New treatment paradigm with systemic therapy in intermediate-stage hepatocellular carcinoma

Abstract

Since the approval of sorafenib for the treatment of unresectable hepatocellular carcinoma in 2007 (in 2009 in Japan), five more regimens have been approved: lenvatinib, and atezolizumab plus bevacizumab for first-line treatment, and regorafenib, cabozantinib, and ramucirumab for second-line treatment, which are currently available for clinical use. The positive results of durvalumab, a programmed cell death ligand 1 antibody, plus tremelimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 antibody, were also presented at the 2022 American Society Clinical Oncology Gastrointestinal Cancers Symposium as superior to sorafenib in prolonging the overall survival; this combination is expected to be approved by the end of 2022. These systemic therapies are changing the treatment paradigm not only for advanced hepatocellular carcinoma but also for intermediate-stage hepatocellular carcinoma. This review focuses on the role of systemic therapy in intermediate-stage hepatocellular carcinoma.

Keywords: Hepatocellular carcinoma; Immune checkpoint inhibitors; Immune microenvironment; Molecular targeted therapy; Systemic therapy.

Fig. 1

Possible sequential systemic therapy for hepatocellular carcinoma. Both atezolizumab + bevacizumab and durvalumab + tremelimumab will be the first-line systemic therapy. When one regimen is selected, another first line regimen will be selected as second-line regimen since in that way substantial triple regimen (anti-PD-L1 + anti-CTLA-4 + anti-VEGF) will be possible. ( Modified from ref# 50)

Fig. 2

Novel treatment strategy for intermediate stage HCC. For intermediate-stage HCC unsuitable for TACE, LEN–TACE sequential therapy or ABC conversion therapy should be applied. In both cases, systemic therapy should be used upfront, and curative treatments such as resection, ablation and curative TACE should be followed to achieve a cancer-free and drug-free status

Fig. 3

Treatment strategy of intermediate-stage HCC. SNEG simple nodular type with extra growth, CMN confluent multinodular type, LEN-TACE Lenvatinib-TACE sequential therapy, ABC conversion therapy, atezolizumab plus bevacizumab followed by curative conversion therapy

Fig. 4

Different response pattern according to different regimens. Atezo + Bev usually achieves tumor shrinkage, whereas lenvatinib (LEN) achieves tumor necrosis through tumor arterial flow reduction. ( Modified from ref # 22 and #23)

Fig. 5

Ongoing phase III clinical trials on hepatocellular carcinoma. A number of ongoing trials are being conducted in patients with early-, intermediate-, and advanced-stage hepatocellular carcinoma using immune checkpoint inhibitors alone or in combination with tyrosine kinase inhibitors, anti-VEGF antibody or anti-CTLA-4 antibody. PBO placebo, LEN lenvatinib, SOR sorafenib