Systemic therapy for intermediate and advanced hepatocellular carcinoma: Sorafenib and beyond

Abstract

The hepatocellular carcinoma (HCC) treatment landscape changed a decade ago, with sorafenib demonstrating survival benefit in the first-line setting and becoming the first systemic therapy to be approved for HCC. More recently, regorafenib and nivolumab have received approval in the second-line setting after sorafenib, with further positive phase 3 studies emerging in the first line (lenvatinib non-inferior to sorafenib) and second line versus placebo (cabozantinib and ramucirumab). A key recommendation in the management of patients receiving sorafenib is to promote close communication between the patient and the physician so that adverse events (AEs) are detected early and severe AEs can be prevented. Sorafenib-related AEs have been identified as clinical biomarkers for sorafenib efficacy. Healthcare professionals have become more efficient in managing AEs, identifying patients who are likely to benefit from treatment, and assessing response to treatment, resulting in a trend towards increased overall survival in the sorafenib arms of clinical studies. The rapidly changing treatment landscape due to the emergence of new treatment options (sorafenib and lenvatinib equally effective in first line; regorafenib, cabozantinib, and ramucirumab showing OS benefit in second line with nivolumab approved by the FDA based on response rate) underscores the importance of re-assessing the role of the first approved systemic agent in HCC, sorafenib.

Sorafenib Induces Pyroptosis in Macrophages and Triggers Natural Killer Cell–Mediated Cytotoxicity Against Hepatocellular Carcinoma

“…Taken together, sorafenib potentiates an effective immunotherapy and, furthermore, does not trigger immune‐related adverse effects such as cytokine release syndrome . However, in order to predict response to this therapy, biomarkers need to be found to identify patients who might benefit . Patients who do not respond to immune checkpoint blockade might be ideal candidates for therapies targeting innate immunity.…”

P4HB modulates epithelial‑mesenchymal transition and the β‑catenin/Snail pathway influencing chemoresistance in liver cancer cells

“…Liver cancer is the sixth most common cancer and is the second leading cause of cancer-associated mortality worldwide in 2018 (1,2). Chemotherapy is one of the most common treatment methods for liver cancer (3,4); however, it is not very efficacious in certain patients (5). Currently, transarterial chemoembolization (TACE) is the preferred therapy for patients with advanced hepatocellular carcinoma (HCC) (6).…”

Molecular diagnosis and therapy of hepatocellular carcinoma: achievements and challenges

“…Currently, nivolumab, a monoclonal antibody targeting PD-1, obtained an accelerated FDA approval in view of tumor response and durability for the therapy of HCC patients already treated with sorafenib in the phase 1/2 single-arm CheckMate 040 study [69] . Nivolumab and pembrolizumab targeted PD-1 are ongoing in clinic [70] .…”

“…Phase III VEGFR1-3, FGFR1-4, PDGFRα, RET and KIT [70] Non-inferior OS, improved PFS, TTP, and ORR [70]…”