背景：進展期肝細胞癌(HCC)合並巨大肝腫塊和大血管侵犯多見於初診，而肝外轉移較少(77.5%比 37.9%)。然而，在 IMbrave150、夏普和亞太夏普的臨床試驗中，肝外轉移的比例分別達到了 63%、53%和 68.7%，而大血管侵犯隻占 38%、36%和 36%。與之前和正在進行的探索 Firstline 治療晚期肝癌的最佳係統用藥的 3 期臨床試驗不同，這項研究主要針對肝內腫瘤負擔增加的人群。

Background: Advanced hepatocellular carcinoma (HCC) with mega liver masses and macrovascular invasion were commonly observed at the first diagnosis, while with less extrahepatic metastases (77.5% vs. 37.9%). However, in clinical trials IMbrave150, SHARP, and Asia-Pacific SHARP, the percentage of extrahepatic metastases reached 63%, 53%, and 68.7%, respectively, while macrovascular invasion only accounted for 38%, 36%, and 36%. Unlike the previous and ongoing phase 3 clinical trials exploring the optimal systemic medication in the first-line treatment of advanced HCC, this study mainly focused on a population with a heavy intrahepatic tumor burden.

方法：在這項開放的 3 期試驗中，患者按 1：1 的比例隨機分配，接受 FOLFOX 方案的肝動脈灌注化療(HAIC-FO)或索拉非尼治療。HAIC-FO 組的患者接受腫瘤和正常組織的活檢，以尋找預測治療反應的潛在基因組生物標誌物。

Methods: In this open-label, phase 3 trial, patients were randomly assigned in a 1:1 ratio to undergo hepatic arterial infusion chemotherapy (HAIC) of FOLFOX regimens (HAIC-FO) or sorafenib treatment. Patients in the HAIC-FO group were recommended to receive tumor and normal tissue biopsy to search for the potential genomic biomarkers in predicting the response to treatment.

結果:2017 年 5 月至 2020 年 5 月期間，共招募了 551 名患者。260 名符合條件的患者被隨機分配接受 HAIC-FO(n=130)或索拉非尼(n=132)治療，並納入意向治療人群。大血管侵犯伴或不伴肝外轉移占 82.8%(84.6%和 81.1%；P=0.446)。腫瘤平均直徑 HAIC-FO 組為 11.7 cm(IQR8.314.0)，索拉非尼組為 10.8 cm(8.7~13.6)(P=0.439)。腫瘤體積>50%的患者肝髒受累比例分別為 41.5%和 39.4%(P=0.724)。截止到數據截止時(2020 年 10 月 31 日，190 例死亡[HAIC-FO 組 79 例，索拉非尼組 111 例])，接受 HAIC-FO 治療的患者的中位總生存期為 13.9 個月(95%可信區間為 10.6-17.2)，而接受索拉非尼治療的患者的中位總生存期為 8.2 月 (7.5-9.0)(HR 0.408[95%可信區間 0.301-0.552]，P<0.001)。HAIC-FO 組有 16 例(12.3%)患者腫瘤減小，其中 15 例(93.8%)接受根治性手術或消融，最終獲得 20.8(16.4)個月(95%CI 9.1~32.5[7.5~25.3])的中位總生存期(無進展生存期)，1 年生存率 93.8%(68.8%)。HAIC-FO 組正在進行基於全基因組測序的預測生物標誌物分析。

Results: Between May 2017 and May 2020, 551 patients were recruited. Two hundred sixty eligible patients were randomly assigned to receive HAIC-FO (n = 130) or sorafenib (n = 132) and were included in the intention-to-treatment population. Macrovascular invasion with or without extrahepatic metastasis was present in 82.8% of patients (84.6% and 81.1%; P = 0.446). The median tumor diameter was 11.7 cm (IQR 8.3-14.0) of the HAIC-FO group and 10.8 cm (8.7-13.6) of the sorafenib group (P = 0.439). The percentage of patients with > 50% tumor volume involvement of the liver was 41.5% and 39.4%, respectively (P = 0.724). At the time of data cutoff (Oct 31, 2020, at 190 deaths [79 of HAIC-FO and 111 of sorafenib]), patients receiving HAIC-FO had a median overall survival of 13.9 months (95%CI 10.6-17.2), compared with 8.2 months (7.5-9.0) for those receiving sorafenib (HR 0.408 [95%CI 0.301-0.552], P < 0.001). Tumor downstaging occurred in 16 (12.3% of 130) patients of the HAIC-FO group, including 15 (93.8%) receiving curative surgery or ablation and finally achieving a median overall survival (progression-free survival) of 20.8 (16.4) months (95%CI 9.1-32.5 [7.5-25.3]) with a 1-year rate of 93.8% (68.8%). Analyses of predictive biomarkers based on the whole genome sequencing were ongoing in the HAIC-FO group.

結論：這項隨機 3 期研究證明，HAIC-FO 在原發性診斷的晚期肝癌一線治療中的療效和生存結果優於索拉非尼，提示對於肝內腫瘤負荷較重的患者，HAIC-FO 單一治療可能是比索拉非尼更好的治療策略。

Conclusions: This randomized phase 3 study proved that HAIC-FO had superior efficacy and survival outcome than sorafenib in the first-line treatment of primary diagnostic, advanced HCC, indicating that patients with heavy intrahepatic tumor burden, HAIC-FO monotherapy might be a better strategy than sorafenib.