Hepatocellular carcinoma - Emerging treatments

Apatinib

Apatinib (also known as rivoceranib) is an investigational tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor-2. In one phase 3 randomised placebo-controlled trial, apatinib significantly improved overall survival in adult patients with advanced hepatocellular carcinoma (HCC) previously refractory or intolerant to at least one line of systemic or chemotherapy or targeted therapy.[124]

Donafenib

Donafenib, an investigational novel multikinase inhibitor and a deuterated sorafenib derivative, has been shown to improve overall survival in patients with unresectable or metastatic HCC who received no prior systemic therapy compared with sorafenib in one open-label, parallel-controlled phase 2-3 trial.[125]

Pembrolizumab plus lenvatinib

Pembrolizumab and lenvatinib combination treatment has been granted breakthrough therapy designation for the treatment of newly diagnosed, advanced HCC by the US Food and Drug Administration (FDA). A phase 1B study is underway examining the safety and efficacy of pembrolizumab plus lenvatinib for patients with unresectable HCC, Barcelona Clinic Liver Cancer (BCLC) stage B (not eligible for transarterial chemoembolisation [TACE]) or C, Child-Pugh class A, and Eastern Cooperative Oncology Group performance status of 0 or 1.[126] Pembrolizumab plus lenvatinib has demonstrated promising anti-tumour activity with acceptable tolerability.[127] An ongoing double-blind randomised controlled phase 3 study of pembrolizumab plus lenvatinib versus lenvatinib plus placebo as first-line treatment of unresectable HCC should confirm the efficacy and safety of this combination.[128]

Radioactive iodine (131-I)-labelled metuximab

Metuximab is an investigational monoclonal antibody against the CD147 antigen that is expressed in HCC. A phase 2 trial investigated 131-I-labelled metuximab's role as an adjuvant therapy after curative-intent resection of HCC expressing CD147. Patients who received one dose of transarterial 131-I-labelled metuximab 4-6 weeks after hepatectomy were compared with patients who received no adjuvant treatment. Five-year recurrence-free survival was significantly higher in the adjuvant 131-I-labelled metuximab group (43.4% vs. 21.7%).[129]

Chimeric antigen receptor (CAR) T-cell therapy

CAR T-cell therapy involves the modification of the patient's T cells to target and destroy cancer cells. One phase 1/2 study of T cells engineered to detect alpha-fetoprotein/human leukocyte antigen complex on HCC cells is in progress.[130] Another phase 1/2 study is investigating T cells engineered to detect cells expressing the HCC antigen glypican 3.[131]

Rencofilstat

Rencofilstat, an investigational oral cyclophilin inhibitor, has been granted orphan drug designation by the FDA for treating HCC. Trials of rencofilstat have been limited to patients with metabolic dysfunction-associated steatohepatitis.[132]

External beam radiotherapy (EBRT)

One Cochrane systematic review found low-quality evidence to suggest that EBRT, in combination with TACE, may be associated with lower mortality and increased complete and overall response rates in patients with unresectable HCC.[133] However, increased liver toxicity was reported.[133] [ ] One further randomised controlled trial of patients with HCC showing macroscopic vascular invasion compared a combination of EBRT and TACE with sorafenib.[134] The study found that the combination of EBRT and TACE was well tolerated and improved progression-free and overall survival compared with sorafenib. The American Society for Radiation Oncology and American College of Radiology recommend EBRT as an option in patients with liver-confined HCC who are not candidates for curative treatment, as consolidative therapy in patients with liver-confined HCC after incomplete response to other treatments, and as a salvage option for local recurrences. EBRT is conditionally recommended as a bridge to transplant or before surgery in selected patients, and palliative EBRT is conditionally recommended for symptomatic primary HCC and/or macrovascular tumour thrombi.[90][135]