He MinKe, Huang YeXing, Du ZeFeng, Lai ZhiCheng, Ouyang Hanyue, Shen JingXian, Wen DongSheng, Li QiJiong, Zhang YaoJun, Wei Wei, Chen MinShan, Xu Li, Kan Anna, Shi Ming
Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Clin Cancer Res. 2023 Dec 15;29(24):5104-5115. doi: 10.1158/1078-0432.CCR-23-0060.
To investigate the efficacy, safety, and biomarkers of systemic chemotherapy with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) in combination with lenvatinib and toripalimab as the first-line treatment for advanced hepatocellular carcinoma (HCC) with extrahepatic metastasis.
In this biomolecular exploratory, phase II trial, eligible patients underwent the triple combination therapy of lenvatinib, toripalimab, plus FOLFOX chemotherapy. Primary endpoint was progression-free survival (PFS) rate at 6 months by RECIST v1.1. Single-nucleus RNA sequencing (snRNA-seq) of tumor biopsy samples was performed for exploratory biomarker analyses.
Between November 19, 2019, and July 4, 2021, 30 patients were enrolled. The primary endpoint was a 6-month PFS rate of 66.7%, with a median PFS of 9.73 months [95% confidence interval (CI), 2.89-16.58]. The median overall survival (OS) was 14.63 months (95% CI, 11.77-17.50), with an objective response rate of 43.3%. Twenty-four (80.0%) patients exhibited high-risk features, among whom the median OS and PFS were 13.7 months (95% CI, 9.24-18.16) and 8.3 months (95% CI, 3.02-13.58), respectively. The most common adverse events were neutropenia, and increased aspartate aminotransferase and alanine aminotransferase levels. Exploratory analyses of snRNA-seq profiles suggested that patients with higher abundance of tumor-infiltrating immune cells were more likely to benefit from this combination. In addition, two subtypes of hepatocytes (AKR1C2+ and CFHR4+ malignant hepatocytes) were associated with reduced clinical benefits.
FOLFOX chemotherapy in combination with lenvatinib and toripalimab showed promising antitumor activity with manageable toxicities in advanced HCC with extrahepatic metastasis. AKR1C2+ and CFHR4+ hepatocyte subtypes may be predictive biomarkers of resistance to the combination therapy.
探讨奥沙利铂、亚叶酸钙和5-氟尿嘧啶（FOLFOX）全身化疗联合乐伐替尼和托瑞帕利单抗作为一线治疗伴有肝外转移的晚期肝细胞癌（HCC）的疗效、安全性和生物标志物。
在这项生物分子探索性II期试验中，符合条件的患者接受了乐伐替尼、托瑞帕利单抗加FOLFOX化疗的三联联合治疗。主要终点是根据RECIST v1.1标准评估的6个月无进展生存期（PFS）率。对肿瘤活检样本进行单核RNA测序（snRNA-seq）以进行探索性生物标志物分析。
在2019年11月19日至2021年7月4日期间，共纳入30例患者。主要终点是6个月PFS率为66.7%，中位PFS为9.73个月[95%置信区间（CI），2.89 - 16.58]。中位总生存期（OS）为14.63个月（95% CI，11.77 - 17.50），客观缓解率为43.3%。24例（80.0%）患者具有高危特征，其中位OS和PFS分别为13.7个月（95% CI，9.24 - 18.16）和8.3个月（95% CI，3.02 - 13.58）。最常见的不良事件是中性粒细胞减少以及天冬氨酸转氨酶和丙氨酸转氨酶水平升高。snRNA-seq图谱的探索性分析表明，肿瘤浸润免疫细胞丰度较高的患者更有可能从这种联合治疗中获益。此外，两种肝细胞亚型（AKR1C2 +和CFHR4 +恶性肝细胞）与临床获益降低相关。
FOLFOX化疗联合乐伐替尼和托瑞帕利单抗在伴有肝外转移的晚期HCC中显示出有前景的抗肿瘤活性，且毒性可控。AKR1C2 +和CFHR4 +肝细胞亚型可能是联合治疗耐药的预测生物标志物。
