Lenvatinib, a multi-kinase inhibitor, has been approved as first-line treatment for advanced hepatocellular carcinoma (HCC), but its efficacy is limited. We have shown previously that lenvatinib and epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) combination therapy overcomes lenvatinib resistance in HCC with high level of EGFR expression (EGFR^high). We present here the results of a single-arm, open-label, exploratory study of lenvatinib plus the EGFR-TKI gefitinib for patients with HCC resistance to lenvatinib (NCT04642547; n = 30). Only patients with EGFR^high HCC and progressive disease after lenvatinib treatment were recruited in the study. The most frequent adverse events of all grades were fatigue (27 patients; 90%), followed by rash (25 patients; 83.3%), diarrhea (24 patients; 80%), and anorexia (12 patients; 40%). Among 30 patients, 9 (30%) achieved a confirmed partial response and 14 (46.7%) had stable disease according to mRECIST criteria. Based on RECIST1.1, 5 (16.7%) achieved a confirmed partial response and 18 (60%) had stable disease. The estimated median progression free survival (PFS) and overall survival (OS) time were 4.4 months (95% CI: 2.5 to 5.9) and13.7 months (95% CI: 9.0 to NA), respectively. The objective response rate (ORR) of the patients in the present study compares very favorable to that seen for the two approved second line treatments for HCC (cabozantinib ORR of 4%; regorafenib ORR of 11%). Given that this combination was well-tolerated, a further clinical study of this combination is warranted.

Lenvatinib 是一种多激酶抑制剂，已被批准作为晚期肝细胞癌 （HCC） 的一线治疗，但其疗效有限。我们之前已经表明，乐伐替尼和表皮生长因子受体酪氨酸激酶抑制剂 （EGFR-TKI） 联合疗法克服了 EGFR 表达水平高 （EGFR^高） 的 HCC 对乐伐替尼的耐药性。我们在这里介绍了 lenvatinib 联合 EGFR-TKI 吉非替尼治疗 HCC 对 lenvatinib 耐药的患者的单臂、开放标签、探索性研究的结果 （NCT04642547;n = 30）。该研究仅招募了 EGFR^高 HCC 和 lenvatinib 治疗后疾病进展的患者。所有级别中最常见的不良事件是疲劳 （27 例患者;90%），其次是皮疹 （25 例患者;83.3%）、腹泻 （24 例患者;80%） 和厌食 （12 例患者;40%）。根据 mRECIST 标准，在 30 例患者中，9 例 （30%） 达到确认的部分缓解，14 例 （46.7%） 病情稳定。根据 RECIST1.1,5 例 （16.7%） 达到确认的部分缓解，18 例 （60%） 病情稳定。估计的中位无进展生存期 （PFS） 和总生存期 （OS） 分别为 4.4 个月 （95% CI： 2.5 至 5.9） 和 13.7 个月 （95% CI： 9.0 至 NA）。本研究中患者的客观缓解率 （ORR） 与两种已批准的 HCC 二线治疗 （卡博替尼 ORR 为 4%;瑞戈非尼 ORR 为 11%） 相比非常有利。鉴于这种组合耐受性良好，有必要对这种组合进行进一步的临床研究。