Editor’s Note: The 18th International Liver Cancer Association (ILCA) Annual Conference took place in Toronto, Canada, from October 17-19, 2024. During the conference, Prof. Richard S. Finn of the David Geffen School of Medicine at UCLA presented subgroup data from the real-world REFINE study, highlighting that patients with unresectable hepatocellular carcinoma (uHCC) who received transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) in addition to regorafenib had better survival trends. Oncology Frontier invited Dr. Yunfei Yuan from the Sun Yat-sen University Cancer Center to discuss and provide insights on this study.

Dr. Yunfei Yuan：Regorafenib, an oral multi-kinase inhibitor, blocks various protein kinases involved in tumor growth and progression, including kinases associated with angiogenesis (VEGFR1-3, TIE2), tumor proliferation (KIT, RET, RAF-1, BRAF), tumor microenvironment (VEGFR3, PDGFR, FGFR), and tumor immunity (CSF1R). The positive results from the international phase 3 RESORCE study led to regorafenib’s approval as the first second-line targeted therapy for uHCC, and the real-world REFINE study further confirmed its efficacy and safety. Since the RESORCE study’s publication (Lancet, 2017), numerous investigations on combined interventional and systemic therapies for advanced HCC have been conducted globally, with TACE plus targeted therapy being a common approach.

Theoretically, interventional therapies like TACE not only reduce tumor burden but also synergize with targeted and immune therapies by promoting tumor vessel normalization, improving the immune microenvironment, and enhancing tumor antigen release. Thus, combining systemic therapies such as targeted and immune therapies with TACE may enhance efficacy and increase survival benefits. The REFINE study’s subgroup analysis presented at ILCA 2024 confirmed this theory, showing that patients treated with regorafenib who also received TACE or TARE had improved survival outcomes. One key clinical concern is the tolerability of combination therapy, and this study found that the incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was similar between patients with and without TACE (50% vs. 58%), indicating that adding TACE did not exacerbate adverse reactions. Although this was a real-world study without specific data on the timing or frequency of interventional treatments, patients appeared generally tolerant of the therapy, with comparable discontinuation rates between those with and without TACE (30% vs. 32%).

Domestically, retrospective studies have reported favorable outcomes with regorafenib combined with TACE as a second-line treatment for uHCC, showing an objective response rate (ORR) of 42.3% and a disease control rate (DCR) of 66.1%, with only nine patients experiencing grade 3/4 adverse events. These findings support the feasibility of TACE combined with regorafenib for advanced HCC.

With the advances in targeted and immune therapies, there has been a surge of studies on TACE combined therapies, particularly given TACE’s role as the standard for intermediate HCC treatment. Evidence-based studies, such as the phase 3 LEAP-012 trial presented at this year’s ESMO conference, have shown that combining TACE with the “Keytruda + Lenvima” regimen for intermediate HCC significantly improved progression-free survival (PFS: 14.6 vs. 10.0 months; HR 0.66, P=0.0002). Similarly, the phase 3 EMERALD-1 trial demonstrated that TACE combined with “D+B” (durvalumab + bevacizumab) significantly improved PFS in patients with locally advanced HCC (15.0 vs. 8.2 months, HR 0.77, P=0.032).

In summary, TACE and other interventional treatments combined with targeted and immune therapies exhibit strong synergistic effects. With an expanding range of drug combinations and broader therapeutic indications, these combination therapies are poised to drive significant advances in HCC treatment, offering hope to more patients.

Reference

[1]Richard S. Finn, et al.OBSERVATIONAL STUDY OF PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA TREATED WITH REGORAFENIB IN ROUTINE CLINICAL PRACTICE (REFINE): SUBGROUP ANALYSIS BY PRIOR TRANSARTERIAL CHEMOEMBOLIZATION (TACE) AND TRANSARTERIAL RADIOEMBOLIZATION (TARE).ILCA 2024;P-69

[2]Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet. 2017 Jan 7;389(10064):36. doi: 10.1016/S0140-6736(16)32615-0]. Lancet. 2017;389(10064):56-66. doi:10.1016/S0140-6736(16)32453-9

[3]Richard S. Finn,et al.Real-world dosing of regorafenib in patients with unresectable hepatocellular carcinoma (uHCC): Final analysis of the prospective, observational REFINE study. Journal of Clinical Oncology,Volume 41, Number 4_suppl. https://doi.org/10.1200/JCO.2023.41.4_suppl.518

[4]Perfahl H, Jain HV, Joshi T, et al. Hybrid Modelling of Transarterial Chemoembolisation Therapies (TACE) for Hepatocellular Carcinoma (HCC). Sci Rep. 2020;10(1):10571. Published 2020 Jun 29. doi:10.1038/s41598-020-65012-1

[5]Tachiiri T, Nishiofuku H, Maeda S, et al. Vascular Normalization Caused by Short-Term Lenvatinib Could Enhance Transarterial Chemoembolization in Hepatocellular Carcinoma. Curr Oncol. 2023;30(5):4779-4786. Published 2023 May 5. doi:10.3390/curroncol30050360

[6]Wang H, Xiao W, Han Y, et al. Study on safety and efficacy of regorafenib combined with transcatheter arterial chemoembolization in the treatment of advanced hepatocellular carcinoma after first-line targeted therapy. J Gastrointest Oncol. 2022;13(3):1248-1254. doi:10.21037/jgo-22-395

[7]Llovet JM, et al. Transarterial chemoembolization (TACE) with or without lenvatinib (len) +pembrolizumab (pembro) for intermediate-stage hepatocellular carcinoma (HCC): Phase III LEAP-012 study.2024ESMO LBA3.

[8]Riccardo Lencioni,et al.EMERALD-1: A phase 3, randomized, placebo-controlled study of transarterial chemoembolization combined with durvalumab with or without bevacizumab in participants with unresectable hepatocellular carcinoma eligible for embolization.Journal of Clinical Oncology,Volume 42, Number 3_suppl.https://doi.org/10.1200/JCO.2024.42.3_suppl.LBA432

Dr. Yunfei Yuan

  • Second-Tier Professor, Second-Tier Research Fellow, Chief Physician, Doctoral Supervisor at Sun Yat-sen University
  • Lead Professor of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center
  • Principal Investigator, National Key Laboratory of Cancer Prevention and Control of South China

Specialization: Surgical and interventional treatments for liver tumors

Professional Affiliations:

  • Expert Member, Hepatic Surgery Expert Group, Surgery Branch, Chinese Medical Doctor Association
  • Chairman, Tumor Metastasis Committee, Guangdong Anti-Cancer Association
  • Chairman, Liver Cancer and Liver Metastasis Committee, Guangdong Clinical Medicine Association

Editorial Roles:

  • Editorial Board Member of Cancer Communications, Chinese Journal of General Surgery (Electronic Edition), Chinese Journal of Hepatic Surgery (Electronic Edition), and Lingnan Modern Clinical Surgery
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Last updated on 2024.11.17