Supplementary Material for: Avelumab in Combination with Axitinib as First-Line Treatment in Patients with Advanced Hepatocellular Carcinoma: Results from the Phase 1b VEGF Liver 100 Trial

<b><i>Introduction:</i></b> Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for the treatment of advanced/metastatic hepatocellular carcinoma (aHCC). Avelumab is a human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We report the final analysis from VEGF Liver 100 (NCT03289533), a phase 1b study evaluating safety and efficacy of avelumab plus axitinib in treatment-naive patients with aHCC. <b><i>Methods:</i></b> Eligible patients had confirmed aHCC, no prior systemic therapy, ≥1 measurable lesion, Eastern Cooperative Oncology Group performance status ≤1, and Child-Pugh class A disease. Patients received avelumab 10 mg/kg intravenously every 2 weeks plus axitinib 5 mg orally twice daily until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and investigator-assessed objective response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST) for HCC. <b><i>Results:</i></b> Twenty-two Japanese patients were enrolled and treated with avelumab plus axitinib. The minimum follow-up was 18 months as of October 25, 2019 (data cutoff). Grade 3 treatment-related adverse events (TRAEs) occurred in 16 patients (72.7%); the most common (≥3 patients) were hypertension (<i>n</i> = 11 [50.0%]), palmar-plantar erythrodysesthesia syndrome (<i>n</i> = 5 [22.7%]), and decreased appetite (<i>n</i> = 3 [13.6%]). No grade 4 TRAEs or treatment-related deaths occurred. Ten patients (45.5%) had an immune-related AE (irAE) of any grade; 3 patients (13.6%) had an infusion-related reaction (IRR) of any grade, and no grade ≥3 irAE and IRR were observed. The objective response rate was 13.6% (95% CI: 2.9–34.9%) per RECIST 1.1 and 31.8% (95% CI: 13.9–54.9%) per mRECIST for HCC. <b><i>Conclusion:</i></b> Treatment with avelumab plus axitinib was associated with a manageable toxicity profile and showed antitumor activity in patients with aHCC.

引言：免疫检查点抑制剂与抗血管生成靶向药物联合使用，可利用二者互补的作用机制治疗晚期/转移性肝细胞癌（advanced/metastatic hepatocellular carcinoma, aHCC）。阿维鲁单抗（avelumab）是靶向PD-L1的人源IgG1单克隆抗体，在多种肿瘤类型中展现临床活性；阿昔替尼（axitinib）是选择性靶向血管内皮生长因子受体1、2、3的酪氨酸激酶抑制剂。本研究报告了VEGF Liver 100（NCT03289533）的最终分析结果，这是一项1b期临床试验，旨在评估阿维鲁单抗联合阿昔替尼用于未经系统治疗的aHCC患者的安全性与有效性。
方法：入组患者需经确诊为aHCC，未接受过既往系统治疗，存在≥1个可测量病灶，东部肿瘤协作组体能状态评分≤1，且肝功能为Child-Pugh A级。患者接受阿维鲁单抗10mg/kg静脉输注，每2周一次，联合阿昔替尼5mg口服，每日两次，直至疾病进展、出现不可接受的毒性反应或患者退出研究。研究终点包括安全性，以及研究者依据实体瘤疗效评价标准1.1版（Response Evaluation Criteria in Solid Tumors 1.1, RECIST 1.1）和肝细胞癌改良版实体瘤疗效评价标准（modified RECIST, mRECIST）评估的客观缓解情况。
结果：共入组并治疗22例日本患者。截至2019年10月25日的数据截止日，最短随访时长为18个月。16例患者（72.7%）出现3级治疗相关不良事件（treatment-related adverse events, TRAEs），最常见（发生例数≥3）的不良事件为高血压（n=11[50.0%]）、掌跖红斑感觉异常综合征（n=5[22.7%]）及食欲下降（n=3[13.6%]）。未观察到4级治疗相关不良事件或治疗相关死亡。10例患者（45.5%）出现任意级别的免疫相关不良事件（immune-related AE, irAE）；3例患者（13.6%）出现任意级别的输液相关反应（infusion-related reaction, IRR），未观察到≥3级的免疫相关不良事件及输液相关反应。依据RECIST 1.1评估的客观缓解率为13.6%（95%置信区间：2.9–34.9%），依据肝细胞癌mRECIST评估的客观缓解率为31.8%（95%置信区间：13.9–54.9%）。
结论：阿维鲁单抗联合阿昔替尼治疗的安全性可控，且在aHCC患者中展现出明确的抗肿瘤活性。