近日，阿斯利康（AstraZeneca）宣布，美国FDA授予PD-L1抑制剂Imfinzi（duravulumab）突破性疗法认定，用于治疗局部晚期、不可切除的非小细胞肺癌（NSCLC）患者，这些患者经过铂类放化疗后疾病未进展。Imfinzi曾在2017年5月1日加速获批用于局部晚期或转移性尿路上皮癌的治疗。
批准日期：2017年5月1日；2018年2月16日 公司：AstraZeneca
IMFINZI(durvalumab) 注射液, 用于静脉使用
美国初步批准: 2017
最近的重大变化
适应症和用法, 非小细胞肺癌：02/2018
剂量和管理, 非小细胞肺癌：02/2018
警告和预防措施：02/2018
作用机制
程序性细胞死亡ligand-1(PD-L1)的表达可以由炎症信号 (如干扰素) 引起, 并且可以在肿瘤微环境中表达在肿瘤细胞和肿瘤相关的免疫细胞中。PD-L1通过与PD-1和CD80(B7.1) 的相互作用, 阻止T细胞功能和活化。通过结合其受体, PD-L1减少细胞毒性T细胞活性, 增殖和细胞因子的产生。
Durvalumab是一种人免疫球蛋白G1卡伯 (IgG1κ)单克隆抗体, 绑定到PD-L1和阻断PD-L1与PD-1和 CD80 的相互作用(B7.1)。阻断PD-L1/PD-1和PD-L1/CD80的相互作用释放免疫反应的抑制, 不诱导抗体依赖细胞介导的毒性 (ADCC)。
PD-L1阻断与durvalumab导致增加T细胞活化的体外和减少肿瘤大小的共同嫁接人肿瘤和免疫细胞移植小鼠模型。
适应症和用法
IMFINZI是一种程序性死亡-配体1(PD-L1) 阻断抗体, 表示治疗患者:
•局部晚期或转移性尿路癌谁:
o在含铂的化疗期间或之后有疾病进展。
o有疾病进展12月内的新辅助或辅助治疗含铂的化疗。
根据肿瘤反应率和反应持续时间的加快, 批准此项指示。继续批准这一指示可能取决于验证性试验的临床益处的核实和说明。
•不可切除的III. 期非小细胞肺癌 (NSCLC), 其疾病在铂基化疗和放疗后没有进展。
剂量和管理
•尿路癌: 每2周10毫克/千克。
•III. 期 NSCLC: 每2周10毫克/千克。
剂型和强度
•注射: 500mg/10毫升(50毫克/毫升) 溶液在单剂量瓶。
•注射: 120毫克/2.4毫升(50毫克/毫升) 溶液在单剂量瓶。
禁忌
没有.
警告和预防措施
•免疫介导的肺炎: 为严重或危及生命的肺炎保留适度和永久性中止。
•免疫介导的肝炎: 监测肝脏功能的变化。对严重或危及生命的转氨酶或总胆红素升高, 保留适度和永久性中止。
•免疫介导结肠炎: 对严重或危及生命的结肠炎保留适度和永久性中止。
•免疫介导的 Endocrinopathies: 保留中度, 严重或危及生命。
•免疫介导肾炎: 监测肾脏功能的变化。为严重或危及生命的肾炎保留适度和永久性中止。
•免疫介导的皮肤病反应: 为严重或危及生命的皮疹保留适度和永久性停止。
•感染: 扣留严重或危及生命的感染。
•输液相关反应: 中断或减慢输液的轻度或中度, 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: 可引起胎儿伤害。向女性提供对胎儿潜在危险的生殖潜能, 并使用有效避孕方法。
不良反应
•最常见的不良反应 (≥15% 的泌尿道癌患者) 是疲劳, 肌肉骨骼疼痛, 便秘, 食欲减退, 恶心, 周围水肿, 尿路感染。
•最常见的不良反应 (≥20% 的患者不能切除, III. 期 NSCLC) 是咳嗽, 疲劳, 肺炎/放射性肺炎, 上呼吸道感染, 呼吸困难和皮疹。
要报告可疑的不良反应, 请与1-800-236-9933 或 fda 联系, 1-800-fda-1088 或 WWW.FDA.GOV/MEDWATCH。
在特定人群中使用
哺乳: 建议不要母乳喂养。
包装提供/存储和处理
IMFINZI(durvalumab) 注射液是一种透明的乳白色, 无色到略带黄色的溶液, 在纸箱中提供一个单剂量瓶, 无论是:
•500毫克/10毫升 (NDC 0310-4611-50)
•120毫克/2.4毫升 (NDC 0310-4500-12)
储存在冰箱在 8°C (36°F到46°F) 在原纸箱, 以防止光线。
不要冻结。不要动摇。
完整说明书附件：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8baba4ea-2855-42fa-9bd9-5a7548d4cec3

IMFINZI™ (durvalumab) significantly reduces the risk of disease worsening or death in the Phase III PACIFIC trial for Stage III unresectable lung cancer
IMFINZI is the only immunotherapy approved for patients with unresectable Stage III non-small cell lung cancer
IMFINZI showed an 11.2 month improvement in median progression-free survival (16.8 months compared to 5.6 months on placebo)
US Food and Drug Administration (FDA) has approved IMFINZI® (durvalumab) for the treatment of patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (CRT).
IMPORTANT SAFETY INFORMATION
There are no contraindications for IMFINZI® (durvalumab).
IMFINZI can cause serious, potentially fatal adverse reactions including immune-mediated pneumonitis, hepatitis, colitis or diarrhea, endocrinopathies, nephritis, rash or dermatitis, other immune-mediated adverse reactions, infection, and infusion-related reactions. Please refer to the full Prescribing Information for important dosage modification and management information specific to adverse reactions.
Immune-Mediated Pneumonitis
IMFINZI can cause immune-mediated pneumonitis, defined as requiring use of corticosteroids. Fatal cases have been reported. Monitor patients for signs and symptoms of pneumonitis and evaluate with radiographic imaging when suspected. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold IMFINZI for Grade 2 pneumonitis; permanently discontinue for Grade 3 or 4 pneumonitis.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, pneumonitis occurred in 5% of patients, including Grade 3 (0.8%), Grade 4 (<0.1%), and Grade 5 (0.3%) pneumonitis. Pneumonitis led to discontinuation of IMFINZI in 1.5% of the 1889 patients. The incidence of pneumonitis (including radiation pneumonitis) was higher in patients in the PACIFIC study who completed treatment with definitive chemoradiation within 42 days prior to initiation of IMFINZI (34%) compared to patients in other clinical studies (2.3%) in which radiation therapy was generally not administered immediately prior to initiation of IMFINZI. In the PACIFIC study, the incidence of Grade 3 pneumonitis was 3.4% and of Grade 5 pneumonitis was 1.1% in the IMFINZI arm. In the PACIFIC study, pneumonitis led to discontinuation of IMFINZI in 6% of patients.
Immune-Mediated Hepatitis
IMFINZI can cause immune-mediated hepatitis, defined as requiring use of corticosteroids. Fatal cases have been reported. Monitor patients for signs and symptoms of hepatitis during and after discontinuation of IMFINZI, including clinical chemistry monitoring. Administer corticosteroids for Grade 2 or higher elevations of ALT, AST, and/or total bilirubin. Withhold IMFINZI for ALT or AST greater than 3 but less than or equal to 8 times the ULN or total bilirubin greater than 1.5 but less than or equal to 5 times the ULN; permanently discontinue IMFINZI for ALT or AST greater than 8 times the ULN or total bilirubin greater than 5 times the ULN or concurrent ALT or AST greater than 3 times the ULN and total bilirubin greater than 2 times the ULN with no other cause.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, hepatitis occurred in 12% of patients, including Grade 3 (4.4%), Grade 4 (0.4%), and Grade 5 (0.2%) hepatitis. Hepatitis led to discontinuation of IMFINZI in 0.7% of the 1889 patients.
Immune-Mediated Colitis
IMFINZI can cause immune-mediated colitis, defined as requiring use of corticosteroids. Administer corticosteroids for Grade 2 or greater colitis or diarrhea. Withhold IMFINZI for Grade 2 colitis or diarrhea; permanently discontinue for Grade 3 or 4 colitis or diarrhea.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, colitis or diarrhea occurred in 18% of patients, including Grade 3 (1.0%) and Grade 4 (0.1%) colitis. Diarrhea or colitis led to discontinuation of IMFINZI in 0.4% of the 1889 patients.
Immune-Mediated Endocrinopathies
IMFINZI can cause immune-mediated endocrinopathies, including thyroid disorders, adrenal insufficiency, type 1 diabetes mellitus, and hypophysitis/hypopituitarism. Monitor patients for clinical signs and symptoms of endocrinopathies.
•Thyroid disorders—Monitor thyroid function prior to and periodically during treatment. Initiate hormone replacement therapy or medical management of hyperthyroidism as clinically indicated. Withhold IMFINZI for Grades 2–4 hyperthyroidism, until clinically stable. Continue IMFINZI for hypothyroidism.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, hypothyroidism occurred in 11% of patients, while hyperthyroidism occurred in 7% of patients. Thyroiditis occurred in 0.9% of patients, including Grade 3 (<0.1%). Hypothyroidism was preceded by thyroiditis or hyperthyroidism in 25% of patients.
•Adrenal insufficiency—Administer corticosteroids as clinically indicated and withhold IMFINZI until clinically stable for Grade 2 or higher adrenal insufficiency. In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, adrenal insufficiency occurred in 0.7% of patients, including Grade 3 (<0.1%) adrenal insufficiency.
•Type 1 diabetes mellitus—Initiate treatment with insulin as clinically indicated. Withhold IMFINZI for Grades 2–4 type 1 diabetes mellitus, until clinically stable. In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, type 1 diabetes mellitus occurred in <0.1% of patients.
•Hypophysitis—Administer corticosteroids and hormone replacement as clinically indicated and withhold IMFINZI until clinically stable for Grade 2 or higher hypophysitis. Hypopituitarism leading to adrenal insufficiency and diabetes insipidus occurred in <0.1% of 1889 patients with various cancers who received IMFINZI.
Immune-Mediated Nephritis
IMFINZI can cause immune-mediated nephritis, defined as evidence of renal dysfunction requiring use of corticosteroids. Fatal cases have occurred. Monitor patients for abnormal renal function tests prior to and periodically during treatment with IMFINZI. Administer corticosteroids as clinically indicated. Withhold IMFINZI for creatinine greater than 1.5 to 3 times the ULN; permanently discontinue IMFINZI and administer corticosteroids in patients with creatinine greater than 3 times the ULN.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, nephritis (reported as any of the following: increased creatinine or urea, acute kidney injury, renal failure, decreased glomerular filtration rate, tubulointerstitial nephritis, decreased creatinine clearance, glomerulonephritis, and nephritis) occurred in 6.3% of the patients including Grade 3 (1.1%), Grade 4 (0.2%), and Grade 5 (0.1%) nephritis. IMFINZI was discontinued in 0.3% of the 1889 patients.
Immune-Mediated Dermatologic Reactions
IMFINZI can cause immune-mediated rash. Bullous dermatitis and Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN) have occurred with other products in this class. Administer corticosteroids for Grade 2 rash or dermatitis lasting for more than 1 week or for Grade 3 or 4 rash or dermatitis. Withhold IMFINZI for Grade 2 rash or dermatitis lasting longer than 1 week or Grade 3 rash or dermatitis; permanently discontinue IMFINZI in patients with Grade 4 rash or dermatitis.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, 26% of patients developed rash or dermatitis and 0.4% of the patients developed vitiligo. Rash or dermatitis led to discontinuation of IMFINZI in 0.1% of the 1889 patients.
Other Immune-Mediated Adverse Reactions
IMFINZI can cause severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system. While immune-mediated reactions usually manifest during treatment with IMFINZI, immune-mediated adverse reactions can also manifest after discontinuation of IMFINZI. For suspected immune-mediated adverse reactions, exclude other causes and initiate corticosteroids as clinically indicated. Withhold IMFINZI for Grade 3 immune-mediated adverse reactions, unless clinical judgment indicates discontinuation; permanently discontinue IMFINZI for Grade 4 adverse reactions.
The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in 1889 patients who received IMFINZI: aseptic meningitis, hemolytic anemia, immune thrombocytopenic purpura, myocarditis, myositis, and ocular inflammatory toxicity, including uveitis and keratitis. Additional clinically significant immune-mediated adverse reactions have been seen with other products in this class (see Warnings and Precautions Section 5.7 of IMFINZI full Prescribing Information).
Infection
IMFINZI can cause serious infections, including fatal cases. Monitor patients for signs and symptoms of infection and treat as clinically indicated. Withhold IMFINZI for Grade 3 or 4 infection, until clinically stable.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, infections occurred in 43% of patients, including Grade 3 (8%), Grade 4 (1.9%), and Grade 5 (1.0%). The overall incidence of infections in IMFINZI-treated patients in the PACIFIC study (56%) was higher compared to patients in other clinical studies (38%) in which radiation therapy was generally not administered immediately prior to initiation of IMFINZI. In patients with UC in Study 1108 (n=182), the most common Grade 3 or higher infection was urinary tract infections, which occurred in 4% of patients. In patients with Stage III NSCLC in the PACIFIC study, the most common Grade 3 or higher infection was pneumonia, which occurred in 5% of patients.
Infusion-Related Reactions
IMFINZI can cause severe or life-threatening infusion-related reactions. Monitor patients for signs and symptoms of an infusion-related reaction. Interrupt or slow the rate of infusion for Grades 1–2 infusion-related reactions; permanently discontinue for Grades 3–4 infusion-related reactions.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, infusion-related reactions occurred in 2.2% of patients, including Grade 3 (0.3%).
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.