Targeted and immune therapies for hepatocellular carcinoma: Predictions for 2019 and beyond

Abstract

Systemic therapy for hepatocellular carcinoma (HCC) has markedly advanced since the survival benefit of a molecular targeted agent, sorafenib, were demonstrated in the SHARP and Asia Pacific trials in 2007. Treatment options for patients with advanced HCC increased by sorafenib, and long-term survival for patients with advanced stage HCC has become possible to some extent. However, development of a more potent first-line novel molecular targeted agent replacing sorafenib and a potent second-line agent after disease progression on or intolerant to sorafenib has been warranted because sorafenib lacks tumor shrinking/necrotizing effects and induces relatively severe adverse events such as hand foot skin reaction. Many agents in the 1st line and 2nd line setting were attempted to develop between 2007 and 2016, but all of these clinical trials failed. On the other hand, clinical trials of 4 agents (regorafenib, lenvatinib, cabozantinib, and ramucirumab) succeeded in succession in 2017 and 2018, and their use in clinical practice is possible (regorafenib and lenvatinib) or underway (cabozantinib and ramucirumab). Furthermore, all of 5 clinical trials of combination therapy with transcatheter chemoembolization (TACE) plus a molecular targeted agent failed to date, however, the combination of TACE and sorafenib (TACTICS trials) was reported to be successful and presented at ASCO in 2018. Phase 3 clinical trials of immune checkpoint inhibitors and a combination therapy of immune checkpoint inhibitors and molecular targeted agents are also ongoing, which suggests treatment paradigm of HCC in all stages from early, intermediate and advanced stage, is expected to be changed drastically in the very near future.

Keywords: Hepatocellular carcinoma; Immune checkpoint inhibitor; Lenvatinib; Molecular targeted agent; Sorafenib.

Figure 1

Systemic therapy in hepatocellular carcinoma: 2018 and beyond[53]. Two first-line systemic agents, sorafenib and lenvatinib, are approved and can be used in the clinical practice. Second-line agent, regorafenib is approved for clinical use for progressors on sorafenib. Cabozantinib and ramucirumab will be approved in 2019. AFP: Alpha fetal protein.

Figure 2

Possible sequential therapies of molecular targeted agents for hepatocellular carcinoma in the real-world practice[53]. There are solid evidence for use of regorafenib, ramucirumab, cabozantinib after sorafenib as confirmed by RESORCE, REACH-2 and CERESTIAL trials. However, lenvatinib has been proven to be effective after sorafenib or regorafenib in the real world practice as a second-line or third-line agent. Effectiveness of second-line agents after lenvatinib failure should be explored in the real-world practice setting. AFP: Alphafeto protein.

Figure 3

Tumor Immuno suppressive microenvironment caused by vascular endothelial growth factor produced by tumor[66]. VEGF-A up-regulates tumor-associated macrophage, regulatory T-cell, and myeloid-derived suppressor cell, which cause immune suppressive microenvironment through the down-regulation of the dendritic cell maturation, NK activation, T cell activation and T cell proliferation. VEGF-A: Vascular endothelial growth factor A; MDSC: Myeloid-derived suppressor cell; DC: Dendritic cell; TAM: Tumor-associated macrophage; Treg: Regulatory T cell; IL: Interleukin.

Figure 4

Mechanism underlying the synergistic effect of combination therapy on hepatocellular carcinoma with lenvatinib and anti-PD-1/PD-L1 antibodies[68]. Lenvatinib inhibits tumor angiogenesis and growth through VEGFR1-R3 and FGFR1-R4 inhibition. Lenvatinib also inhibits VEGF-mediated tumor suppressive microenvironment, such as immunosuppressive cells (tumor associated macrophage, regulatory T cells and myeloid-derived suppressor T cells) or tumor suppressive cytokines (IL10 or TGF-β). Lenvatinib also suppress the co-inhibitory checkpoint inhibitor, TIM 3 and increase the co-stimulatory molecules, CD137, OX40 or ICOS. Finally, PD-1/PD-L1 Ab restores the exhausted T cell activity to kill the cancer cell. Therefore, synergistic effect is obtained by this combination.

Figure 5

Improved Overall Survival after combination therapy with molecular targeted agents and immune checkpoint inhibitors[70]. Molecular targeted agents improve survival compared with chemotherapy by cytotoxic agents, but will become resistant sooner or later. Durable long-lasting response is obtained by immune checkpoint inhibitors, but only small portion of patients (15%-20%). Durable long-lasting response will be expected by a combination therapy with molecular targeted agents and immune checkpoint inhibitors in the majority of the patients (50%-70%) with advanced hepatocellular carcinoma.