Liu Xing, Li Jing-Jing, Ding Ya, Li Dan-Dan, Wen Xi-Zhi, Weng De-Sheng, Wang Jiu-Hong, Jiang Hang, Zhang Xiao-Shi
Biotherapy Center, Sun Yat-sen University Cancer Center, Guangzhou, China.
Front Oncol. 2021 Apr 1;11:582676. doi: 10.3389/fonc.2021.582676. eCollection 2021.
The toxicity spectrum between Chinese and Caucasian patients with melanoma who were treated with BRAF inhibitors (BRAFi) may differ. The purpose of the present study was to assess the safety and tolerability of BRAFi and BRAFi-based combination therapies [MEK inhibitors (MEKi) or anti-programmed death-1 (PD-1) antibody] in Chinese patients with mutation-positive metastatic melanoma. We also investigated whether treatment-related adverse events (AEs) correlated with the prognosis. This retrospective study collected data from 43 patients with mutation-positive metastatic melanoma from a single Chinese cancer center. Of the 43 patients, 12 patients received BRAFi monotherapy, 12 patients received BRAFi+MEKi, and 19 patients received BRAFi combined with the anti-PD-1 antibody. The median follow-up time was 19 months. In the BRAFi group, the most common AEs were rashes, palmoplantar erythrodysesthesia, and arthralgia. Four out of 12 (30%) patients experienced grade 3-4 treatment-related AEs. All grades of AEs in the BRAFi+MEKi group were similar to the BRAFi group, except for higher pyrexia (58.3%) and fewer cutaneous AEs. Three out of 12 (25%) patients experienced grade 3-4 AEs, especially pyrexia (16.7%). In the BRAFi+anti-PD-1 antibody group, AEs were similar to the BRAFi group, except for an increased aminotransferase level (36.8%), increased bilirubin (31.6%), and hypothyroidism (15.8%). Eleven out of 19 (57.9%) patients experienced grade 3-4 AEs and four out of 19 (21%) patients discontinued the therapy due to AEs. Treatment-related hepatotoxicity (trHE), defined as an increase in either alanine aminotransferase (ALT), aspartate transaminase (AST), or bilirubin levels, was the only AE identified as a significant poor-prognosis indicator in this study. The median progression-free survival of patients with trHE (41.9%) was 8 months, whereas it was 18 months for those without trHE [ = 0.046, hazard ratio (HR) = 2.116]. Moreover, this association was independent of medication regimens ( = 0.014, HR = 2.971). The overall response rate of patients with trHE was significantly lower than those without trHE (44.4 vs. 60.0%, = 0.024), and we observed a similar trend in patients treated with BRAFi, BRAFi+MEKi, and BRAFi+anti-PD-1 antibody. In conclusion, BRAFi and BRAFi-based combination therapies were tolerable with reversible AEs in Chinese patients with melanoma. The trHE in patients receiving BRAFi and BRAFi-based regimens might indicate a poor therapy-related prognosis.
接受BRAF抑制剂（BRAFi）治疗的中国黑色素瘤患者与高加索患者之间的毒性谱可能有所不同。本研究的目的是评估BRAFi以及基于BRAFi的联合疗法[MEK抑制剂（MEKi）或抗程序性死亡-1（PD-1）抗体]在中国携带突变的转移性黑色素瘤患者中的安全性和耐受性。我们还研究了治疗相关不良事件（AE）是否与预后相关。这项回顾性研究收集了来自中国一家癌症中心的43例携带突变的转移性黑色素瘤患者的数据。在这43例患者中，12例患者接受BRAFi单药治疗，12例患者接受BRAFi+MEKi治疗，19例患者接受BRAFi联合抗PD-1抗体治疗。中位随访时间为19个月。在BRAFi组中，最常见的AE是皮疹、掌跖红细胞感觉异常和关节痛。12例患者中有4例（30%）经历了3-4级治疗相关AE。BRAFi+MEKi组的所有级别AE与BRAFi组相似，只是发热更高（58.3%），皮肤AE更少。12例患者中有3例（25%）经历了3-4级AE，尤其是发热（16.7%）。在BRAFi+抗PD-1抗体组中，AE与BRAFi组相似，只是转氨酶水平升高（36.8%）、胆红素升高（31.6%）和甲状腺功能减退（15.8%）。19例患者中有11例（57.9%）经历了3-4级AE，19例患者中有4例（21%）因AE停止治疗。治疗相关肝毒性（trHE）定义为丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）或胆红素水平升高，是本研究中唯一被确定为显著不良预后指标的AE。发生trHE的患者（41.9%）的中位无进展生存期为8个月，而未发生trHE的患者为18个月[P = 0.046，风险比（HR）= 2.116]。此外，这种关联独立于用药方案（P = 0.014，HR = 2.971）。发生trHE的患者的总缓解率显著低于未发生trHE的患者（44.4%对60.0%，P = 0.024），并且我们在接受BRAFi、BRAFi+MEKi和BRAFi+抗PD-1抗体治疗的患者中观察到了类似趋势。总之，BRAFi以及基于BRAFi的联合疗法在中国黑色素瘤患者中具有可耐受性，AE可逆。接受BRAFi和基于BRAFi方案治疗的患者中的trHE可能表明与治疗相关的预后不良。
