The small molecule multikinase inhibitor sorafenib remains the only molecularly targeted therapy approved by the FDA for the treatment of hepatocellular carcinoma, with ongoing clinical trials diligently testing the potential for novel targeted agents or combination therapies to further improve patient outcomes in this setting.
The small molecule multikinase inhibitor sorafenib remains the only molecularly targeted therapy approved by the FDA for the treatment of hepatocellular carcinoma (HCC). Ongoing clinical trials are diligently testing the potential for novel targeted agents or combination therapies to further improve patient outcomes in this setting.
Sorafenib tosylate (Nexavar) was approved by the FDA in late 2007 for the treatment of unresectable HCC, a decision based on the findings of the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial.1According to this multicenter, double-blind, phase III study, a randomized protocol of either sorafenib or placebo in 602 advanced, untreated patients with HCC, sorafenib led to statistically significant improvement in overall survival compared with placebo.
Sorafenib is a small molecule inhibitor of two tyrosine kinases, the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR), as well as members of the Raf kinase family. Its administration has the ability to induce autophagy, which in the setting of cancer can suppress tumor growth.
Compared with a median overall survival of 7.9 months in the SHARP trial’s placebo arm, the use of sorafenib significantly extended this outcome to 10.7 months. While no significant improvement was observed in time to symptomatic progression, the median time to radiologic progression was significantly decreased from 5.5 months to 2.8 months in the placebo versus sorafenib groups, respectively.1Overall, the trial demonstrated that the use of sorafenib could extend median survival and time to progression by nearly 3 months for patients with advanced HCC.
In 2009, these findings were followed with results from a similar trial in the Asia-Pacific region, which also demonstrated the effectiveness of sorafenib in treating advanced HCC.2As the majority of HCC cases occur in areas with endemic hepatitis B (HBV) or hepatitis C virus (HCV) infection, this multinational phase III trial was critical for establishing the safety and efficacy of sorafenib in patients from a relevant geographic region.
In this setting, median overall survival increased by more than 2 months with the use of sorafenib, from 4.2 months to 6.5 months compared with placebo. Time to progression was cut in half, from 2.8 months to 1.4 months, respectively, in those receiving sorafenib compared with controls. Hand-foot skin reactions, diarrhea, and fatigue were the most frequently reported grade 3/4 drug-related adverse events; however, these occurrences rarely led to the discontinuation of patients from the trial.
In response to these findings, a subsequent study went on to measure plasma biomarkers in the patients enrolled in the SHARP trial, in order to identify correlates of prognosis or predictors of sorafenib response.3Two biomarkers of angiogenesis, angiopoietin 2 and VEGF, were found to independently predict survival among patients with advanced HCC. However, none of the biomarkers tested in the study demonstrated significant predictive value when determining patient response to sorafenib.
The Promise of Combination Therapy: Sorafenib Plus TACE
Numerous studies have begun investigating the potential for combining treatment modalities in HCC, in order to further prolong patient survival and promote tumor regression. Efforts have included studies combining sorafenib with transarterial chemoembolization (TACE), stereotactic body radiation therapy (SBRT), as well as various chemotherapy regimens.
TACE is a minimally invasive technique that was originally used to treat patients with liver tumors with emergent humoral hypercalcemia.4Stemming from a combination of diagnostic angiography and transcatheter injection, TACE injects small embolic particles coated with chemotherapeutic agents directly into the tumor’s blood supply in an effort to reduce tumor size. This technique has been used extensively in recent years for the palliative treatment of unresectable HCC, and has begun to show indication in selected patients with early-stage disease.
The combination of TACE and sorafenib has been investigated in several studies for use in patients with intermediate or advanced HCC.5,6While survival outcomes among these studies remain an area of controversy, one recent meta-analysis was able to confirm the benefit of combination therapy in this setting, where TACE plus sorafenib appeared to improve overall survival, time to progression, and objective response rate.5
While it may have the ability to improve outcomes, this systematic review also uncovered the finding that the risk of adverse reactions was significantly increased with the combination of TACE and sorafenib.5Grade 3/4 adverse reactions, including hand-foot skin reaction, diarrhea, rash or desquamation, and hypertension, were elevated in the combination therapy group when compared with TACE alone.
In the multicenter phase II SOCRATES trial completed in late 2014, the combination of TACE and sorafenib appeared to be tolerable in previously untreated HCC patients.7Participants with unresectable HCC and a Child-Pugh score ≤8 demonstrated a median time to progression and overall survival of 16.4 months and 20.1 months, respectively. Complete responses were observed in 7% of patients, with partial responses in 41.8% of patients.
Sorafenib Plus Radiation
Combining sorafenib with radiation therapy has also shown promise in improving responses in HCC. A preclinical study in 2013 demonstrated that by downregulating the phosphorylation of STAT3 and reducing the expression of related proteins, sorafenib was able to overcome radiation resistance in HCC cells.8In other words, the addition of sorafenib to radiation therapy could promote radiation-induced apoptosis among tumor cells that were previously resistant.
A subsequent phase I study investigated the concurrent use of stereotactic body radiation and sorafenib in patients with advanced HCC.9As SBRT may aid in focusing the dose of radiation directly on the tumor, this combination has the potential to enhance sorafenib-induced survival benefits while minimizing the deleterious effects of radiation on normal tissue.
Unfortunately, results presented at the American Society for Radiation Oncology meeting in 2012 emphasized that the concurrent use of sorafenib and radiation therapy still faces several important toxicity-related challenges, where lowering drug dose and irradiated volume may be required.9Due to toxicity risks and advanced tumor burden, the combination of concurrent sorafenib and SBRT was not recommended for locally advanced HCC outside the setting of carefully designed clinical trials. Despite these limitations, response rates in this study reached approximately 40%.
An ongoing phase III study by the Radiation Therapy Oncology Group is now investigating the sequential use of SBRT followed by sorafenib when compared with sorafenib alone.10
Sorafenib Plus Chemotherapy
In late 2010, a phase III study investigated the combination of sorafenib with doxorubicin hydrochloride chemotherapy versus doxorubicin plus placebo in a population of patients with advanced HCC with Child-Pugh A (CP-A) liver disease.11The combination did result in a significant improvement in time to progression, overall survival, and progression-free survival. Moreover, the beneficial effects observed did not adversely impact toxicity profiles compared with monotherapy alone.
Further studies combining sorafenib and doxorubicin are currently underway.12,13These include a phase III study in patients with advanced HCC with metastases to other sites,12as well as a phase II study investigating this combination among patients with advanced HCC who progressed on a first-line sorafenib treatment.13
Sorafenib has also recently been evaluated in combination with another chemotherapy regimen, gemcitabine and oxaliplatin (GEMOX), in the randomized phase II GONEXT trial.14Here, patients with advanced or metastatic HCC (Barcelona Clinic Liver Cancer stage B or C) and a liver disease score of CP-A were randomized to receive sorafenib alone or in combination with GEMOX. Overall, the combination therapy met its primary endpoint of 4-month progression-free survival ≥50%. Compared with sorafenib alone, sorafenib plus GEMOX showed improved response rate, median progression-free survival, and overall survival.
Mixed Results With Other Molecularly Targeted Therapies
In addition to advancements in the combination of sorafenib with TACE, radiation, or chemotherapy, other investigations have taken an alternative approach, attempting to apply novel molecularly targeted therapies to the treatment of HCC. Although the potential for several agents appeared promising in early trials, larger studies have been met with conflicting results.
The phase III study, EVOLVE-1, evaluated the use of the mammalian target of rapamycin (mTOR) inhibitor, everolimus, in patients with advanced HCC who were intolerant to sorafenib or who had progressed during or after sorafenib treatment.15Everolimus has been approved for use in several settings, including advanced renal cell carcinoma and progressive neuroendocrine tumors.16Unfortunately, in the setting of HCC, the EVOLVE-1 trial demonstrated that everolimus was unable to improve overall survival or time to progression in the study population when compared with placebo.
A phase II study of dovitinib (TKI258) versus sorafenib in the first-line treatment of advanced HCC also yielded disappointing results.17While sorafenib inhibits VEGFR and PDGFR to delay tumor progression, dovitinib inhibits fibroblast growth factor receptor (FGFR), a third pathway through which tumor angiogenesis can occur. Despite the hypothesis that VEGFR, PDGFR, and FGFR inhibition may further improve upon the responses seen in the SHARP trial, dovitinib demonstrated comparable activity to sorafenib, with no benefit in median overall survival or time to progression.
The oral inhibitor of hepatocyte growth factor receptor (HGFR, or MET) and VEGFR2, cabozantinib, has also gained attention as a promising therapeutic agent.18,19Unlike results with everolimus and dovitinib, cabozantinib demonstrated promising activity in patients with advanced HCC in a recent phase II randomized discontinuation trial, even among those who had received prior treatment with sorafenib.18The ongoing phase III CELESTIAL study was designed thereafter, to evaluate the effects of cabozantinib versus placebo on overall survival in patients with advanced HCC with prior sorafenib use.19
Promising Immunotherapy Approaches on the Horizon
Another area of active research is in the field of antibody-based immunotherapy. Immunotherapy approaches have gained the most traction in melanoma research, where the programmed cell death protein-1 (PD-1) inhibitors, nivolumab and pembrolizumab, as well as the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitor, ipilimumab, have gained FDA approval.20These agents have also begun to show promise in a variety of other cancer types, which has led to their investigation in the field of HCC.
The inhibition of PD-1, an immune checkpoint receptor that inhibits T cell activation, has shown efficacy against a variety of solid tumor types in phase I clinical trials. This receptor may play a role in HCC as its ligand, PD-L1, is overexpressed on HCC tumors and the PD-1 pathway is involved in the exhaustion of T cells in response to viral hepatitis.21As such, interfering with the PD-1/PD-L1 pathway may promote T cell activation, leading to anti-tumoral responses.
This hypothesis is currently being pursued in a phase I dose-escalation study evaluating the safety of nivolumab in patients with advanced HCC.21,22Cohorts with and without HBV and HCV infection are being assessed in a population of patients with CP-A liver disease and progressive HCC who demonstrated intolerance after one or more lines of therapy.
In another pilot study, a monoclonal antibody against CTLA-4, tremelimumab, is being assessed for the treatment of HCC in combination with either TACE or radiofrequency ablation.23,24Expressed on the surface of activated T cells, the interaction of CTLA-4 with its ligand, B7 (also known as CD80 and CD86), results in the downregulation of T cell activation. As such, the inhibition of this pathway with tremelimumab is thought to promote the proper activation of a T cell response. At the 2014 American Society of Clinical Oncology Annual Meeting, preliminary safety data were reported, demonstrating the feasibility of the first 2 planned dose levels, which support further enrollment to the final planned dose of the trial.23
A novel strategy involving autologous T cell receptor-redirected therapy has also shown promise in a preliminary study published in theJournal of Hepatologyearly in 2015.25This approach involved a patient with HBV-related HCC, who had residual, chemoresistant extrahepatic metastases after receiving liver transplantation. Unlike the donor liver, these extrahepatic metastases still expressed HBV antigens, leaving them vulnerable to HBV antigen-specific T cells.
In this study, HCC autologous T cells were genetically modified to express a T cell receptor specific to the HBV surface antigen (HBsAg). Findings confirmed that the engineered lymphocytes were able to expand and facilitate a reduction in HBsAg levels. Liver inflammation and other toxicities were not exacerbated as a result of this approach; however, clinical efficacy could not yet be established. Further studies will certainly investigate the potential of this novel therapeutic strategy in HBV-related HCC.25
Overall, despite the success of several molecularly targeted therapies and immunotherapy approaches in the treatment of other malignancies, sorafenib remains the only targeted agent with FDA approval for the treatment of HCC. While progress in the field has been modest, ongoing clinical trials continue to investigate novel approaches and combination therapies that may have the potential to improve patient outcomes in HCC.
Erik Knudsen, PhD, from the University of Texas Southwestern Medical Center, notes that it will become “critically important to consider the incredible diversity of HCC when investigating therapeutic response.”26Knudsen adds that the “plethora of ongoing early stage trials provides hope for more effective regimens.”