2015年7月20日,PD-1/PD-L1免疫治疗领域的王者——百时美施贵宝（BMS）在欧洲监管方面再传特大喜讯，该公司PD-1免疫疗法Opdivo（nivolumab）喜获欧盟批准，用于既往已治疗过的局部晚期或转移性鳞状（SQ）非小细胞肺癌（NSCLC）患者。
此次批准，标志着Opdivo成为过去10多年来，鳞状非小细胞肺癌（SQ-NSCLC）领域的首个重大治疗进展，该药同时也成为首个也是唯一一个在既往已治疗转移性SQ-NSCLC群体中展现出总生存（OS）利益的PD-1免疫疗法。
Opdivo的批准，是基于2项研究（Checkmate-017，-063）的积极顶线数据。Checkmate-017是一项里程碑III期研究，在含铂化疗方案治疗期间或治疗后病情恶化的晚期鳞状非小细胞肺癌（SQ-NSCLC）患者中开展，将Opdivo（3mg/kg体重，每2周一次静脉注射）与标准护理多西他赛（75mg/㎡，每3周一次静脉注射）进行了对比。
数据显示，Opdivo在横跨所有终点均表现出相对于多西他赛化疗的显著优越性；总生存（OS）方面，Opdivo使一年生存率几乎提高一倍（42% vs 24%），死亡风险显著降低41%，中位总生存期提高3.2个月（9.2个月 vs 6.0个月）。此外，在无进展生存期（PFS）和总缓解率（ORR）方面，与多西他赛相比，Opdivo均表现出临床意义的统计学显著改善，而且治疗受益独立于PD-L1表达状态。Checkmate-063是一项II期研究，数据显示，Opdivo治疗组预计的一年生存率为41%，中位总生存期（OS）为8.2个月。研究中，Opdivo安全性与以往临床一致，相比多西他赛更有利。
在欧洲，肺癌的发病率和死亡率都在上升，目前约占所有癌症死亡病例的20%。非小细胞肺癌（NSCLC）是一种最常见的肺癌，约占肺癌病例的85%。鳞状非小细胞肺癌（SQ-NSCLC）占所有肺癌病例的25-30%。经化疗治疗后病情复发或恶化的NSCLC患者，临床治疗选择十分有限，而且预后极差，在全球范围内的5年生存率仅为2%左右。
当前，PD-1/PD-L1免疫竞赛异常激烈，市场峰值高达350亿美元，该领域的佼佼者包括默沙东、百时美施贵宝、罗氏、阿斯利康。此次竞赛中，百时美遥遥领先，其PD-1免疫疗法Opdivo在全球三大主要市场（美日欧）均已收获批文：日本（黑色素瘤）、美国（黑色素瘤，非小细胞肺癌）、欧洲（黑色素瘤，非小细胞肺癌）。默沙东则紧跟其后，其PD-1免疫疗法Keytruda在美国已收获黑色素瘤适应症，有望10月收获非小细胞肺癌适应症；欧洲方面，Keytruda很可能7月收获黑色素瘤适应症。而罗氏atezolizumab和阿斯利康MEDI4736目前尚未收获任何适应症。医药市场调研机构eva luatePharma预测，Opdivo将成为PD-1/PD-L1领域最成功的免疫疗法，2020年销售额将达到88亿美元，而Keytruda也将达到55亿美元，罗氏atezolizumab峰值仅为20亿美元。
PD-1/PD-L1免疫疗法是当前备受瞩目的新一类抗癌免疫疗法，旨在利用人体自身的免疫系统抵御癌症，通过阻断PD-1/PD-L1信号通路使癌细胞死亡，具有治疗多种类型肿瘤的潜力。
目前，各大巨头正在火速推进各自的临床项目，调查单药疗法和组合疗法用于多种癌症的治疗，以彻底发掘该类药物的最大临床潜力。
Important Safety Information for
OPDIVO® (nivolumab)
OPDIVO® can cause problems that can sometimes become serious or life-threatening and can lead to death. Serious side effects may include lung problems (pneumonitis); intestinal problems (colitis) that can lead to tears or holes in your intestine; liver problems (hepatitis); hormone gland problems (especially the thyroid, pituitary, adrenal glands, and pancreas); kidney problems, including nephritis and kidney failure; skin problems; inflammation of the brain (encephalitis); problems in other organs; and severe infusion reactions. The most common side effects of OPDIVO in people with non-small cell lung cancer include: feeling tired; pain in muscles, bones, and joints; decreased appetite; cough; and constipation.
OPDIVO is a medicine that may treat your lung cancer by working with your immune system. OPDIVO can cause your immune system to attack normal organs and tissues in many areas of your body and can affect the way they work. These problems can sometimes become serious or life-threatening and can lead to death. These problems may happen anytime during treatment or even after your treatment has ended.
Serious side effects may include:
•Lung problems (pneumonitis). Symptoms of pneumonitis may include: new or worsening cough; chest pain; and shortness of breath.
•Intestinal problems (colitis) that can lead to tears or holes in your intestine. Signs and symptoms of colitis may include: diarrhea (loose stools) or more bowel movements than usual; blood in your stools or dark, tarry, sticky stools; and severe stomach area (abdomen) pain or tenderness.
•Liver problems (hepatitis). Signs and symptoms of hepatitis may include: yellowing of your skin or the whites of your eyes; severe nausea or vomiting; pain on the right side of your stomach area (abdomen); drowsiness; dark urine (tea colored); bleeding or bruising more easily than normal; and feeling less hungry than usual.
•Hormone gland problems (especially the thyroid, pituitary, adrenal glands, and pancreas). Signs and symptoms that your hormone glands are not working properly may include: headaches that will not go away or unusual headaches; extreme tiredness; weight gain or weight loss; dizziness or fainting; changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness; hair loss; feeling cold; constipation; voice gets deeper; and excessive thirst or lots of urine.
•Kidney problems, including nephritis and kidney failure. Signs of kidney problems may include: decrease in the amount of urine; blood in your urine; swelling in your ankles; and loss of appetite.
•Skin problems. Signs of these problems may include: rash; itching; skin blistering; and ulcers in the mouth or other mucous membranes.
•Inflammation of the brain (encephalitis). Signs and symptoms of encephalitis may include: headache; fever; tiredness or weakness; confusion; memory problems; sleepiness; seeing or hearing things that are not really there (hallucinations); seizures; and stiff neck.
•Problems in other organs. Signs of these problems may include: changes in eyesight; severe or persistent muscle or joint pains; and severe muscle weakness.
Getting medical treatment right away may keep these problems from becoming more serious.
Your healthcare provider will check you for these problems during treatment. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment, if you have severe side effects.
OPDIVO can cause serious side effects, including:
•Severe infusion reactions. Tell your doctor or nurse right away if you get these symptoms during an infusion of OPDIVO: chills or shaking; itching or rash; flushing; difficulty breathing; dizziness; fever; and feeling like passing out.
Pregnancy and Nursing:
Tell your healthcare provider if you are pregnant or plan to become pregnant. OPDIVO can harm your unborn baby. Females who are able to become pregnant should use an effective method of birth control during and for at least 5 months after the last dose of OPDIVO. Talk to your healthcare provider about birth control methods that you can use during this time. Tell your healthcare provider right away if you become pregnant during treatment. Before receiving treatment, tell your healthcare provider if you are breastfeeding or plan to breastfeed. It is not known if OPDIVO passes into your breast milk. Do not breastfeed during treatment.
Tell your healthcare provider about:
•Your health problems or concerns if you have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus; have had an organ transplant; have lung or breathing problems; have liver problems; or have any other medical conditions.
•All the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
The most common side effects of OPDIVO in people with non-small cell lung cancer include: feeling tired; pain in muscles, bones, and joints; decreased appetite; cough; and constipation. |
