近日，Opdivo（Nivolumab）通过加速审批程序获美国食品药品监督管理局（以下简称FDA）批准，用于治疗其他药物无效的无法切除（无法通过手术切除肿瘤）或转移性（晚期）黑色素瘤患者的新药。
Opdivo通过抑制细胞表面的PD-1蛋白起作用，因为PD-1蛋白阻止人体免疫系统攻击黑色素瘤。Opdivo的适用人群是接受过Ipilimumab治疗的黑色素瘤患者以及具有BRAF V600基因突变且接受过Ipilimumab和BRAF抑制剂治疗的黑色素瘤患者。
黑色素瘤是美国第五大最常见癌症，它形成于产生皮肤色素的人体黑色素细胞。据美国国家癌症研究所预计，2104年美国将有76,100名新增黑色素瘤病例，将有9,710人死于黑色素瘤。
FDA的药品评价和研究中心血液学和肿瘤学产品室主任Richard Pazdur，医学博士说：“Opdivo是自2011年被FDA批准的第七个新黑色素瘤药物。”“根据我们肿瘤免疫学和分子学通路增加了解继续发展和批准新颖治疗正在改变对严重和危及生命疾病治疗范式。”
临床试验评估了Opdivo的安全性。临床试验中，使用Opdivo治疗的患者总共268位，使用化疗方法的患者共102位。经评估，Opdivo的常见副作用有：皮疹、皮肤瘙痒、咳嗽、上呼吸道感染、体液潴留（水肿）。而最严重的副作用是严重的免疫介导的器官损伤，侵及的健康器官包括肺、结肠、肝、肾、内分泌腺体等。
批准日期： 2014年12月22日；公司：施贵宝公司
OPDIVO(nivolumab)注射液，为静脉使用
美国初次批准：2014
适应证和用途
OPDIVO是一个人程序死亡受体-1(PD-1)阻断抗体适用为the 治疗of患者有不能切除货转移黑色素瘤和易普利姆玛[ipilimumab]和，如BRAF V600突变阳性，一种BRAF抑制剂后疾病进展。
这个适应症是根据肿瘤反应率和反应的持久性加速批准下被批准。对这个适应证的继续批准可能取决于验证和在验证试验中临床获益的描述。
剂量和给药方法
每2周历时60分钟静脉输注给予3mg/kg。
剂型和规格
注射液:40mg/4mL和100mg/10mL溶液在一次性小瓶中。
禁忌证
无。
警告和注意事项
免疫介导不良反应：根据反应严重程度给予糖皮质激素。
⑴ 免疫介导肺炎：对中度不给和对严重或危及生命肺炎永久终止。
⑵ 免疫介导结肠炎：不给对中度或严重和对危及生命结肠炎永久终止。
⑶ 免疫介导肝炎：监视对肝功能中变化。对中度不给和对严重或危及生命转氨酶或总胆红素升高永久终止。
⑷ 免疫介导肾炎和肾功能不全：监视在肾功能中变化。对中度不给和对严重或危及生命血清肌酐升高永久终止。
⑸ 免疫介导甲状腺功能减退和甲状腺功能亢进：监视甲状腺功能变化。需要时开始甲状腺激素替代.
⑹ 胚胎胎儿毒性：可能致胎儿危害。忠告对胎儿潜在风险和使用有效避孕。
不良反应
最常见不良反应(≥20%)是皮疹。
在特殊人群中使用
⑴ 哺乳：终止哺乳。

Bristol-Myers Squibb Receives Accelerated Approval of Opdivo (nivolumab) from the U.S. Food and Drug Administration
First approval of Opdivo in the United States
 U.S. Food and Drug Administration (FDA) approved Opdivo (nivolumab) injection, for intravenous use. Opdivo is a human programmed death receptor-1 (PD-1) blocking antibody indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Metastatic melanoma is the deadliest form of skin cancer, and despite recent advances, there are limited treatment options available for patients who have been previously treated with approved agents.
Opdivo is associated with immune-mediated: pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism and hyperthyroidism, other adverse reactions; and embryofetal toxicity. Please see the Important Safety Information section below.
Opdivo Delivered A Response Rate of 32%
Opdivo is the only PD-1 that has demonstrated efficacy in a Phase 3, pivotal clinical trial with advanced melanoma in patients who had been previously treated and progressed with Yervoy and, if BRAF mutation positive, a BRAF inhibitor. The efficacy of Opdivo was evaluated based on a single-arm, non-comparative planned interim analysis of the first 120 patients who received Opdivo with a minimum of 6 months follow-up in the Phase 3 CheckMate -037 trial.
Opdivo achieved a 32% (95% CI: 23, 41) response rate (38/120) with a dosing strength and frequency of 3 mg/kg intravenously over 60 minutes every 2 weeks. 3% of patients (4/120) achieved a complete response, and 28% (34/120) achieved a partial response. Of 38 patients with responses, 33 patients (87%) had ongoing responses with durability of response ranging from 2.6+ to 10+ months, which included 13 patients with ongoing responses of 6 months or longer. Responses to Opdivo were demonstrated in both patients with and without BRAF mutation.
The safety profile of Opdivo has been demonstrated in the pivotal, Phase 3 CheckMate-037 trial. Serious adverse reactions occurred in 41% of patients receiving Opdivo. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving Opdivo. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving Opdivo were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common adverse reaction (≥20%) reported with Opdivo was rash (21%). Please see the Important Safety Information section below.
“The approval of Opdivo gives patients and physicians an important new treatment option for a population where they were once very limited,” said Jeffrey S. Weber, MD, Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center. “For the first time, a PD-1 blocking antibody has shown a response rate of 32% in a Phase 3 randomized clinical trial of patients with unresectable or metastatic melanoma, who have progressed following first line therapy.” Efficacy was evaluated in a single-arm, non-comparative, planned interim analysis of the first 120 patients who received Opdivo in the CheckMate -037 trial in whom the minimum duration of follow up was 6 months.
“The emergence of effective immuno-oncology therapies that are capable of successfully treating metastatic melanoma has reinvigorated the field of cancer immunology with an optimism that immune based treatments will play a central role in therapeutic strategies for cancer patients,” said Jill O’Donnell-Tormey, Ph.D., CEO and director of Scientific Affairs at the Cancer Research Institute, a nonprofit organization dedicated to advancing the science of cancer immunology.
About the CheckMate -037 Trial
CheckMate -037 was a randomized, Phase 3 trial evaluating Opdivo 3 mg/kg (n=268), administered every two weeks, or chemotherapy (n=102) (investigator's choice of either single-agent dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks) in patients with advanced melanoma who had been previously treated and progressed with Yervoy and, if BRAF mutation positive, a BRAF inhibitor. No premedication is required with Opdivo.
The primary objective of this analysis of the CheckMate -037 trial was Objective Response Rate (ORR). CheckMate -037 included 90 participating trial sites in 14 countries, and included both institutional and community practice centers. The clinical study is ongoing to determine whether there is an overall survival benefit.
In the Opdivo treated patients (n=120), 76% of patients had M1C disease, 18% of patients had a history of brain metastases, and 56% of patients had elevated LDH levels. The median age of patients was 58. 22% of patients were BRAF V600 mutation positive.
Distinct Immune Pathway
Opdivo is approved for use in patients previously treated with Yervoy. Although both treatments are immunotherapies, PD-1 and CTLA-4 are distinct pathways.
IMPORTANT SAFETY INFORMATION
Immune-Mediated Pneumonitis
•Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 574 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.9% (5/574) of patients receiving OPDIVO; no cases occurred in Trial 1. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.
Immune-Mediated Colitis
•In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.
Immune-Mediated Hepatitis
•In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.
Immune-Mediated Nephritis and Renal Dysfunction
•In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.
Immune-Mediated Hypothyroidism and Hyperthyroidism
•In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.
Other Immune-Mediated Adverse Reactions
•In Trial 1, the following clinically significant, immune-mediated adverse reactions occurred in less than 1% of OPDIVO-treated patients: pancreatitis, uveitis, demyelination, autoimmune neuropathy, adrenal insufficiency, and facial and abducens nerve paresis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillian-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone- replacement therapy.
Embryofetal Toxicity
•Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO.
Lactation
•It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment.
Serious Adverse Reactions
•Serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.
Common Adverse Reactions
The most common adverse reaction (≥20%) reported with OPDIVO was rash (21%).
Please see US Full Prescribing Information for OPDIVO.
About Metastatic Melanoma
Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease, and occurs when cancer spreads beyond the surface of the skin to the other organs, such as the lymph nodes, lungs, brain or other areas of the body. The incidence of melanoma has been increasing for at least 30 years. In 2014, an estimated 76,100 melanoma cases will be diagnosed in the U.S. Melanoma is mostly curable when treated in its early stages. However, in its late stages, the average survival rate is just 6 months with a 1-year survival of 25.5%, making it one of the most aggressive forms of cancer.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit www.bms.com, or follow us on Twitter at http://twitter.com/bmsnews