Hematology-Oncology Division, Department of Medicine, Greater Los Angeles VA Healthcare Center, UCLA Medical Center, Jonsson Comprehensive Cancer Center, Los Angeles, CA.
Division of Hematology/Oncology, Department of Medicine, Geffen School of Medicine at UCLA, Santa Monica, CA.
J Clin Oncol. 2022 Aug 20;40(24):2763-2773. doi: 10.1200/JCO.21.02605. Epub 2022 Jun 1.
The treatment landscape for advanced hepatocellular carcinoma has changed dramatically over the past 4 years. We now have numerous options for patients in frontline, second-line, and beyond. The most significant impact has been the introduction of immunotherapy into our treatment paradigms. We now have regimens that induce consistent double-digit objective response rates and markedly improve overall survival (OS) with favorable side effect profiles. The combination of atezolizumab and bevacizumab has demonstrated that the combination of targeting programmed death-ligand 1 and the vascular endothelial growth factor axis can improve outcomes versus sorafenib in the IMBrave150 study. Results from the COSMIC-312 study evaluating the multikinase vascular endothelial growth factor receptor, hepatocyte growth factor receptor, and tyrosine kinase receptor inhibitor cabozantinib in combination with atezolizumab improved progression-free survival versus sorafenib, but at this time, there is no improvement in OS and response rates were lower than expected. Additional data with similar combinations are awaited on the basis of encouraging early-phase data. In addition, the combination of cytotoxic T-lymphocyte-associated protein 4 and programmed cell death-1/programmed death-ligand 1 targeting is yielding similar promising early results, and the phase III HIMALAYA study met its primary end points of improving OS versus sorafenib for durvalumab plus tremelimumab and demonstrated noninferiority for single-agent durvalumab as well. However, this combination did not improve progression-free survival and objective response rates with this combination did not seem significantly different from that with single-agent durvalumab. Although there are still knowledge gaps in this rapidly changing landscape, we will address some of the important questions relevant to making therapeutic decisions in the management of advanced hepatocellular carcinoma in the modern era on the basis of our current knowledge of the safety and efficacy of these evolving regimens. The goal is to provide clinicians with the knowledge needed to optimize outcomes for their patients.
在过去的 4 年中，晚期肝细胞癌的治疗格局发生了巨大变化。我们现在为一线、二线和更后的患者提供了许多选择。最显著的影响是免疫疗法被引入我们的治疗方案。我们现在有方案可以诱导一致的双位数客观缓解率，并显著改善总生存期（OS），同时具有良好的副作用谱。在 IMBrave150 研究中，阿替利珠单抗联合贝伐珠单抗表明，靶向程序性死亡配体 1 和血管内皮生长因子轴的联合治疗可以改善索拉非尼的疗效。COSMIC-312 研究评估多激酶血管内皮生长因子受体、肝细胞生长因子受体和酪氨酸激酶受体抑制剂卡博替尼联合阿替利珠单抗的结果显示，与索拉非尼相比，无进展生存期有所改善，但此时 OS 没有改善，缓解率低于预期。基于令人鼓舞的早期数据，正在等待类似组合的数据。此外，细胞毒性 T 淋巴细胞相关蛋白 4 和程序性细胞死亡-1/程序性死亡配体 1 靶向的联合治疗也取得了类似的早期有希望的结果，III 期 HIMALAYA 研究达到了其主要终点，即在 OS 方面优于索拉非尼，用于度伐利尤单抗联合 Tremelimumab，并且单药度伐利尤单抗也显示出非劣效性。然而，这种联合治疗并没有改善无进展生存期，而且这种联合治疗的客观缓解率似乎与单药度伐利尤单抗没有显著差异。尽管在这个快速变化的领域仍然存在知识空白，但我们将根据我们对这些不断发展的方案的安全性和疗效的现有了解，解决一些与在现代管理晚期肝细胞癌时做出治疗决策相关的重要问题。目标是为临床医生提供优化患者治疗结果所需的知识。
