Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center; Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Department of Internal Medicine, Pusan National University School of Medicine and Medical Research Institute, Busan, Republic of Korea.
Clin Cancer Res. 2014 Dec 1;20(23):5976-85. doi: 10.1158/1078-0432.CCR-13-3445. Epub 2014 Oct 7.
There is an unmet need for treatment options in hepatocellular carcinoma (HCC). Sorafenib is currently the only approved systemic treatment for HCC. Refametinib, an oral, allosteric MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in vitro and in vivo. A phase II study evaluated efficacy and safety of refametinib plus sorafenib in Asian patients with HCC (NCT01204177).
Eligible patients received twice-daily refametinib 50 mg plus twice-daily sorafenib 200 mg (morning)/400 mg (evening), with dose escalation to sorafenib 400 mg twice daily from cycle 2 if no grade ≥ 2 hand-foot skin reaction, fatigue, or gastrointestinal toxicity occurred. Primary efficacy endpoint: disease control rate. Secondary endpoints: time to progression, overall survival, pharmacokinetic assessment, biomarker analysis, safety, and tolerability.
Of 95 enrolled patients, 70 received study treatment. Most patients had liver cirrhosis (82.9%) and hepatitis B viral infection (75.7%). Disease control rate was 44.8% (primary efficacy analysis; n = 58). Median time to progression was 122 days, median overall survival was 290 days (n = 70). Best clinical responders had RAS mutations; majority of poor responders had wild-type RAS. Most frequent drug-related adverse events were diarrhea, rash, aspartate aminotransferase elevation, vomiting, and nausea. Dose modifications due to adverse events were necessary in almost all patients.
Refametinib plus sorafenib showed antitumor activity in patients with HCC and was tolerated at reduced doses by most patients. Frequent dose modifications due to grade 3 adverse events may have contributed to limited treatment effect. Patients with RAS mutations appear to benefit from refametinib/sorafenib combination.
肝细胞癌（HCC）的治疗选择存在未满足的需求。索拉非尼是目前唯一被批准用于 HCC 的系统治疗药物。Refametinib 是一种口服、变构 MEK 抑制剂，在体外和体内与索拉非尼联合应用显示出抗肿瘤活性。一项评估 refametinib 联合索拉非尼在亚洲 HCC 患者中的疗效和安全性的 II 期研究（NCT01204177）。
符合条件的患者接受每天两次 refametinib 50mg 联合每天两次索拉非尼 200mg（早上）/400mg（晚上）治疗，如果没有发生≥2 级手足皮肤反应、疲劳或胃肠道毒性，则从第 2 周期开始增加索拉非尼剂量至每天 2 次 400mg。主要疗效终点：疾病控制率。次要终点：无进展生存期、总生存期、药代动力学评估、生物标志物分析、安全性和耐受性。
在 95 名入组患者中，70 名患者接受了研究治疗。大多数患者患有肝硬化（82.9%）和乙型肝炎病毒感染（75.7%）。疾病控制率为 44.8%（主要疗效分析；n=58）。中位无进展生存期为 122 天，中位总生存期为 290 天（n=70）。最佳临床应答者有 RAS 突变；大多数不良应答者有野生型 RAS。最常见的药物相关不良事件是腹泻、皮疹、天门冬氨酸氨基转移酶升高、呕吐和恶心。由于不良事件，几乎所有患者都需要调整剂量。
Refametinib 联合索拉非尼在 HCC 患者中显示出抗肿瘤活性，大多数患者可以耐受降低剂量。由于 3 级不良事件频繁需要调整剂量，可能导致治疗效果有限。有 RAS 突变的患者似乎从 refametinib/sorafenib 联合治疗中获益。
