Novel Therapies on the Horizon in Hepatocellular Carcinoma

HCC MonitorApril 2016
Volume 2
Issue 1

Both in the United States and worldwide, the incidence of hepatocellular carcinoma (HCC) is on the rise, and, despite extensive research, sorafenib (Nexavar) remains the only FDA-approved systemic therapy available for advanced tumors.


Despite sorafenib’s ability to improve clinical outcomes, the average overall survival (OS) is limited to between 7 and 11 months.2,3Given that clinical trials of first- and second-line therapies have not provided suitable alternatives,4additional novel therapies are urgently needed in order to improve patient outcomes for patients with HCC.

Ongoing Clinical Trials of New Agents in the First-Line Setting

Nivolumab (Opdivo) is a monoclonal antibody that targets PD-1 on activated T cells, allowing the immune system to attack the tumor. In this way, nivolumab blocks negative regulators of T-cell activation, the PD-1 ligands, and serves as an immune checkpoint blockade. The FDA-approved uses for nivolumab include unresectable or metastatic melanoma, metastatic non—small cell lung cancer, and advanced renal cell carcinoma. Nivolumab has not been extensively studied in HCC.

In May 2015, lead investigator Anthony El-Khoueiry, MD, University of Southern California Norris Comprehensive Cancer Center, and colleagues presented phase I/II clinical data on the safety and antitumor activity of nivolumab in patients with advanced HCC, at the 2015 ASCO Annual Meeting.5

The study of 42 patients demonstrated that nearly 20% had a tumor response (reduction beyond 30%) with nivolumab treatment, including a complete response (CR) in 2 patients. Stable disease (SD) was observed in nearly 50% of patients, with the longest duration lasting over 17 months; the OS rate after 12 months was 62%. In comparison, sorafenib response rates are typically 2% to 3%, with an OS rate of about 30% after 12 months. Grade 3 or above adverse events (AEs) occurred in less than 20% of patients.

"While we have to verify this early signal in larger studies, this is one of the first signs that immunotherapy with immune checkpoint inhibitors will have a role in the treatment of liver cancer," Dr. El-Khoueiry said in a press statement.6

An ongoing randomized phase III trial, CheckMate-459, of nivolumab versus sorafenib as a first-line treatment in advanced HCC is currently under way with over 700 patients enrolled. The primary outcomes of the study are time to progression (TTP) and OS, with an estimated completion date of May 2017.7

Lenvatinib is a receptor TKI with activity against multiple receptors, including those of VEGF and fibroblast growth factor (FGF). Lenvatinib is currently approved for use in patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer and is pending an FDA decision for use in patients with renal cell carcinoma.

The phase I/II safety and efficacy study of lenvatinib in patients with advanced HCC was presented by Kiwamu Okita, MD, PhD, Yamaguchi University, Japan, and colleagues at the ASCO Gastrointestinal Cancers Symposium in 2012.8Among the 42 patients who were enrolled in the study, 33% had a partial response (PR). Grade 3 AEs included hypertension, anorexia, proteinuria, and thrombocytopenia.

A multicenter, randomized phase III clinical trial of lenvatinib versus sorafenib as first-line therapy in nearly 1000 patients with unresectable HCC is ongoing, with completion estimated for later this year.9

Novel Second-Line Therapies Following First-Line Therapy Failure

Other agents, such as regorafenib (Stivarga), cabozantinib (Cometriq), ramucirumab (Cyramza), and tivantinib, are being investigated in patients who have progressed following first-line treatment with sorafenib. Sorafenib is commonly used in the frontline setting, and remains effective across various prognostic factors and liver function scores,10making this the standard frontline therapy that most patients will have received in second-line trial.

Regorafenib is a multikinase inhibitor of VEGF receptors, c-kit, Ret, and FGF receptor, and targets various pathways important for angiogenesis, oncogenesis, and the tumor microenvironment. The FDA has previously approved regorafenib for the treatment of advanced gastrointestinal stromal tumors and previously treated metastatic colorectal cancer.

Jordi Bruix, MD, University of Barcelona, Spain, and colleagues reported phase II findings of regorafenib in the November 2013 issue ofEuropean Journal of Cancer.11The analysis evaluated the safety and efficacy of regorafenib as a second-line therapy following sorafenib failure in 36 patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C HCC.

Adverse events related to treatment were mostly mild and occurred in 39% of patients; 14% of patients experienced serious AEs. During the median treatment duration of nearly 20 weeks, 72% of patients exhibited disease control, reaching a TTP of 4.3 months and OS of 13.8 months.11

The results of the phase II trial prompted further investigation in a phase III trial, RESOURCE, which is currently ongoing. Eligible patients, who have failed prior sorafenib therapy, will be randomly assigned to receive either regorafenib or placebo in a 2:1 ratio. The primary endpoint is OS, and the anticipated trial completion is later in 2016.12

Cabozantinib is a small-molecule inhibitor of multiple receptor tyrosine kinases, including HGF receptor (MET), Ret, and the VEGF receptor. The FDA has approved the agent for the treatment of progressive, metastatic medullary thyroid cancer, and an application is pending for metastatic renal cell carcinoma.

In advanced HCC, cabozantinib has shown promising results in a phase II trial, and ongoing data are being gathered in a phase III trial. The phase II data were presented by Chris Verslype, MD, PhD, University Hospital Gasthuisberg, Leuven, Belgium, and colleagues at the 2012 ASCO annual meeting.13

In the phase II randomized discontinuation trial, 41 patients with HCC who had received 1 line of prior systemic therapy and classified as Child-Pugh score A were eligible to participate. Among patients who received cabozantinib in the lead-in phase of the trial, 5% achieved a PR, 78% achieved SD, and 7% had progressive disease. The median OS was 15.1 months, and the median progression-free survival (PFS) was 4.4 months, independent of prior sorafenib therapy. The most common grade 3 or higher AEs were diarrhea, palmar-plantar erythrodysesthesia, and thrombocytopenia.13

The ongoing phase III trial, CELESTIAL, will compare the OS of cabozantinib versus placebo in patients who have received prior sorafenib therapy. The primary completion date is estimated for late 2016.14

“Patients with advanced HCC who have progressed on sorafenib have few therapeutic options, and new approaches to managing their disease are much needed,” said Ghassan Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center, New York City, the lead investigator of CELESTIAL. “Phase II data investigating cabozantinib in this patient population are worthy of more study, and cabozantinib’s target profile, which includes inhibition of both MET and VEGFR, is highly relevant in HCC.”15

Tivantinib is a receptor TKI that is selective for MET. Ongoing studies are evaluating MET as a prognostic and predictive indicator of tumor progression and response to tivantinib. Lorenza Rimassa, MD, Humanitas Cancer Center, Rozzano, Milan, Italy, and colleagues recently presented their findings at the 2016 ASCO Gastrointestinal Cancers Symposium.16

In the phase II analysis, 107 patients who had previously failed prior first-line treatment were randomized to receive tivantinib or placebo. Patients were stratified by high or low circulating levels of MET and hepatocyte growth factor (HGF), and also by levels of alpha-fetoprotein (AFP). Circulating levels of MET were prognostic (OS: 4.6 months high vs 8.9 months low; HR, 0.61;P=.023). MET expression also correlated with sorafenib treatment; 40% of patient biopsies prior to treatment were MET-high compared with 82% of biopsies after sorafenib. A significant interaction in OS between tivantinib and MET expression was observed (P=.039). The other biomarkers examined were not predictive of tivantinib response.16

An ongoing phase III, randomized, double-blind clinical trial of over 350 patients with inoperable, high-expressing MET tumors who have been treated previously with systemic therapy is currently under way. The primary endpoint is OS, and secondary outcomes are PFS and safety. The anticipated study completion date is mid-2017.17

Ramucirumab is an anti-VEGFR-2 antibody that binds to the receptor with high affinity and prevents ligand activation. VEGF, among other angiogenic factors, is highly expressed in HCC and associated with worse outcomes, making it a highly attractive therapeutic target.

Andrew X. Zhu, MD, Massachusetts General Hospital, Boston, and colleagues reported their initial phase III findings of ramucirumab in the June 18, 2015, issue ofThe Lancet Oncology.18

The randomized, double-blind trial, REACH, examined 565 patients who were refractory or not amenable to locoregional therapy and who had previously received sorafenib. The primary endpoint, OS, was not significantly different with ramucirumab when compared with placebo (9.2 months vs 7.6 months; HR, 0.87; 95% CI, 0.72-1.05;P=.14). However, improvements were noted in the secondary endpoints of PFS, TTP, and objective response rate (ORR). The most common grade 3 or above AEs included ascites, hypertension, asthenia, malignant neoplasm progression, and increased aspartate aminotransferase concentration.18

Although the primary endpoint was not reached, additional analysis that stratified patients by AFP concentration demonstrated a significant difference in OS between ramucirumab and placebo in patients with AFP levels greater than 400 ng/mL (7.8 months vs 4.2 months; HR, 0.67; 95% CI, 0.51-0.90;P=.006). Similarly, in patients with a baseline AFP 1.5 times the upper limit of normal or greater, the median OS was 8.6 versus 5.7 months for ramucirumab and placebo, respectively (HR, 0.749; 95% CI, 0.603-0.930;P=.0088).19These results suggested that patients with elevated AFP, a diagnostic and prognostic marker of HCC, might be more likely to benefit from ramucirumab.

A follow-up prospective phase III trial, REACH 2, will examine the safety and efficacy of ramucirumab as a second-line therapy specifically in patients with elevated baseline AFP. The estimated primary completion date is late 2017.20

Oncolytic Immunotherapeutic Viruses — A New Class of Agents in HCC

The majority of agents that are currently in phase III trials specifically target and bind to various RTKs expressed on the tumor cell surface. A new class of agents, oncolytic immunotherapies, function through a unique mechanism of action, and selectively replicate within and lyse tumor cells. JX-594, also known as Pexa-Vec, is an oncolytic and immunotherapeutic vaccinia virus that is currently being investigated in patients with advanced HCC.

Jeong Heo, MD, PhD, Pusan National University Hospital, Busan, Korea, and colleagues reported the results of an initial phase II dose-finding trial of JX-594 in the February 10, 2013, issue ofNature Medicine.21

JX-594 uses a dual-pronged approach to target cancer cells. First, JX-594 targets tumor cells with active epidermal growth factor receptor (EGFR)/RAS signaling and uses that kinase pathway to replicate and induce oncolysis. Second, the expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) triggers an anti-tumor immune response.22

In the phase II study, investigators compared low-dose with high-dose (10x greater) JX-594 in 30 patients with advanced HCC. Survival duration was directly related to dosage; patients achieved a median survival of 6.7 months and 14.1 months on the low and high dose, respectively (HR, 0.39;P=.020). Treatment was generally well tolerated in both cohorts, and the rate of AEs was similar in both treatment groups, with flu-like symptoms being the most common.21

Trials of JX-594/Pexa-Vec are ongoing. A phase III randomized study, PHOCUS, will compare JX-594 followed by sorafenib with sorafenib alone in patients with advanced HCC who have not received prior systemic therapy. The primary outcome measure is OS, and secondary outcome measures include TTP, PFS, ORR, and disease control rate. The study is expected to reach its primary completion in late 2017.23

Abou-Alfa, lead investigator of the phase III trial, stated, "We are still desperately in need of additional treatment options for advanced liver cancer. Cancer immunotherapy holds much promise, and I'm greatly looking forward to having the opportunity to evaluate Pexa-Vec in patients with advanced liver cancer."  

Overall, numerous therapies are in late-stage clinical development that show promise for patients with advanced HCC. Because most will present with advanced-stage disease at diagnosis, only liver resection and transplantation are considered curative. Thus, there is a critical need to improve the therapeutic landscape. The alternative first-line and second-line therapies described may provide hope for patients in the near future.


  1. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245-1255.
  2. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390.
  3. Cheng A-L, Kang Y-K, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25-34.
  4. Villanueva A, Hernandez-Gea V, Llovet JM. Medical therapies for hepatocellular carcinoma: a critical view of the evidence. Nat Rev Gastroenterol Hepatol. 2013;10(1):34-42.
  5. El-Khoueiry AB, Melero I, Crocenzi TS, et al. Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. J Clin Oncol. 2015;33(15_suppl; abstr LBA101).
  6. Mulcahy N. Add Liver Cancer to Nivolumab’s List of Victims. Medscape Medical News; May 29, 2015.
  7. A Study of Nivolumab Versus Sorafenib as First-Line Treatment in Patients With Advanced Hepatocellular Carcinoma. Identifier: NCT02576509.
  8. Okita K, Kumada H, Ikeda K, et al. Phase I/II study of E7080 (lenvatinib), a multitargeted tyrosine kinase inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC): Initial assessment of response rate. J Clin Oncol. 2012;30(4_suppl; abstr 320).
  9. A Multicenter, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) Versus Sorafenib in First-Line Treatment of Subjects With Unresectable Hepatocellular Carcinoma. Identifier: NCT01761266.
  10. Lencioni R, Kudo M, Ye S-L, et al. GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib): second interim analysis. Int J Clin Pract. 2014;68(5):609-617.
  11. Bruix J, Tak W-Y, Gasbarrini A, et al. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study. Eur J Cancer. 1990. 2013;49(16):3412-3419.
  12. Study of Regorafenib After Sorafenib in Patients With Hepatocellular Carcinoma. Identifier: NCT01774344.
  13. Verslype C, Cohn AL, Kelley RK, et al. Activity of cabozantinib (XL184) in hepatocellular carcinoma patients (pts): results from a phase II randomized discontinuation trial (RDT). J Clin Oncol. 2012;30(4_suppl; abstr 261).
  14. Study of Cabozantinib (XL184) vs Placebo in Subjects With Hepatocellular Carcinoma Who Have Received Prior Sorafenib (CELESTIAL). Identifier: NCT01908426.
  15. Exelixis. Exelixis Initiates Phase 3 Clinical Trial of Cabozantinib in Patients With Advanced Hepatocellular Carcinoma [press release]; September 10, 2013.
  16. Rimassa L, Abbadessa G, Personeni N, et al. Tumor and plasma biomarker analysis from the randomized controlled phase II trial (RCT) of tivantinib in second-line hepatocellular carcinoma (HCC). J Clin Oncol. 2016;34(4_suppl; abstr 197).
  17. Study of Tivantinib in Subjects With Inoperable Hepatocellular Carcinoma Who Have Been Treated With One Prior Therapy. Identifier: NCT01755767.
  18. Zhu AX, Park JO, Ryoo B-Y, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015;16(7):859-870.
  19. Zhu AX, Ryoo B-Y, Yen C-J, et al. Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): analysis of patients with elevated {alpha}-fetoprotein (AFP) from the randomized phase III REACH study. J Clin Oncol. 2015;33(3_suppl; abstr 232).
  20. A Study of Ramucirumab (LY3009806) Versus Placebo in Participants With Hepatocellular Carcinoma and Elevated Baseline Alpha-Fetoprotein (REACH-2). Identifier: NCT02435433.
  21. Heo J, Reid T, Ruo L, et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med. 2013;19(3):329-336.
  22. Hernandez-Gea V, Alsinet C, Llovet JM. Oncolytic immunotherapeutic virus in HCC: can it compete with molecular therapies? J Hepatol. 2013;59(4):882-884.
  23. Hepatocellular Carcinoma Study Comparing Vaccinia Virus Based Immunotherapy Plus Sorafenib vs Sorafenib Alone (PHOCUS). Identifier: NCT02562755.
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