- Hepatocellular carcinoma (HCC) accounts for 90% of liver cancers worldwide and are often diagnosed at advanced stages when treatments are limited.
- Recent advances include the identification of three subtypes of HCC by The Cancer Genome Atlas, one of which has an especially poor prognosis.
- Regorafenib was recently approved by the U.S. Food and Drug Administration for patients with HCC who have been previously treated with sorafenib, based on RESORCE study findings.
- Immunotherapy has emerged as a treatment option with recent approval of nivolumab and continues to be further investigated in a number of ongoing studies.
Liver cancers worldwide account for more than 850,000 new cancer cases annually, and approximately 90% of these are hepatocellular carcinoma (HCC).1,2 Chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) is the leading cause of HCC.3 HCC is often diagnosed at advanced stages for which highly effective therapies are limited. The last decade has witnessed the advent of sorafenib as a systemic treatment option for patients with advanced HCC. Since then, newer treatments have appeared, some of which are discussed herein.
Using data from The Cancer Genome Atlas (TCGA), an analysis of 363 HCC cases was conducted by whole-exome sequencing and DNA copy number analyses, and 196 HCC cases were analyzed by DNA methylation, RNA, microRNA, and proteomic expression.4 This analysis identified three subtypes of HCC, one of which was associated with a significantly poorer prognosis. Potential therapeutic targets identified, for which inhibitors exist, included Wnt signaling, MDM4, MET, VEGFA, MCL1, IDH1, and TERT. With a growing understanding of the HCC tumor environment, an increasing number of studies continue to investigate novel agents.
Sorafenib has remained a stalwart standard for years based on data from the SHARP trial.5 This past year, data emerged presenting lenvatinib as another new option in the first-line space. Lenvatinib is an oral multi-tyrosine–kinase receptor inhibitor targeting VEGFR1-3, FGFR 1-4, PDGFRa, and the KIT and RET proto-oncogenes. A phase II study evaluating lenvatinib for HCC treatment showed a positive outcome, with a median overall survival (OS) of 18.7 months, a time to progression of 7.4 months, an objective response rate (ORR) of 37%, and a disease control rate of 78%.6
A phase III noninferiority trial involving 954 patients with unresectable HCC randomly assigned patients to lenvatinib versus sorafenib in the first-line setting. Overall survival noninferiority was achieved. Interestingly, the secondary endpoints of progression-free survival (PFS), time to progression, and ORR were in favor of lenvatinib and were statistically superior to sorafenib at 7.4 versus 3.7 months (HR 0.66), 8.9 versus 3.7 months (HR 0.63), and 24% versus 9%, respectively.7 These results raise the specter of yet another approval of a novel agent for patients with HCC. Any potential scientific differential for use of lenvatinib versus sorafenib has yet to be determined.
In the RESORCE study, 843 patients with advanced HCC with Child–Pugh A liver function who progressed on sorafenib were randomly assigned to the multikinase inhibitor regorafenib or placebo (NCT01774344).8 Regorafenib improved overall survival with a median survival of 10.6 months for regorafenib versus 7.8 months for placebo (HR 0.63; p < 0.0001). In an analysis by HCC etiology, the benefit was generally consistent across groups (alcohol use, HBV, or HCV). Median PFS was 3.1 versus 1.5 months. ORR was 7% versus 3% (p < 0.02), with a disease control rate of 66% and 35% (p < 0.0001), respectively. The most common clinically relevant grade 3 and 4 treatment-emergent events were hypertension (15% in the regorafenib group vs. 5% in the placebo group), hand-foot skin reaction (13% vs. 1%), fatigue (9% vs. 5%), and diarrhea (3% vs. 0%). As a result of this study’s findings, regorafenib was subsequently approved by the U.S. Food and Drug Administration for patients with HCC who have been previously treated with sorafenib.
The c-Met pathway has been a target of interest in HCC, with serious preclinical support, and already has been explored in the second-line setting. Tivantinib, an agent targeting the c-Met kinase, was studied in a phase III METIV-HCC study (NCT01755767), based on a prior phase II study. In the phase II study, c-Met overexpression was noted to be more prevalent in patients who had received prior sorafenib. These patients had poorer prognosis compared to those with low c-Met expression and an intriguing response rate to tivantinib. In the METIV-HCC study, 340 patients with c-Met–high HCC following treatment with sorafenib were randomly assigned to tivantinib or placebo. Median OS was 8.4 months in the tivantinib arm compared with 9.1 months in the placebo arm (HR 0.97, p = 0.81). Median PFS was 2.1 months and 2.0 months, respectively (HR 0.96, p = 0.81). The JET-HCC (NCT02029157) study in Japan also recently demonstrated no significant clinical benefit, with very similar results in patients randomly assigned to tivantinib versus placebo in the second-line setting.9 Median PFS was 2.8 versus 2.3 months (HR 0.72, p = 0.065), respectively. Median OS was 9.9 versus 8.5 months (HR 0.85).
In a counterargument about the necessity of c-Met expression, another c-Met inhibitor, cabozantinib—which targets c-Met, VEGFR2, and RET—is under investigation in the phase III CELESTIAL study also in the second-line setting but open to all patients irrespective of c-Met level of expression (NCT01908426).10 This is based on the phase II study in 41 patients, which demonstrated a response rate of 9% and an overall disease control rate of 71%, with a median OS of 15.1 months and a median PFS of 4.4 months.11Ramucirumab, targeting VEGFR2, was evaluated in the REACH study in which 565 patients with advanced HCC were randomly assigned to ramucirumab or placebo.12 Median OS for the ramucirumab group was 9.2 months versus 7.6 months for the placebo group (HR 0.87; p = 0.14).12 In a prespecified subgroup of patients with a baseline alpha-fetoprotein (AFP) concentration of ≥ 400 ng/mL, median OS was 7.8 versus 4.2 months, respectively (HR 0.67; p = 0.006). On such basis, the follow-up study REACH-2 (NCT02435433) was launched for patients with advanced HCC with baseline AFP > 400 ng/mL with progression during or after sorafenib.
FGF- and FGFR-signaling abnormalities are increasingly identified in numerous human cancers, and FGFR4 may contribute to hepatic carcinogenesis. FGFR4 expression has been noted in about 50% of HCCs and has emerged as a potential therapeutic target.13-20 Phase I safety and clinical activity data of BLU-554, a potent, highly selective oral FGFR4 inhibitor, in 61 patients with advanced HCC recently demonstrated that it is well tolerated and has clinical activity in FGF19 immunohistochemistry-positive patients in whom prior systemic therapy had failed.21 There are currently three ongoing studies evaluating the activity of FGFR inhibitors in patients with HCC, two of them biomarker driven. Results are eagerly awaited and will be an important step forward in biomarker-driven therapeutics for HCC.
Histopathologic analyses of TCGA samples of HCC recently revealed that 22% displayed high or moderate levels of lymphocyte infiltration.4 Characterization of the immune microenvironment of HCC included clustering of gene expression of 66 immune markers that encompass cell surface markers of different immune cell populations. The report identified six clusters of tumor samples, with two clusters exhibiting high expression of the 66 immune markers, including the immune checkpoint genes CTLA-4, PD-1, and PD-L1. No significant association was observed with HBV or HCV infection status and immune clustering. Likewise, overall survival was not significantly related to immune clustering. An analysis of the cellular immune component of the tumor microenvironment revealed a transformation to a resting immunosuppressive environment. Further exploration of immunotherapeutics in HCC has thus been warranted.
A study evaluating dual checkpoint inhibition (durvalumab and tremelimumab) or monotherapy with either (NCT02519348) is underway22 based on the immunosuppressive environment; an initial phase I study evaluating the anti–CTLA-4 agent tremelimumab in a small group of patients with advanced HCC, which demonstrated a manageable safety profile; preliminary evidence of antitumor activity; the evidence of HCC responses to anti–PD-L1 therapy; and experiences with the combination of anti–PD-L1 and anti–CTLA-4 therapies in other malignancies.
Now, nivolumab has garnered accelerated approval for treatment of HCC in patients who have previously been treated with sorafenib. This is based on data from the CheckMate-040 study, a phase I/II, open-label, dose-escalation and expansion trial of nivolumab in 262 patients with advanced HCC with or without HCV or HBV infection, which showed a manageable safety profile for nivolumab and evidence of efficacy (NCT01658878). The ORR was 20% in patients treated with nivolumab in the dose-expansion phase and 15% in the dose-escalation phase. These response rates were comparable regardless of HBV or HCV infection status, or whether patients had or had not previously been treated with sorafenib. Objective responses were seen regardless of PD-L1 expression on tumor cells. Median duration of response was 9.9 months, with responses ongoing in 67% of patients. Median OS had not yet been reached at time of publication. Nivolumab is also being evaluated in the first-line setting, compared to sorafenib, in the CheckMate-459 study (NCT02576509). Immunotherapy also continues to be investigated in a number of other forms in ongoing studies including the KEYNOTE-240 study with second-line pembrolizumab versus best supportive care (NCT02702401).
HCC is one of the world’s most prevalent malignancies, and too many cases are still diagnosed at an advanced stage. Glimmers of real hope with the advent of different therapeutic approaches are underway and should be followed closely.
About the Author: Dr. Mody is assistant professor of medicine in the Division of Hematology/Oncology, Department of Internal Medicine at Mayo Clinic Jacksonville. Dr. Abou-Alfa is a medical oncologist at Memorial Sloan Kettering Cancer Center.