D'Alessio Antonio, Prete Maria Giuseppina, Cammarota Antonella, Personeni Nicola, Rimassa Lorenza
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), 20090, Italy.
Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), 20089, Italy.
J Hepatocell Carcinoma. 2021 Mar 29;8:177-191. doi: 10.2147/JHC.S268310. eCollection 2021.
The systemic treatment of advanced hepatocellular carcinoma (HCC) has significantly changed over the last years, with the introduction of two new standard-of-care first-line treatments (lenvatinib and the combination of atezolizumab and bevacizumab) and the success of several new agents in second line. In particular, after the approval of regorafenib, ramucirumab and cabozantinib, the landscape of second-line treatment has become notably complex, providing a serious challenge in clinical practice. In this review, we focus on cabozantinib, a multikinase inhibitor which was proven effective in improving overall and progression-free survival of patients previously treated with sorafenib in the randomized Phase III CELESTIAL trial. CELESTIAL is the only phase III study to have included patients in the third-line setting and cabozantinib efficacy was confirmed in several post hoc analyses, irrespective of alpha-fetoprotein levels, albumin-bilirubin score, age, and duration of previous sorafenib treatment. The safety profile of cabozantinib in the CELESTIAL trial was comparable with other multikinase inhibitors used for HCC and the most frequent grade ≥3 adverse events were diarrhea, palmar-plantar erythrodysesthesia, fatigue, hypertension, and aspartate aminotransferase increase. Tolerability did not differ between younger and older patients and quality of life was significantly improved compared to placebo during the treatment. In this review, we also make a particular mention to the use of cabozantinib in populations which are normally excluded from clinical trials, such as older patients and Child-Pugh B patients. Finally, we present the new treatment strategies in which cabozantinib is being tested, most notably the combination of cabozantinib and atezolizumab in the first-line setting in the phase III COSMIC-312 trial and the use of cabozantinib after progression on immune-checkpoint inhibitors.
在过去几年中，晚期肝细胞癌（HCC）的系统治疗发生了显著变化，引入了两种新的一线标准治疗方案（乐伐替尼以及阿替利珠单抗和贝伐单抗联合治疗），并且几种新药物在二线治疗中取得了成功。特别是在瑞戈非尼、雷莫西尤单抗和卡博替尼获批后，二线治疗格局变得尤为复杂，给临床实践带来了严峻挑战。在本综述中，我们聚焦于卡博替尼，这是一种多激酶抑制剂，在随机III期CELESTIAL试验中被证明可有效提高先前接受索拉非尼治疗患者的总生存期和无进展生存期。CELESTIAL是唯一一项纳入三线治疗患者的III期研究，并且在多项事后分析中均证实了卡博替尼的疗效，无论甲胎蛋白水平、白蛋白 - 胆红素评分、年龄以及先前索拉非尼治疗时长如何。卡博替尼在CELESTIAL试验中的安全性与用于HCC治疗的其他多激酶抑制剂相当，最常见的≥3级不良事件为腹泻、手足红斑感觉异常、疲劳、高血压以及天门冬氨酸氨基转移酶升高。年轻患者和老年患者的耐受性无差异，并且与安慰剂相比，治疗期间生活质量有显著改善。在本综述中，我们还特别提及了卡博替尼在通常被排除于临床试验之外的人群中的应用，例如老年患者和Child-Pugh B级患者。最后，我们介绍了正在测试卡博替尼的新治疗策略，最值得注意的是在III期COSMIC-312试验中一线使用卡博替尼和阿替利珠单抗联合治疗，以及在免疫检查点抑制剂治疗进展后使用卡博替尼。
