日常学习FDA批准肿瘤治疗的新适应症信息~~
On October 21, 2022, the Food and Drug Administration approved tremelimumab (Imjudo, AstraZeneca Pharmaceuticals) in combination with durvalumab for adult patients with unresectable hepatocellular carcinoma (uHCC).
2022年 10月 21日，美国食品药品监督管理局（the Food and Drug Administration）批准 tremelimumab (Imjudo, AstraZeneca Pharmaceuticals) + 度伐利尤单抗用于治疗不可切除的肝细胞癌（uHCC）成人患者。
tremelimumab是一种CTLA-4（细胞毒性T淋巴细胞抗原-4）免疫检查点抑制剂。
Efficacy was evaluated in HIMALAYA (NCT03298451), a randomized (1:1:1), open-label, multicenter study in patients with confirmed uHCC who had not received prior systemic treatment for HCC. Patients were randomized to one of three arms: tremelimumab 300 mg as a one-time single intravenous (IV) infusion plus durvalumab 1500 mg IV on the same day, followed by durvalumab 1500 mg IV every 4 weeks; durvalumab 1500 mg IV every 4 weeks; or sorafenib 400 mg orally twice daily until disease progression or unacceptable toxicity. This approval is based on a comparison of the 782 patients randomized to tremelimumab plus durvalumab to sorafenib.
该适应症的获批基于HIMALAYA (NCT03298451)研究，782例随机分配至 tremelimumab+度伐利尤单抗治疗患者与索拉非尼治疗患者对比的疗效数据。
HIMALAYA (NCT03298451)研究是一项随机化（1：1：1）、开放标签、多中心研究，主要纳入未经系统治疗的uHCC确诊患者。
受试者入组后随机分配至以下3个队列接受治疗，直至疾病进展或发生不能接受的毒性：
1）tremelimumab 300 mg IV 给药1次，度伐利尤单抗 1500 mg IV 同一天给药，然后度伐利尤单抗 1500 mg IV 4周1次；2）度伐利尤单抗 1500 mg IV 4周1次；3）索拉非尼 400 mg 口服 一天2次。
The major efficacy outcome was overall survival (OS). Tremelimumab plus durvalumab demonstrated a statistically significant and clinically meaningful improvement in OS compared to sorafenib (stratified hazard ratio [HR] of 0.78 [95% CI: 0.66, 0.92], 2-sided p value = 0.0035); median OS was 16.4 months (95% CI: 14.2, 19.6) versus 13.8 months (95% CI: 12.3, 16.1). Additional efficacy outcomes included investigator-assessed progression-free survival (PFS) and overall response rate (ORR) according to RECIST v1.1. Median PFS was 3.8 months (95% CI: 3.7, 5.3) and 4.1 months (95% CI: 3.7, 5.5) for the tremelimumab plus durvalumab and sorafenib arms, respectively (stratified HR 0.90; 95% CI: 0.77, 1.05). ORR was 20.1% (95% CI: 16.3, 24.4) in the tremelimumab plus durvalumab arm and 5.1% (95% CI: 3.2, 7.8) for those treated with sorafenib.
主要疗效终点是总生存期（OS）。
与索拉非尼相比，tremelimumab+度伐利尤单抗显示了具有显著统计学差异且有临床意义改善的OS数据：HR 0.78，95%CI 0.66-0.92， 2-sided p value = 0.0035。
中位OS：tremelimumab+度伐利尤单抗 vs 索拉非尼 = 16.4 个月 (95% CI: 14.2, 19.6) vs 13.8个月 (95% CI: 12.3, 16.1)。
其他疗效终点包括研究中评估的无进展生存期（PFS）和基于RECIST 1.1的客观缓解率（ORR）。
中位PFS：tremelimumab+度伐利尤单抗 vs 索拉非尼 = 3.8 个月 (95% CI: 3.7, 5.3) vs 4.1 个月 (95% CI: 3.7, 5.5) ；HR 0.90，95% CI 0.77-1.05。
ORR：tremelimumab+度伐利尤单抗 vs 索拉非尼 = 20.1% (95% CI 16.3-24.4) vs 5.1% (95% CI 3.2-7.8)。
The most common (≥20%) adverse reactions occurring in patients were rash, diarrhea, fatigue, pruritis, musculoskeletal pain and abdominal pain.
患者最常见（≥20%）的不良反应是皮疹、腹泻、疲劳、瘙痒、肌肉骨骼疼痛和腹痛。
The recommended tremelimumab dose for patients weighing 30 kg or more is 300 mg IV as a single dose in combination with durvalumab 1500 mg at Cycle 1/Day 1, followed by durvalumab 1500 mg IV every 4 weeks. For those weighing less than 30 kg, the recommended tremelimumab dose is 4 mg/kg IV as a single dose in combination with durvalumab 20 mg/kg IV, followed by durvalumab 20 mg/kg IV every 4 weeks.
推荐剂量：
≥30kg：tremelimumab 300 mg IV + 度伐利尤单抗 1500 mg 第1周期的第1天，然后度伐利尤单抗 1500 mg IV 每4周给药1次。
＜30kg：tremelimumab 4mg/kg IV + 度伐利尤单抗 20mg/kg IV 第1周期的第1天，然后度伐利尤单抗 20mg/kg IV 每4周给药1次。
参考文献：
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tremelimumab-combination-durvalumab-unresectable-hepatocellular-carcinoma
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