https://orcid.org/0000-0003-4863-6924
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ABSTRACT
Introduction
Although hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, there are limited therapeutic options for the advanced stages. Sorafenib was the first tyrosine-kinase inhibitor (TKI) approved for unresectable HCC and remained the only effective choice for a decade. The horizon of systemic treatments drastically expanded in the latest years, opening new interesting possibilities.
Areas covered
In this manuscript, the authors have analysed the recent advances in pharmacotherapy for HCC, discussing their mechanisms of action, the clinical efficacy and the safety profile of currently available first, second-and third-line treatments. The authors have also analysed the role of immune system modulators, in particular immune checkpoints inhibitors (ICIs), based on the limited data published so far.
Expert opinion
The emergence of new targeted therapies, such as lenvatinib, have changed the landscape of HCC therapy. Tumor extension, differences in objective response rates and adverse events profiles should be considered to tailor the choice of the first-line agent. Sorafenib remains the most studied drug, with much real-world data available. The efficacy of second line therapies has only been proven in non-responder or sorafenib-intolerant patients. Unfortunately, studies directly comparing the second-line agents regorafenib, ramucirumab and cabozantinib are still lacking.
Abbreviations
| AIFA | = | Agenzia Italiana del Farmaco |
| AEs | = | adverse events |
| AFP | = | α-fetoprotein |
| DEB-TACE | = | drugs-eluting beads transarterial chemoembolization |
| BMI | = | body mass index |
| CSF1R | = | colony stimulating factor 1 receptor |
| CT | = | computed tomographic |
| CTLA4 | = | cytotoxic T lymphocyte antigen-4 |
| DCR | = | disease control rate |
| ECOG | = | Eastern Cooperative Oncology Group |
| EGF | = | epidermal growth factor (EGF) |
| EGFR | = | epidermal growth factor receptor |
| EMA | = | European Medicines Agency |
| FDA | = | Food and Drug Administration |
| FGF | = | fibroblast growth factor (FGF) |
| FGFR | = | fibroblast growth factor receptor |
| FLT-3 | = | fms like tyrosine kinase 3 |
| HCC | = | hepatocellular carcinoma |
| HIF-1α | = | hypoxia inducible factor-1α |
| ICI | = | immune checkpoint inhibitors |
| MAPK | = | Mitogen-activated protein kinase |
| MDTB | = | multidisciplinary tumor board |
| mRECIST | = | modified Response Evaluation Criteria in Solid Tumors |
| MAPK | = | Mitogen-Activated Protein Kinase |
| MVI | = | macroscopic vascular invasion |
| NAFLD | = | non-alcoholic fatty liver disease |
| NF-κB | = | nuclear factor kappa-light-chain-enhancer of activated B cells |
| NK | = | natural killer |
| ORR | = | objective response rate |
| OS | = | overall survival |
| PAMPs | = | pathogen associated molecular patterns |
| PDGF | = | Platelet-derived growth factor |
| PDGFR | = | Platelet-derived growth factor receptors |
| PD-1 | = | programmed death-1 (PD-1) |
| PDL-1, 2 | = | programmed death ligand-1 or 2 (PDL-1/PDL-1) |
| PFS | = | progression-free survival |
| QALYs | = | quality-adjusted life-years |
| RECIST | = | Response evaluation criteria in solid tumors |
| RET | = | REarranged during Transfection |
| RET/PTC | = | REarranged during Transfection/Papillary thyroid carcinoma |
| RRR | = | radiological response rate |
| RT | = | radiotherapy |
| SIRT | = | selective internal radiation therapy |
| TARE | = | transarteria radioembolization |
| TACE | = | transarterial chemoembolization |
| TKI | = | tyrosine kinase inhibitor |
| TME | = | tumor microenvironment |
| TTP | = | time-to-progression |
| TTRP | = | time to radiological progression |
| TTSP | = | time to symptomatic progression |
| TTUP | = | time to untreatable (unTACEable) progression |
| VEGF | = | vascular endothelial growth factor; |
| VEGFR | = | vascular endothelial growth factor receptor |
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Article Highlights
Sorafenib was the first tyrosine-kinase inhibitor approved for advanced HCC and remained the only effective choice for a decade.
Lenvatinib demonstrated a non-inferior overall survival compared to Sorafenib in the first-line treatment of advanced HCC, with a statistically significant improvement in all the secondary efficacy endpoints (progression-free survival, time to progression, and objective response rate)
Second-line treatment includes regorafenib, ramucirumab (for patients with alfafetoprotein > 400 ng/ml) and cabozantinib. Cabozantinib can be used also for third-line treatment.
There is evidence of intra-hepatic immune response activation in tumor microenvironment and so immune checkpoint blockade may have a strong rationale even in the treatment of HCC
IMbrave150 is the first study that has demonstrated a new regimen (bevacizumab + atezolizumab) to be superior to sorafenib for improving median overall survival in first-line setting.
Reviewer Disclosures
Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.