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最新研究结果振奋人心：Nivolumab明显提高非小细胞肺癌-鳞癌生存率
继施贵宝PD-1抑制剂Nivolumab（商品名Opdivo）作为二线药物治疗黑色素瘤取得良好疗效后，该公司研究人员在该药治疗晚期肺鳞癌研究中取得突破，三期临床已经顺利结束并取得非常好的疗效，即将转入4期临床。该药是一种单克隆抗体，它通过激活和加强人体自身免疫系统来抵御病毒细胞的入侵，目前主要用于治疗癌症，自身免疫性疾病和器官移植到抗排斥反应。将单克隆抗体与看癌药物或者毒素结合起来，就成为威力强大的抗体生物导弹。
PD-1抑制剂已经在6、7种癌症显示疗效，但最大的成就当属肺癌。Opdivo和Keytruda都在肺癌显示非常显著的疗效，Opdivo已经在三期临床显示生存优势，今年可望批准上市。
在2015年1月11日该公司发布的公告中，一项随机对比多西他赛作为二线治疗方案治疗进展或者有转移的晚期非小细胞肺癌-鳞癌的研究中取得非常满意疗效，因为疗效确切因此研究者终止了该研究，并将转入四期临床研究。具体的研究结果数据并未显示。
该药最常见的副作用是皮疹。其他的副作用包括免疫反应引起的肺炎，肠炎，肝炎，肾炎及肾功能失常；甲减及甲亢均有可能；不建议孕妇服用，并建议患者在服药期间避孕，也不建议服用该药物的患者哺乳。
约有41%的患者出现较为严重的副作用，达到3级和4级副作用的约占42%。最常见的包括腹痛，低钠血症及一些酶指标偏高。
Nivolumab的研制去年被认为是癌症治疗领域里一件重量级的事件，这是基于早先的研究结果，该结果表明Nivolumab对多种癌症的持续肿瘤反应率达到20%-30%。用专家的话讲，这种新药突破了持续肿瘤反应率在10%-15%的限制，这种限制在过去30年里一直阻碍着癌症免疫治疗的发展。
屈立新教授点评：
一种药物同时对于三种癌症有效确实很了不起。这也是继非小细胞肺癌-腺癌出现多种靶向药物并取得良好疗效后，终于出现了一种鳞癌的特效药物了，而且估计很快将会进入市场。因为该药已经进入市场用于治疗黑色素瘤，只是三期临床刚证实对于肺鳞癌也有显著效果。该研究是通过将二线治疗肺鳞癌化疗药物多西他赛作为对照的并取得明显的优势显得尤为珍贵。
该药是否与常规治疗如放疗，微创消融治疗相结合？效果如何？多长时间出现耐药？是否能取代化疗？因为化疗，放疗都是抑制人体免疫力的，而消融治疗如射频消融冷冻消融-氩氦刀对于人体的免疫系统影响不大甚至因为破坏了肿瘤细胞而出现免疫增强。这种增强作用能否被药物放大？
这些都是有待于临床应用证实的问题。不过该药的出现确实应该为非小细胞肺癌-鳞癌的治疗带来了很大的希望，有望成为继肺腺癌靶向药物易瑞沙特罗凯后又一里程碑式的药物！
原文如下：
CheckMate -017， A Phase 3 Study of Opdivo (Nivolumab) Compared to Docetaxel in Patients with Second-Line Squamous Cell Non-small Cell Lung Cancer， Stopped Early
Opdivo demonstrates superior overall survival in this Phase 3 trial
Sunday， January 11， 2015 9：06 pm EST
Dateline：
PRINCETON， N.J.
Public Company Information：
NYSE：
BMY
PRINCETON， N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE：BMY) today announced that an open-label， randomized Phase 3 study evaluating Opdivo versus docetaxel in previously treated patients with advanced， squamous cell non-small cell lung cancer (NSCLC) was stopped early because an assessment conducted by the independent Data Monitoring Committee (DMC) concluded that the study met its endpoint， demonstrating superior overall survival in patients receiving Opdivo compared to the control arm. The company will share these data – which for the first time indicate a survival advantage with an anti-PD1 immune checkpoint inhibitor in lung cancer – with health authorities.
CheckMate -017 investigators are being informed of the decision to stop the comparative portion of the trial. Bristol-Myers Squibb is working to ensure that eligible patients will be informed of the opportunity to continue or start treatment with Opdivo in an open-label extension as part of the company’s commitment to providing patient access to Opdivo， and characterizing long-term survival. The company will complete a full evaluation of the final CheckMate -017 data and work with investigators on the future presentation and publication of the results.
About the Study
CheckMate -017 is a Phase 3， open-label， randomized study of Opdivo versus docetaxel in previously treated patients with advanced or metastatic squamous cell NSCLC. The trial randomized 272 patients to receive either nivolumab 3 mg/kg intravenously every two weeks or docetaxel 75 mg/m2 intravenously every three weeks. The primary endpoint is overall survival. Secondary endpoints include objective response rate and progression free survival.
About Lung Cancer
Lung cancer is the leading cause of cancer deaths globally， resulting in more than 1.5 million deaths each year according the World Health Organization. NSCLC is one of the most common types of the disease and accounts for approximately 85 percent of cases. Survival rates vary depending on the stage and type of the cancer when it is diagnosed. Globally， the five-year survival rate for Stage I NSCLC is between 47 and 50 percent; for Stage IV NSCLC， the five-year survival rate drops to two percent. Historically， the expected one-year survival rate for third-line squamous cell NSCLC patients is approximately 5.5% - 18%.
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 research 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.
About Opdivo
Bristol-Myers Squibb has a broad， global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 7，000 patients have been enrolled worldwide.
In the U.S.， Opdivo is 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.
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%).
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