膀胱癌免疫疗法Imfinzi（durvalumab）获美国FDA加速批准，治疗晚期或转移性尿路上皮癌患者
近日，美国FDA加速批准阿斯利康（AstraZeneca）的Imfinzi（durvalumab）上市，治疗晚期或转移性尿路上皮癌患者。这些患者在先前的铂类化疗中或化疗后病情依旧出现进展，或在接受辅助或新辅助铂类化疗（neoadjuvant or adjuvant treatment with platinum-containing chemotherapy）的12个月内疾病出现进展。值得一提的是，本次批准较预期快了将近6周。
尿路上皮癌是最常见的膀胱癌类型，占了膀胱癌病例总数的90%。在美国，膀胱癌的发病率在所有癌症中排名第五。它也是男性发病率最高的十大癌症之一。根据美国癌症学会（American Cancer Society）的数据，如果得到及时的诊断与治疗，早期膀胱癌患者的五年生存率可高达98%。一旦疾病进展到晚期并发生转移，他们的五年生存率就会锐减为15%，预后情况相当不乐观。因此，这些患者也需要更多治疗方案，来控制病情。
durvalumab属于近期火热的肿瘤免疫疗法药物。作为一种针对PD-L1蛋白的单克隆抗体，它能够结合肿瘤表面表达的PD-L1蛋白，抑制它们与T细胞表面的PD-1蛋白结合。因此，肿瘤细胞就无法利用PD-L1/PD-1途径来逃避免疫系统的追杀。Durvalumab也正是利用这一机理，起到激活免疫系统杀伤肿瘤的效果。
批准日期：2017年5月2日  公司：AstraZeneca
IMFINZI™（durvalumab）注射,用于静脉注射
美国初步批准：2017年
作用机制
程序性细胞死亡配体-1（PD-L1）的表达可以通过炎症信号（例如IFN-γ）诱导，并且可以在肿瘤微环境中的肿瘤细胞和肿瘤相关免疫细胞上表达。 PD-L1通过与PD-1和CD80（B7.1）的相互作用阻断T细胞功能和活化。 通过结合其受体，PD-L1降低细胞毒性T细胞活性，增殖和细胞因子产生。
Durvalumab是阻断PD-L1与PD-1和CD80（B7.1）相互作用的人免疫球蛋白G1卡帕（IgG1κ）单克隆抗体。 阻断PD-L1/PD-1和PD-L1/CD80相互作用释放免疫应答的抑制，而不诱导抗体依赖性细胞介导的细胞毒性（ADCC）。
与durvalumab的PD-L1阻断导致体外增加的T细胞活化并降低共同移植的人肿瘤和免疫细胞异种移植小鼠模型中的肿瘤大小。
适用范围及用途
IMFINZI是一种程序性死亡配体1（PD-L1）阻断抗体，用于治疗患者：
•局部晚期或转移性尿路上皮癌：
•含铂化疗期间或之后患有疾病进展。
•在含铂化疗的新辅助或辅助治疗后12个月内有疾病进展。
该指征根据肿瘤反应率和反应持续时间加快批准。继续批准该指征可能取决于确认试验中临床获益的验证和描述。
剂量和管理
•每2周60分钟内静脉输注10mg/kg。
•静脉注射前先稀释。
剂量形式和强度
•注射：500mg/10mL（50mg/mL）溶液在单剂量小瓶中。
•注射液：单剂量小瓶中的120mg/2.4mL（50mg/mL）溶液。
禁忌症
没有。
警告和注意事项
•免疫介导性肺炎：中止和永久中止严重或危及生命的肺炎。
•免疫介导的肝炎：监测肝功能的变化。暂停中度和永久停止严重或危及生命的转氨酶或总胆红素升高。
•免疫介导性结肠炎：中止和永久中止严重或危及生命的结肠炎。
•免疫介导的内分泌病：
•肾上腺不全，下咽炎或1型糖尿病：中度，严重或危及生命。
•免疫介导性肾炎：监测肾功能的变化。暂停中度和永久停止严重或危及生命的肾炎。
•感染：禁止严重或危及生命的感染。
•输液相关反应：中断输注或缓慢输注温和或中等并永久停止严重或危及生命的输液相关反应。
•胚胎 - 胎儿毒性：可引起胎儿的伤害。向女性提供潜在的胎儿潜在生殖潜力，并使用有效的避孕措施。
不良反应
最常见的不良事件（报告≥15％的患者）是疲劳，肌肉骨骼疼痛，便秘，食欲降低，恶心，外周水肿和尿路感染。
要报告可疑的不良反应，请联系阿斯利康（AstraZeneca）1-800-236-9933或FDA（1-800-FDA-1088）或WWW.FDA.GOV/MEDWATCH。
在特定人口中使用
哺乳：建议不要母乳喂养。
提供/存储和处理
IMFINZI（durvalumab）注射液是一种透明的乳白色无色至微黄色溶液，在含有一个单剂量小瓶的纸盒中提供：
•500mg/10mL（NDC 0310-4611-50）
•120mg/2.4mL（NDC 0310-4500-12）
储存在原装纸箱中的2°C至8°C（36°F至46°F）的冰箱中，以防止光照。
不要冻结 不要动摇

Imfinzi will be available in single-dose vials in 500mg/10mL or 120mg/2.4mL strengths

PD-L1 expression: The role of programmed cell death ligand-11
Expression of programmed cell death ligand-1 (PD-L1) can be induced by inflammatory signals (eg, IFN-gamma) and can be expressed on both tumor cells and tumor-associated immune cells in tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation, and cytokine production.
Although testing is not required, knowing your patient's PD-L1 expression status may aid in treatment selection and help manage patient
IMFINZI mechanism of action1
Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity (ADCC).
PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models.
Important Safety Information
There are no contraindications for IMFINZITM (durvalumab).
Monitor patients for clinical signs and symptoms of immune-mediated pneumonitis, hepatitis, colitis or diarrhea, endocrinopathies, nephritis, rash or dermatitis, and other immune-mediated adverse reactions. Please refer to the full Prescribing Information for important dose management information specific to adverse reactions.
Immune-Mediated Pneumonitis
In the combined safety database (n=1414), immune-mediated pneumonitis occurred in 32 patients (2.3%), including 1 fatal case (0.1%) and 6 Grade 3–4 cases (0.4%). In Study 1 (n=182), 1 patient (0.5%) died from immune-mediated pneumonitis. Monitor patients for signs and symptoms of pneumonitis and evaluate with radiographic imaging when suspected. Administer corticosteroids for ≥Grade 2 pneumonitis. Withhold IMFINZI for Grade 2 pneumonitis; permanently discontinue for Grade 3–4 pneumonitis.
Immune-Mediated Hepatitis
In the combined safety database (n=1414), immune-mediated hepatitis occurred in 16 patients (1.1%), including 1 fatal case (<0.1%) and 9 Grade 3 cases (0.6%). Grade 3–4 elevations in ALT occurred in 40/1342 patients (3.0%), AST in 58/1336 patients (4.3%), and total bilirubin in 37/1341 patients (2.8%). In Study 1 (n=182), 1 patient (0.5%) died from immune-mediated hepatitis, and 2 patients (1.1%) experienced immune-mediated hepatitis, including 1 Grade 3 case (0.5%). Monitor patients for abnormal liver tests in each cycle during treatment with IMFINZI. Administer corticosteroids and withhold IMFINZI for Grade 2–3 ALT or AST >3–5X ULN or ≤8X ULN or total bilirubin >1.5–3X ULN or ≤5X ULN. Permanently discontinue IMFINZI in patients with Grade 3 ALT or AST >8X ULN or total bilirubin >5X ULN, or in patients with concurrent ALT or AST >3X ULN and total bilirubin >2X ULN with no other cause.
Immune-Mediated Colitis
In the combined safety database (n=1414), immune-mediated colitis or diarrhea occurred in 18 patients (1.3%), including 1 Grade 4 case (<0.1%) and 4 Grade 3 cases (0.3%). In Study 1 (n=182), 23 patients (12.6%) experienced colitis or diarrhea, including 2 Grade 3–4 cases (1.1%). Monitor patients for signs and symptoms of colitis or diarrhea. Administer corticosteroids for ≥Grade 2 colitis or diarrhea. Withhold IMFINZI for Grade 2 colitis or diarrhea; permanently discontinue for Grade 3–4 colitis or diarrhea.
Immune-Mediated Endocrinopathies
Immune-mediated thyroid disorders, adrenal insufficiency, type 1 diabetes mellitus and hypophysitis/hypopituitarism have occurred with IMFINZI. Monitor patients for clinical signs and symptoms of endocrinopathies. For Grade 2–4 endocrinopathies (except hypothyroidism) withhold dose until clinically stable and offer symptomatic management for hyperthyroidism. For Grade 2–4 hypothyroidism, initiate thyroid hormone replacement as needed
Immune-mediated hypothyroidism and hyperthyroidism—In the combined safety database (n=1414), immune-mediated hypothyroidism and hyperthyroidism occurred in 136 patients (9.6%) and 81 patients (5.7%), respectively. Thyroiditis occurred in 10 patients (0.7%), including 1 Grade 3 case (<0.1%) in a patient who had a myocardial infarction. In 9 patients with thyroiditis, transient hyperthyroidism preceded hypothyroidism. In Study 1 (n=182), Grade 1–2 hypothyroidism or thyroiditis occurred in 10 patients (5.5%). Grade 1–2 hyperthyroidism or thyroiditis leading to hyperthyroidism occurred in 9 patients (4.9%). Monitor patients for abnormal thyroid function tests prior to and periodically during treatment
Immune-mediated adrenal insufficiency—In the combined safety database (n=1414), immune-mediated adrenal insufficiency occurred in 13 patients (0.9%), including 2 Grade 3 cases (0.1%). In Study 1 (n=182), Grade 1 adrenal insufficiency occurred in 1 patient (0.5%). Administer corticosteroids and hormone replacement as clinically indicated
Type 1 diabetes mellitus—In the combined safety database (n=1414), new onset type 1 diabetes mellitus without an alternative etiology occurred in 1 patient (<0.1%). For type 1 diabetes mellitus, initiate insulin as indicated and withhold IMFINZI until clinically stable
Hypophysitis—In the combined safety database (n=1414), hypopituitarism leading to adrenal insufficiency and diabetes insipidus occurred in 1 patient (<0.1%). Administer corticosteroids and hormone replacement as clinically indicated
Other Immune-Mediated Adverse Reactions
IMFINZI has caused immune-mediated rash. Other immune-related adverse reactions, including aseptic meningitis, hemolytic anemia, immune thrombocytopenic purpura, myocarditis, myositis, nephritis, and ocular inflammatory toxicity including uveitis and keratitis, have occurred in ≤1.0% of patients treated with IMFINZI
Immune-mediated rash or dermatitis—In the combined safety database (n=1414), immune-mediated rash or dermatitis occurred in 220 patients (15.6%) and 4 patients (0.3%) developed vitiligo. In Study 1 (n=182), 20 patients (11.0%) developed rash, including 1 Grade 3 case (0.5%). Patients should be monitored for signs and symptoms of rash or dermatitis. Administer corticosteroids if indicated. Withhold IMFINZI for Grade 3 rash or dermatitis or Grade 2 rash or dermatitis lasting >1 week. Permanently discontinue IMFINZI in patients with Grade 4 rash or dermatitis
Immune thrombocytopenic purpura—In the combined safety database (n=1414), 1 fatal case (<0.1%) of immune thrombocytopenic purpura occurred. Monitor patients for signs and symptoms of immune thrombocytopenic purpura
Nephritis—In the combined safety database (n=1414), immune-mediated nephritis occurred in 3 patients (0.2%), including 2 Grade 3 cases (0.1%). Monitor patients for abnormal renal function tests prior to and during each cycle of IMFINZI. Administer corticosteroids for ≥Grade 2 nephritis (creatinine >1.5X ULN). Withhold IMFINZI for Grade 2 nephritis; permanently discontinue for ≥Grade 3 nephritis (creatinine >3X ULN)
Infection
Severe infections, including sepsis, necrotizing fasciitis, and osteomyelitis, occurred in patients receiving IMFINZI. In the combined safety database (n=1414), infections occurred in 531 patients (37.6%). In Study 1 (n=182), infections occurred in 54 patients (29.7%). 11 patients (6.0%) experienced Grade 3–4 infection and 5 patients (2.7%) were experiencing infection at the time of death. 8 patients (4.4%) experienced urinary tract infection, the most common ≥Grade 3 infection. Monitor patients for signs and symptoms of infection and treat with anti-infectives for suspected or confirmed infections. Withhold IMFINZI for ≥Grade 3 infection.
Infusion-Related Reactions
In the combined safety database (n=1414), severe infusion-related reactions occurred in 26 patients (1.8%). In Study 1 (n=182), infusion-related reactions occurred in 3 patients (1.6%). There were 5 Grade 3 (0.4%) and no Grade 4 or 5 reactions. Patients should be monitored for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1–2 infusion-related reactions and permanently discontinue for Grade 3–4 infusion-related reactions.
Embryo-Fetal Toxicity
Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. There are no data on the use of IMFINZI in pregnant women. Advise pregnant women of the potential risk to a fetus and advise women of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of IMFINZI.
Nursing Mothers
There is no information regarding the presence of IMFINZI in human milk; however, because of the potential for adverse reactions in breastfed infants from IMFINZI, advise a lactating woman not to breastfeed during treatment and for at least 3 months after the last dose.
Most Common Adverse Reactions
The most common adverse reactions (≥15%) were fatigue (39%), musculoskeletal pain (24%), constipation (21%), decreased appetite (19%), nausea (16%), peripheral edema (15%), and urinary tract infection (15%). The most common Grade 3 or 4 adverse reactions (≥3%) were fatigue, urinary tract infection, musculoskeletal pain, abdominal pain, dehydration, and general physical health deterioration
Adverse reactions leading to discontinuation of IMFINZI occurred in 3.3% of patients. Serious adverse reactions occurred in 46% of patients. The most frequent serious adverse reactions (>2%) were acute kidney injury (4.9%), urinary tract infection (4.4%), musculoskeletal pain (4.4%), liver injury (3.3%), general physical health deterioration (3.3%), sepsis, abdominal pain, and pyrexia/tumor associated fever (2.7% each)
The safety and effectiveness of IMFINZI have not been established in pediatric patients.
Indications and Usage
IMFINZI is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:
have disease progression during or following platinum-containing chemotherapy
have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8baba4ea-2855-42fa-9bd9-5a7548d4cec3