日常学习FDA批准肿瘤治疗的新适应症信息~~
度伐利尤单抗，英文：durvalumab（商品名：英飞凡，英文：Imfinzi）。
度伐利尤单抗是一个人源化的PD-L1单克隆抗体，能够阻断PD-L1跟PD-1和CD80的结合，从而阻断肿瘤免疫逃逸并解除对免疫反应的抑制。
2019年12月9日，NMPA批准度伐利尤单抗用于在接受铂类药物为基础的化疗同步放疗后未出现疾病进展的不可切除、Ⅲ期非小细胞肺癌（NSCLC）患者的治疗。
2021年7月19日，NMPS批准度伐利尤单抗联合依托泊苷和卡铂或顺铂，作为广泛期小细胞肺癌（ES-SCLC）成人患者的一线治疗方案。
来看一下新增适应症的获批信息吧！
美国FDA批准度伐利尤单抗用于治疗局部进展期或转移性胆道癌
On September 2, 2022, the Food and Drug Administration approved durvalumab (Imfinzi, AstraZeneca UK Limited) in combination with gemcitabine and cisplatin for adult patients with locally advanced or metastatic biliary tract cancer (BTC).
2022年 9月 2日，美国食品药品监督管理局（the Food and Drug Administration）批准 度伐利尤单抗 (Imfinzi, AstraZeneca UK Limited) 联合吉西他滨和顺铂用于治疗局部进展期或转移性胆管癌（BTC）成人患者。
Efficacy was evaluated in TOPAZ-1 (NCT03875235), a randomized, double-blind, placebo-controlled, multiregional trial that enrolled 685 patients with histologically confirmed locally advanced unresectable or metastatic BTC who had not previously received systemic therapy for advanced disease.
该适应症的获批主要基于 TOPAZ-1 (NCT03875235) 的疗效数据。
TOPAZ-1 研究是一项随机化、双盲、安慰剂对照的多中心临床试验，共纳入685例既往未接受过系统治疗的、经组织学确诊的、局部进展期不可切除的或转移性胆管癌患者。
Trial demographics were as follows: 56% Asian, 37% White, 2% Black, and 4% other race; 7% Hispanic or Latino; 50% male and 50% female; median age was 64 years (range 20-85) and 47% were 65 years or older. Fifty-six percent had intrahepatic cholangiocarcinoma, 25% had gallbladder cancer, and 19% had extrahepatic cholangiocarcinoma.
该试验的人口学统计数据如下：56% 的亚洲人、37% 的白人、2% 的黑人和 4% 的其他种族；7% 西班牙裔或拉丁裔；50% 男性和 50% 女性；中位年龄为 64 岁（范围 20-85 岁），47% 为 65 岁或以上。56% 患有肝内胆管癌，25% 患有胆囊癌，19% 患有肝外胆管癌。
Patients were randomized 1:1 to receive:
durvalumab 1,500 mg on Day 1+ gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on Days 1 and 8 of each 21-day cycle up to 8 cycles, followed by durvalumab 1,500 mg every 4 weeks, or
placebo on Day 1+ gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on Days 1 and 8 of each 21-day cycle up to 8 cycles, followed by placebo every 4 weeks.
患者1：1随机接受以下治疗：
度伐利尤单抗 1500 mg Day 1， 吉西他滨 1000 mg/m2 + 顺铂 25 mg/m2 day 1，8，21天一个周期，最多使用8周期。然后度伐利尤单抗 1500 mg 每4周给药1次。
安慰剂 Day 1， 吉西他滨 1000 mg/m2 + 顺铂 25 mg/m2 day 1，8，21天一个周期，最多使用8周期。然后安慰剂 每4周给药1次。
Durvalumab or placebo were continued until disease progression or unacceptable toxicity. Treatment was permitted beyond disease progression if the patient was clinically stable and deriving clinical benefit, as determined by the investigator.
度伐利尤单抗或安慰剂持续使用，直至疾病进展或出现不能耐受的毒性。
如果患者临床稳定并获益，则经过研究者确定后，允许疾病进展后继续用药。
The major efficacy outcome measure was overall survival (OS). Tumor assessments were conducted every 6 weeks for the first 24 weeks, then every 8 weeks until confirmed objective disease progression. A statistically significant improvement in OS was demonstrated in patients randomized to receive durvalumab with gemcitabine and cisplatin compared to those randomized to receive placebo with gemcitabine and cisplatin. Median OS was 12.8 months (95% CI: 11.1, 14) and 11.5 months (95% CI: 10.1, 12.5) in the durvalumab and placebo arms, respectively (hazard ratio 0.80; 95% CI: 0.66, 0.97, p=0.021). The median progression-free survival was 7.2 months (95% CI: 6.7, 7.4) and 5.7 months (95% CI: 5.6, 6.7) in the durvalumab and placebo arms, respectively. Investigator-assessed overall response rate was 27% (95% CI: 22% - 32%) and 19% (95% CI: 15%-23%) in the durvalumab and placebo arms, respectively.
主要疗效终点是总生存期（OS）。
前 24 周每 6 周进行一次肿瘤评估，然后每 8 周进行一次肿瘤评估，直至确认客观疾病进展。
与安慰剂组相比，度伐利尤单抗治疗组患者的 OS 有统计学意义的改善。
中位OS分别为：度伐利尤单抗组 12.8个月（95% CI：11.1，14），安慰剂组 11.5 个月（95% CI：10.1，12.5）（HR 0.80；95% CI：0.66,0.97，p=0.021 ）。
中位无进展生存期（PFS）分别为：度伐利尤单抗组 7.2个月（95% CI：6.7, 7.4），安慰剂组 5.7 个月（95% CI：5.6, 6.7）。
研究者评估的客观缓解率（ORR）分别为：度伐利尤单抗组 27%（95% CI：22% ，32%），安慰剂组 19%（95% CI：15%，23%）。
The most common (≥20%) adverse reactions occurring in patients were fatigue, nausea, constipation, decreased appetite, abdominal pain, rash, and pyrexia.
患者最常见（≥20%）的不良反应是疲乏、恶心、便秘、食欲下降、腹痛、皮疹和发热。
The recommended durvalumab dose is 1,500 mg every 3 weeks for patients with a body weight ≥30 kg when given with gemcitabine and cisplatin, followed by 1,500 mg every 4 weeks as a single agent until disease progression or unacceptable toxicity. For patients with a body weight <30 kg, the recommended dose is 20 mg/kg every 3 weeks with gemcitabine and cisplatin followed by 20 mg/kg every 4 weeks until disease progression or unacceptable toxicity.
度伐利尤单抗的推荐剂量：
体重≥30kg的患者，度伐利尤单抗 1500 mg， 每3周给药1次，联合吉西他滨和顺铂；随后 度伐利尤单抗 1500 mg，每4周给药1次，直至疾病进展或出现不能耐受的毒性。
体重＜30kg的患者，度伐利尤单抗 20 mg/kg， 每3周给药1次，联合吉西他滨和顺铂；随后 度伐利尤单抗 20 mg/kg，每4周给药1次，直至疾病进展或出现不能耐受的毒性。
参考文献：
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-locally-advanced-or-metastatic-biliary-tract-cancer
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