website: www.hpra.ie; e-mail: medsafety@hpra.ie, or United Kingdom: Yellow Card Scheme; Website: www.mhra.gov.uk/yellowcard. 4.9 Overdose There is no data on overdose in humans. Cyramza has been administered in a Phase 1 study up to 10 mg/kg every two weeks without reaching a maximum tolerated dose. In case of overdose, supportive therapy should be used. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies ATC code: L01XC21. Mechanism of action Vascular Endothelial Growth Factor (VEGF) Receptor 2 is the key mediator of VEGF induced angiogenesis. Ramucirumab is a human receptor-targeted antibody that specifically binds VEGF Receptor 2 and blocks binding of VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand stimulated activation of VEGF Receptor 2 and its downstream signalling components, including p44/p42 mitogen-activated protein kinases, neutralizing ligand-induced proliferation and migration of human endothelial cells. Clinical efficacy and safety RAINBOW RAINBOW, a global, randomised, double-blind, study of Cyramza plus paclitaxel versus placebo plus paclitaxel, was conducted in 665 patients with locally recurrent and unresectable or metastatic gastric cancer (including GEJ adenocarcinoma) following platinum- and fluoropyrimidine-containing chemotherapy, with or without anthracycline. The primary endpoint was overall survival (OS) and the secondary endpoints included progression free survival (PFS) and overall response rate (ORR). Patients were required to have experienced disease progression during, or within 4 months after the last dose of first-line therapy and with ECOG PS 0-1. Patients were randomised in a 1:1 ratio to receive Cyramza plus paclitaxel (n=330) or placebo plus paclitaxel (n=335). Randomisation was stratified by geographic region, time to progression from the start of first-line therapy (<6 months versus ≥6 months) and disease measurability. Cyramza at 8 mg/kg or placebo was administered by intravenous infusion every 2 weeks (on days 1 and 15) of a 28-day cycle. Paclitaxel at 80 mg/m2 was administered by intravenous infusion on days 1, 8, and 15 of each 28-day cycle. A majority (75%) of patients randomised in the study received prior platinum and fluoropyrimidine combination therapy without anthracycline. The remainder (25%) received prior platinum and fluoropyrimidine combination therapy with anthracycline. Two-thirds of the patients experienced disease progression while still on first-line therapy (66.8%). Baseline patient demographics and disease characteristics were generally balanced between arms: the median age was 61 years; 71% of patients were male; 61% were Caucasian, 35% Asian; the ECOG PS was 0 for 39% of patients, 1 for 61% of patients; 81% of patients had measurable disease and 79% had gastric cancer; 21% had GEJ adenocarcinoma. The majority of patients (76%) had experienced disease progression within 6 months from the start of first-line therapy. For patients treated with Cyramza plus paclitaxel the median duration of therapy was 19 weeks, and for patients treated with placebo plus paclitaxel the median duration of therapy was 12 weeks. The median relative dose intensity of Cyramza was 98.6% and of placebo was 99.6%. The median relative dose intensity of paclitaxel was 87.7% for the Cyramza plus paclitaxel arm and 93.2% for the placebo plus paclitaxel arm. A similar percentage of patients discontinued treatment due to adverse events: 12% of patients treated with Cyramza plus paclitaxel compared with 11% of patients treated with placebo plus paclitaxel. Post discontinuation systemic anti-cancer therapy was given to 47.9% of patients receiving Cyramza plus paclitaxel and 46.0% of patients receiving placebo plus paclitaxel. Overall survival was statistically significantly improved in patients receiving Cyramza plus paclitaxel compared with those receiving placebo plus paclitaxel (HR 0.807; 95%CI: 0.678 to 0.962; p=0.0169). There was an increase in median survival of 2.3 months in favour of the Cyramza plus paclitaxel arm: 9.63 months in the Cyramza plus paclitaxel arm and 7.36 months in the placebo plus paclitaxel arm. Progression-free survival was statistically significantly improved in patients receiving Cyramza plus paclitaxel compared with those receiving placebo plus paclitaxel (HR 0.635; 95%CI: 0.536 to 0.752; p<0.0001). There was an increase in median PFS of 1.5 months in favour of the Cyramza plus paclitaxel arm: 4.4 months in the Cyramza plus paclitaxel arm and 2.9 months in the placebo plus paclitaxel arm. Objective response rate (complete response [CR] + partial response [PR]) was significantly improved in patients receiving Cyramza plus paclitaxel compared with those receiving placebo plus paclitaxel (Odds ratio 2.140; 95% CI: 1.499 to 3.160; p=0.0001). The ORR in the Cyramza plus paclitaxel arm was 27.9% and in the placebo plus paclitaxel arm was 16.1%. Improvements in OS and PFS were consistently observed in pre-specified subgroups based on age, sex, race and in most other pre-specified subgroups. Efficacy results are shown in Table 4. Table 4: Summary of efficacy data –ITT population Cyramza plus paclitaxel N=330 Placebo plus paclitxel N=335 Overall survival, months     Median (95% CI) 9.6 (8.5, 10.8) 7.4 (6.3, 8.4) Hazard ratio (95% CI) 0.807 (0.678, 0.962) Stratified log-rank p-value 0.0169 Progression free survival, months     Median (95% CI) 4.4 (4.2, 5.3) 2.9 (2.8, 3.0) Hazard ratio (95% CI) 0.635 (0.536, 0.752) Stratified log-rank p-value <0.0001 Objective response rate (CR +PR)     Rate- percent (95% CI) 27.9 (23.3, 33.0) 16.1 (12.6, 20.4) Odd ratio 2.140 (1.449, 3.160) Stratified CMH p-value 0.0001 Abbreviations: CI = confidence interval, CR= complete response, PR= partial response, CMH= Cochran-Mantel-Haenszel Figure 1: Kaplan-Meier curves of overall survival for Cyramza plus paclitaxel versus placebo plus paclitaxel in RAINBOW Figure 2: Kaplan-Meier curves of progression-free survival for Cyramza plus paclitaxel versus placebo plus paclitaxel in RAINBOW REGARD REGARD, a multinational, randomised, double-blind study of Cyramza plus BSC versus placebo plus BSC, was conducted in 355 patients with locally recurrent and unresectable, or metastatic gastric cancer (including GEJ adenocarcinoma) following platinum- or fluoropyrimidine-containing chemotherapy. The primary endpoint was OS and secondary endpoints included PFS. Patients were required to have experienced disease progression during, or within 4 months after the last dose of, first-line therapy for metastatic disease, or during adjuvant treatment or within 6 months after the last dose of adjuvant therapy, and had ECOG PS 0-1. To be included in the study, patients were required to have total bilirubin of ≤ 1.5mg/dl and AST and ALT ≤ 3 times ULN, or ≤ 5 times ULN if liver metastases were present. Patients were randomised in a 2:1 ratio to receive an intravenous infusion of Cyramza 8 mg/kg (n= 238) or placebo (n= 117) every 2 weeks. Randomisation was stratified by weight loss over the prior 3 months (≥ 10% versus < 10%), geographic region, and location of the primary tumour (gastric versus GEJ). Baseline demographics and disease characteristics were balanced. The ECOG PS was 1 for 72% of patients. There were no patients with Child-Pugh B or C liver cirrhosis enrolled in REGARD. 11% of patients treated with Cyramza and 6% of patients on placebo discontinued therapy due to adverse events. Overall survival was statistically significantly improved in patients receiving Cyramza as compared with patients receiving placebo (hazard ratio [HR] 0.776; 95%CI: 0.603 to 0.998; p= 0.0473), corresponding to a 22% reduction in the risk of death and an increase in median survival to 5.2 months for Cyramza from 3.8 months for placebo. Progression-free survival was statistically significantly improved in patients receiving Cyramza as compared with patients receiving placebo (HR 0.483; 95%CI: 0.376 to 0.620; p<0.0001), corresponding to a 52% reduction in the risk of progression or death and an increase in median PFS to 2.1 months for Cyramza from 1.3 months for placebo. Efficacy results are shown in Table 5. Table 5: Summary of efficacy data – Intent to treat (ITT) population Cyramza N=238 Placebo N=117 Overall survival, months     Median (95% CI) 5.2 (4.4, 5.7) 3.8 (2.8, 4.7) Hazard ratio (95% CI) 0.776 (0.603, 0.998) Stratified log-rank p-value 0.0473 Progression free survival, months     Median (95% CI) 2.1 (1.5, 2.7) 1.3 (1.3, 1.4) Hazard ratio (95% CI) 0.483 (0.376, 0.620) Stratified log-rank p-value <0.0001 12-week PFS rate% (95% CI) 40.1 (33.6, 46.4) 15.8 (9.7, 23.3) Abbreviations: CI = confidence interval Figure 3: Kaplan-Meier curves of overall survival for Cyramza versus placebo in REGARD Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≥2 patients Patients with ECOG score ≥2 were excluded from the pivotal studies, therefore the safety and efficacy of Cyramza in this patient population is unknown. Based on limited data from REGARD patients with HER2-positive gastric or GEJ adenocarcinoma and patients previously treated with trastuzumab (in RAINBOW), it is considered unlikely that Cyramza has a detrimental effect or that it has no effect in patients with HER2-positive gastric cancer. Post hoc unstratified subgroup analyses from RAINBOW patients previously treated with trastuzumab (n= 39) suggested a survival benefit in such patients (HR 0.679, 95% CI 0.327, 1.419) and demonstrated a benefit for progression free survival (PFS) (HR 0.399, 95% CI 0.194, 0.822). Immunogenicity Patients in two Phase 3 studies, RAINBOW and REGARD were tested at multiple time-points for anti-drug antibodies (ADAs). Samples were tested from 956 patients: 527 ramucirumab treated patients and 429 control treated patients. Eleven (2.2%) of ramucirumab treated patients and two (0.5%) of control treated patients developed ADAs. None of the patients with ADAs experienced an IRR. No patients had neutralising antibodies to ramucirumab. There is insufficient data to evaluate the effects of ADAs on the efficacy or safety of ramucirumab. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Cyramza in all subsets of the paediatric population in gastric adenocarcinoma (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Following the dose regimen of 8 mg/kg every 2 weeks, the geometric means of ramucirumab Cmin were 49.5 μg/ml (range of 6.3-228 μg/ml) and 74.4 μg/ml (range of 13.8-234 μg/ml) prior to administration of the fourth and seventh dose, respectively of ramucirumab given as a single agent, in serum from patients with advanced gastric cancer. Absorption Cyramza is administered as an intravenous infusion. There have been no studies performed with other routes of administration. Distribution Based on population pharmacokinetic approach PK (PopPK), the mean volume of distribution at steady state for ramucirumab was 5.5L. Biotransformation The metabolism of ramucirumab has not been studied. Antibodies are principally cleared by catabolism. Elimination Based on PopPK, the mean clearance of ramucirumab was 0.014L/hour and the mean half-life was 15 days. Time and dose dependency There was no clear deviation from dose proportionality in pharmacokinetics of ramucirumab from 6 mg/kg to 20 mg/kg. An accumulation ratio of 1.5 was observed for ramucirumab when dosed every 2 weeks. Based on simulations using the PopPK model, steady state would be attained by the sixth dose. Elderly patients Based on PopPK, there was no difference in ramucirumab exposure in patients ≥ 65 years of age compared to patients < 65 years old. Renal impairment No formal studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ramucirumab. Based on PopPK, ramucirumab exposure was similar in patients with mild renal impairment (calculated creatinine clearance [CrCl] ≥ 60 to < 90 ml/min) and moderate renal impairment (CrCl ≥ 30 to <60 ml/min) as to patients with normal renal function (CrCl ≥ 90 ml/min). No data are available from patients with severe renal impairment (CrCl < 30 ml/min). Hepatic impairment No formal studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ramucirumab. Based on PopPK, ramucirumab exposure in patients with mild hepatic impairment (total bilirubin 1.0-1.5 upper limit of normal (ULN) or AST > ULN as defined using NCI criteria) were similar to those in patients with normal hepatic function (total bilirubin and AST ≤ ULN). Ramucirumab has not been studied in patients with moderate or severe hepatic impairment (total bilirubin > 1.5 to ≤ 3.0 ULN and any AST; and total bilirubin > 3.0 ULN and any AST, respectively). Other special populations Based on PopPK, the following covariates were found to have no impact on ramucirumab disposition: age (range, 19 to 86 years), sex (316 males, 181 females), race (337 White and 139 Asians), body weight (range, 31.9 to 133.0 kg), albumin levels (range, 15.5 to 64.8 g/L). Exposure response relationships: RAINBOW Exposure-response analyses indicated that efficacy and specific measures of safety of ramucirumab were correlated with ramucirumab exposure. Efficacy, as measured by improvements in OS and PFS, was associated with increasing ramucirumab exposure range produced by 8 mg/kg ramucirumab given on days 1 and 15 of a 28 day cycle. The incidences of Grade ≥3 hypertension, neutropenia, and leukopenia were also increased with higher ramucirumab exposure. Exposure response relationship: REGARD Based on limited PK data, exposure-response analysis suggested that efficacy of ramucirumab was correlated with ramucirumab exposure. 5.3 Preclinical safety data No animal studies have been performed to test ramucirumab for potential of carcinogenicity or genotoxicity. The target organs identified in repeated dose cynomolgus monkey toxicity studies were kidney (glomerulonephritis), bone (thickening and abnormal endochondral ossification of the epiphyseal growth plate) and female reproductive organs (decreased weight of ovaries and uterus). A minimal grade of inflammation and/or mononuclear cell infiltration was seen in several organs. Reproductive toxicity studies with ramucirumab have not been performed, however, animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryo-foetal development, and postnatal development. Based on ramucirumab's mechanism of action, it is likely that in animals, ramucirumab will inhibit angiogenesis and result in adverse effects on fertility (ovulation), placental development, developing foetuses and postnatal development. A single dose of ramucirumab did not impair wound healing in monkeys using a full-thickness incisional model. 6. Pharmaceutical particulars 6.1 List of excipients Histidine Histidine monohydrochloride Sodium chloride Glycine (E640) Polysorbate 80 (E433) Water for injections 6.2 Incompatibilities Cyramza should not be administered or mixed with dextrose solutions. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life Unopened vial 3 years. After dilution When prepared as directed, infusion solutions of Cyramza contain no antimicrobial preservatives. Chemical and physical in-use stability of Cyramza in sodium chloride 9 mg/ml (0.9%) solution for injection has been demonstrated for 24 hours at 2 °C to 8 °C or for 4 hours at 25 °C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions. 6.4 Special precautions for storage Store in a refrigerator (2 °C to 8 °C ). Do not freeze. Keep the vial in the outer carton in order to protect from light. For storage conditions after dilution of the medicinal product, see section 6.3. 6.5 Nature and contents of container 10 ml solution in a vial (Type I glass) with a chlorobutyl rubber stopper, an aluminium seal and a polypropylene cap. 50 ml solution in a vial (Type I glass) with a chlorobutyl rubber stopper, an aluminium seal and a polypropylene cap. Pack of 1 vial of 10 ml. Pack of 2 vials of 10 ml. Pack of 1 vial of 50 ml. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Do not shake the vial. Prepare the infusion solution using aseptic technique to ensure the sterility of the prepared solution. Each vial is intended for single use only. Inspect the content of the vials for particulate matter and discolouration (the concentrate for solution for infusion should be clear to slightly opalescent and colourless to slightly yellow without visible particles) prior to dilution. If particulate matter or discolouration is identified, discard the vial. Calculate the dose and volume of ramucirumab needed to prepare the infusion solution. Vials contain either 100 mg or 500 mg as a 10 mg/ml solution of ramucirumab. Only use sodium chloride 9 mg/ml (0.9%) solution for injection as a diluent. In case of prefilled intravenous infusion container usage Based on the calculated volume of ramucirumab, remove the corresponding volume of sodium chloride 9 mg/ml (0.9%) solution for injection from the prefilled 250 ml intravenous container. Aseptically transfer the calculated volume of ramucirumab to the intravenous container. The final total volume in the container should be 250 ml. The container should be gently inverted to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medicinal products. In case of empty intravenous infusion container usage Aseptically transfer the calculated volume of ramucirumab into an empty intravenous infusion container. Add a sufficient quantity of sodium chloride 9 mg/ml (0.9%) solution for injection to the container to make the total volume 250 ml. The container should be gently inverted to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medicinal products. Parenteral medicinal products should be inspected visually for particulate matter prior to administration. If particulate matter is identified, discard the infusion solution. Discard any unused portion of ramucirumab left in a vial, as the product contains no antimicrobial preservatives. Administer via infusion pump. A separate infusion line with a protein sparing 0.22 micron filter must be used for the infusion and the line must be flushed with sodium chloride 9 mg/ml (0.9%) solution for injection at the end of the infusion. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Eli Lilly Nederland B.V. Grootslag 1-5 NL-3991 RA, Houten The Netherlands 8. Marketing authorisation number(s) Cyramza 10 ml Vial (1 Vial):       EU/1/14/957/001 Cyramza 10 ml Vial (2 Vials):     EU/1/14/957/002 Cyramza 50 ml Vial (1 Vial):       EU/1/14/957/003 9. Date of first authorisation/renewal of the authorisation 19 December 2014 10. Date of revision of the text 31 August 2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 包装规格 欧洲包装 Cyramza 1x10ml(10mg/ml) Cyramza 1x 50ml(10mg/ml) 美国包装 CYRAMZA  100mg/10mL (10mg/mL) 00002-7669-01 100mg X 1 single-use vial CYRAMZA  500mg/50mL (10mg/mL) 00002-7678-01 500mg X 1 single-use vial 单抗Cyramza获美国FDA批准第3个适应症：非小细胞肺癌 2014年12月18日，抗癌药物Cyramza（ramucirumab）收获了FDA的第3个适应症。具体而言，FDA已批准Cyramza联合多西他赛（docetaxel，一种化疗药物），用于既往经含铂化疗治疗后病情恶化的转移性非小细胞肺癌（NSCLC）患者的治疗。此前，FDA已分别于今年4月和11月批准Cyramza及Cyramza+紫杉醇化疗联合疗法用于晚期或转移性胃癌和胃食管交界腺癌（GEJA）的治疗。另外，礼来已计划于2015年上半年向FDA提交Cyramza/紫杉醇组合疗法治疗结直肠癌的上市申请。 Cyramza是一种血管生成抑制剂，能够阻断肿瘤的血液供应，该药被认为是礼来研发管线中最重要的产品之一。不过，Cyramza的临床项目并不都是一帆风顺。去年秋天，Cyramza在乳腺癌III期临床中以失败告终，未能达到改善无进展生存期（PFS）的主要终点。 Cyramza非小细胞肺癌（NSCLC）适应症的获批，是基于III期REVEL研究的数据。该项研究调查了Cyramza联合化疗用于非小细胞肺癌（NSCLC）的二线治疗。数据表明，与安慰剂+多西他赛化疗相比，Cyramza+多西他赛化疗显著改善了总生存期（OS：10.5个月 vs 9.1个月，p=0.023；死亡风险降低14%）、显著改善了无进展生存期（PFS：4.5个月 vs 3.0个月，p＜0.001；疾病恶化风险降低24%）、显著改善了客观缓解率（ORR：23% vs 14%，p＜0.0001）。该研究是首个证明一种生物制剂联合化疗用于二线治疗时可改善NSCLC总生存期的III期研究。 在美国，肺癌是癌症致死的首要病因，其中非小细胞肺癌（NSCLC）占到了总病例的85%。据估计，约有一半的NSCLC患者正接受二线治疗。尽管目前有可用的药物，但仍需要新的二线治疗药物。 关于Cyramza（ramucirumab）： ramucirumab是一种全人源化IgG1单克隆抗体，是一种受体拮抗剂，靶向结合于血管内皮生长因子（VEGF）受体2的胞外域，从而阻断血管内皮生长因子配体（VEGF-A，-C，-D）的相互作用，并抑制受体激活。 Ramucirumab由礼来于2008年耗资65亿美元收购ImClone公司后获得，目前正在开展相关临床试验，评估该药作为单药疗法及与其他抗癌药物的联合疗法，用于治疗乳腺癌、胃癌、非小细胞肺癌、大肠癌、肝癌、膀胱癌、尿道癌、输尿管癌、肾盂癌、前列腺癌、卵巢癌、多形性成胶质细胞瘤。目前乳腺癌、大肠癌、胃癌、肝癌、肺癌均处于III期临床开发。