Introduction: Atezolizumab (ATEZO) plus bevacizumab (BEVA) represents the new standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, the choice of the second-line treatment after the failure of immunotherapy-based first-line remains elusive. Taking into account the weaknesses of the available evidence, we developed a simulation model based on available phase III randomized clinical trials (RCTs) to identify optimal risk/benefit sequential strategies. Methods: A Markov model was built to estimate the overall survival (OS) of sequential first- and second-line systemic treatments. Sequences starting with first-line ATEZO plus BEVA followed by 5 second-line treatments (sorafenib [SORA], lenvatinib [LENVA], regorafenib, cabozantinib, and ramucirumab) were compared. The probability of transition between states (initial treatment, cancer progression, and death) was derived from RCTs. Life-year gained (LYG) was the main outcome. Rates of severe adverse events (SAEs) (≥ grade 3) were calculated. The incremental safety-effectiveness ratio (ISER) was calculated as the difference in probability of SAEs divided by LYG between the 2 most effective sequences. Results: ATEZO plus BEVA followed by LENVA (median OS, 24 months) or SORA (median OS, 23 months) was the most effective sequence, producing a LYG of 0.50 and 0.42 year, respectively. ATEZO plus BEVA followed by SORA was the safest sequence (SAEs 63%). At a willingness-to-risk threshold of 10% of SAEs for LYG, ATEZO plus BEVA followed by second-line SORA was favored in 72% of cases, while at a threshold of 30% of SAEs for LYG, ATEZO plus BEVA followed by second-line LENVA was favored in 69% of cases. Conclusion: Our simulation model provides a strong rationale to support ongoing trials evaluating second-line tyrosine-kinase inhibitors after first-line ATEZO plus BEVA. Future evidence from ongoing RCTs and prospective real-world studies are needed to prove the net health benefit of sequential treatment options for advanced HCC.
Liver Cancer

中文翻译：

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基于一线免疫检查点抑制剂的晚期肝细胞癌序贯疗法：未来试验的基本原理

简介：阿特珠单抗 (ATEZO) 加贝伐单抗 (BEVA) 代表了治疗晚期肝细胞癌 (HCC) 的新护理标准。然而，基于免疫治疗的一线治疗失败后二线治疗的选择仍然难以捉摸。考虑到现有证据的弱点，我们开发了一个基于现有 III 期随机临床试验 (RCT) 的模拟模型，以确定最佳风险/收益顺序策略。方法：建立马尔科夫模型来估计序贯一线和二线全身治疗的总生存期 (OS)。比较了从一线 ATEZO 加 BEVA 开始的序列，然后是 5 种二线治疗（索拉非尼 [SORA]、乐伐替尼 [LENVA]、瑞戈非尼、卡博替尼和雷莫芦单抗）。状态（初始治疗、癌症进展和死亡）之间转换的概率来自 RCT。获得生命年（LYG）是主要结果。计算了严重不良事件 (SAE) (≥ 3 级) 的发生率。增量安全有效性比 (ISER) 计算为 SAE 概率的差异除以 2 个最有效序列之间的 LYG。结果：ATEZO 加 BEVA，其次是 LENVA（中位 OS，24 个月）或 SORA（中位 OS，23 个月）是最有效的序列，分别产生 0.50 年和 0.42 年的 LYG。ATEZO 加 BEVA，然后是 SORA 是最安全的顺序（SAE 63%）。在 LYG 的 SAE 的风险意愿阈值为 10% 时，ATEZO 加 BEVA 继之以二线 SORA 在 72% 的病例中受到青睐，而在 LYG 的 SAE 阈值为 30% 时，ATEZO 加 BEVA 继之以69% 的病例首选二线 LENVA。结论：我们的模拟模型提供了强有力的理由来支持正在进行的试验，以评估一线 ATEZO 加 BEVA 之后的二线酪氨酸激酶抑制剂。需要来自正在进行的 RCT 和前瞻性现实世界研究的未来证据来证明晚期 HCC 序贯治疗方案的净健康益处。
肝癌