Review Article
Treating Advanced Hepatocellular Carcinoma: How To Get Out of First Gear James J. Harding, MD; and Ghassan K. Abou-Alfa, MD
Hepatocellular carcinoma is common malignancy with a poor prognosis. Sorafenib is the only systemic therapy known to improve the overall survival of patients with advanced disease. The clinical benefit of sorafenib is modest and the mechanistic basis for its activity is unknown. Four phase 3 clinical trials have failed to improve on sorafenib in the frontline setting and no agent has been shown to impact outcomes after sorafenib failure. Several factors have contributed to this recent stall in drug development but new approaches hold promise and currently are being investigated. This review will focus on the current pipeline of experimental therapeutics for patients with advanced hepatocellular carcinoma and shed a light on scientific limitations that hamper the advancement C 2014 American Cancer Society. of new therapies for this disease, and ways around it. Cancer 2014;000:000-000. V KEYWORDS: hepatocellular carcinoma, targeted therapy, sorafenib, angiogenic, doxorubicin, cabozantinib, tivantinib, everolimus, pegylated arginine deiminase (ADI-PEG 20), tremelimumab.
INTRODUCTION Approximately 80% of patients with hepatocellular carcinoma (HCC) present with disease that is not amenable to curative resection or transplantation.1 As such, the 5-year overall survival rate for patients with locally advanced and metastatic disease is dismal at 10% and 3%, respectively.2,3 For decades, cytotoxic chemotherapy, as monotherapy or in combination, formed the backbone of treatment for patients with advanced HCC.4,5 These agents have low response rates, high toxicity, and do little to meaningful improve survival over best supportive care. Progress in the molecular characterization of HCC has led to important treatment advances in the last decade. The multitargeted receptor tyrosine kinase inhibitor sorafenib exhibits antitumor activity and is the only agent known to modestly improve survival over best supportive care in patients with advanced HCC.6,7 The validation of sorafenib as a new standard of care for patients with advanced HCC led to the empiric application of therapeutics aimed at blocking vascular endothelial growth factor (VEGF) and other relevant angiogenic factors. Such attempts have not been fruitful to date. This review article will focus on systemic therapy for patients with advanced disease, address barriers to progress, and highlight the current landscape of phase 3 clinical trials in HCC. Angiogenesis
Solid tumors acquire a blood supply by several mechanisms, including vasculogenesis, angiogenesis (sprouting and intussusceptive models), and co-option.8,9 Angiogenesis is the specific process of new blood vessel formation from preexisting blood vessels.10 Angiogenic signals activate blood vessel endothelial cells, leading to sequential degradation of the vessel basement membrane, proliferation of endothelial cells, vessel sprouting, stromal cell recruitment, targeting, and new vessel luminzation. Folkman pioneered the concept of antiangiogenic therapy, a therapeutic approach in which blockade of angiogenic stimuli might result in antitumor efficacy.11 The signaling molecule VEGF is a critical regulator of angiogenesis and is overexpressed in HCC and many malignancies.9 Many other mediators participate in the angiogenic process, including fibroblast growth factor (FGF), angiopoietin (Ang)21/2, platelet-derived growth factor (PDGF), tumor growth factor (TGF)-b, matrix metalloproteinases, integrins, other cellular elements, and stromal cells.10 Numerous studies have indicated that VEGF/VEGF receptor (VEGFR) and other angiogenic factors are abundantly expressed on HCC cell lines and tumor specimens and are present in excess in the circulating blood of patients with this disease.12 These findings often correspond with more aggressive disease biology and worse clinical outcomes.13,14
Corresponding author: Ghassan K. Abou-Alfa, MD, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 300 East 66th St, New York, NY 10065; Fax: (212) 396-5561; [email protected] Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York. DOI: 10.1002/cncr.28850, Received: March 12, 2014; Revised: April 3, 2014; Accepted: April 23, 2014, Published online Month 00, 2014 in Wiley Online Library (wileyonlinelibrary.com)
Cancer
Month 00, 2014
1
Review Article
Sorafenib blocks new blood vessel formation and cell proliferation, leading to tumor cell apoptosis in vitro.15,16 Its antitumor activity is multifactorial and may be mediated by blockade of VEGFR2/VEGFR3, plateletderived growth factor receptor-beta (PDGFR-b), and/or other receptor tyrosine kinases.9 The drug also inhibits the RAF kinases, key constituents of the mitogenactivated protein kinase (MAPK) pathway.17 Sorafenib has activity in patients with advanced HCC and was licensed by the US Food and Drug Administration for this indication in 2007 after a pivotal, multicenter, doubleblind, placebo-controlled, randomized phase 3 study of sorafenib versus best supportive care in patients with advanced HCC, called the SHARP trial.6 Patients were selected mostly from the Western hemisphere and had no more than Child-Pugh class A liver function. The HCC etiologic factors of hepatitis C virus (HCV) infection, hepatitis B virus (HBV) infection, and alcohol were identified in most participants and well distributed at 28%, 18%, and 26%, respectively. Overall survival (OS) and time to symptomatic disease progression were the coprimary endpoints of the study. Sorafenib rarely caused tumor shrinkage (2% overall response rate); however, the agent led to stable disease in 71% of patients. This cytostatic effect translated into a median OS of 10.7 months in the sorafenib arm versus 7.9 months in the cohort receiving best supportive care (hazard ratio [HR], 0.69; 95% confidence interval [95% CI], 0.55-0.87). Pretreatment and on-treatment serum levels of VEGF, VEGFR, and Ang-2 were not predictive of response.18 This observation is not unexpected given that the complexity and redundancy of angiogenic pathways makes it difficult to ascribe the antitumor activity to blockade of VEGF signalling alone. The Asia-Pacific study assessed the activity of sorafenib in comparison with best supportive care in patients with advanced HCC from Asia.7 As expected and in contrast to SHARP, the Asia-Pacific study was comprised mostly of patients with HBV-related HCC (73% of the study population). A greater percentage of patients also had poorer Eastern Cooperative Oncology Group performance status and a higher disease burden. Despite these dissimilarities, the trial confirmed that sorafenib led to a statistically significant improvement in disease control, time to radiographic disease progression, and OS when compared with best supportive care (6.5 months for sorafenib vs 4.2 months for placebo; HR, 0.69 [95% CI, 0.50-0.93]). The magnitude of the OS benefit to sorafenib on the Asia-Pacific study was not as substantial as that observed 2
on the SHARP study. Minor differences in the study population might explain this difference. It is interesting to note that in an unplanned subset analysis of the SHARP study, patients with HBV-related HCC (N 5 60) who were treated with sorafenib had a modest prolongation in median OS over placebo (9.7 months vs 6.1 months)19 In contrast, patients with HCV-related HCC (N 5 167) who were treated with sorafenib appeared to derive greater clinical benefit, with substantial improvements in OS noted over placebo (14.0 months vs 7.4 months). Retrospective analysis of an initial phase 2 study of sorafenib observed similar etiologic-dependent trends in survival,20,21 and the recently reported phase 3 study of firstline sunitinib versus sorafenib indicates that there are differential outcomes relative to disease cause and ethnic origin (median OS of 18.3 months for patients with HCVassociated HCC living outside of Asia vs 7.9 months for patients with HBV-associated HCC living in Asia).22 A hypothesis requiring further investigation is that etiologic factors might affect prognosis and/or influence the responsiveness of liver cancer to sorafenib. Etiologicdependent genomic differences in HCC have been observed in several molecular studies.23-25 Activating CTNNB1 mutations are more common in HCV-related compared with HBV-related HCC, and these mutations are associated with a particular WNT gene expression profile.24,26,27 Sorafenib modulates this transciptomic signature and leads to HCC growth suppression in preclinical models.27 HCV has also been shown to upregulate CRAF, a known sorafenib target.28 In vitro data have suggested that sorafenib inhibits HCV viral replication directly. This observation may have important clinical implications and is being tested prospectively on an ongoing phase 3 study of doxorubicin and sorafenib versus sorafenib alone.29 Thus, it is plausible that patient outcomes with sorafenib might be dependent on the specific factors that lead to the development of HCC. These observations suggest that the stratification of clinical trials based on HCC etiologic factors will be important for drug development. However, it should be stressed that sorafenib remains a life-prolonging therapy for patients with HCC, irrespective of etiologic factors. Potential Limitations To Antiangiogenic Therapy
Several agents believed to be more precise and/or more potent inhibitors of angiogenic pathways than sorafenib have been tested extensively in patients with HCC. Sunitinib,22 brivanib,30 and linifanib31 all failed to improve on sorafenib in large, randomized, phase 3 clinical studies, either due to inactivity, toxicity, or both (Table 1). One Cancer
Month 00, 2014
HCC-Targeted Therapy/Harding and Abou-Alfa
TABLE 1. Results of Randomized Phase 3 Studies Evaluating Multi-targeted Receptor Tyrosine Kinase Inhibitors Versus Sorafenib in Patients With Advanced HCC SUN1170 HCC
Study Arm Median OS, mo OS HR (95% CI) TTP, mo TTP HR (95% CI) Response CR PR SD Toxic death rate
BRISK-FL
Linifanib
Sunitinib N 5 530
Sorafenib N 5 544
Brivanib N 5 578
Sorafenib N 5 577
Linifanib
7.9
10.2
9.5
9.9
9.1
1.30 (1.13-1.50) 4.1
1.06 (0.93-1.22) 3.8
4.2
1.13 (0.98-1.31) < 1.0% 6.2% 43.8% 18.5%
4.1 1.01 (0.88-1.16)
Treating Advanced Hepatocellular Carcinoma: How To Get Out of First Gear James J. Harding, MD; and Ghassan K. Abou-Alfa, MD
Hepatocellular carcinoma is common malignancy with a poor prognosis. Sorafenib is the only systemic therapy known to improve the overall survival of patients with advanced disease. The clinical benefit of sorafenib is modest and the mechanistic basis for its activity is unknown. Four phase 3 clinical trials have failed to improve on sorafenib in the frontline setting and no agent has been shown to impact outcomes after sorafenib failure. Several factors have contributed to this recent stall in drug development but new approaches hold promise and currently are being investigated. This review will focus on the current pipeline of experimental therapeutics for patients with advanced hepatocellular carcinoma and shed a light on scientific limitations that hamper the advancement C 2014 American Cancer Society. of new therapies for this disease, and ways around it. Cancer 2014;000:000-000. V KEYWORDS: hepatocellular carcinoma, targeted therapy, sorafenib, angiogenic, doxorubicin, cabozantinib, tivantinib, everolimus, pegylated arginine deiminase (ADI-PEG 20), tremelimumab.
INTRODUCTION Approximately 80% of patients with hepatocellular carcinoma (HCC) present with disease that is not amenable to curative resection or transplantation.1 As such, the 5-year overall survival rate for patients with locally advanced and metastatic disease is dismal at 10% and 3%, respectively.2,3 For decades, cytotoxic chemotherapy, as monotherapy or in combination, formed the backbone of treatment for patients with advanced HCC.4,5 These agents have low response rates, high toxicity, and do little to meaningful improve survival over best supportive care. Progress in the molecular characterization of HCC has led to important treatment advances in the last decade. The multitargeted receptor tyrosine kinase inhibitor sorafenib exhibits antitumor activity and is the only agent known to modestly improve survival over best supportive care in patients with advanced HCC.6,7 The validation of sorafenib as a new standard of care for patients with advanced HCC led to the empiric application of therapeutics aimed at blocking vascular endothelial growth factor (VEGF) and other relevant angiogenic factors. Such attempts have not been fruitful to date. This review article will focus on systemic therapy for patients with advanced disease, address barriers to progress, and highlight the current landscape of phase 3 clinical trials in HCC. Angiogenesis
Solid tumors acquire a blood supply by several mechanisms, including vasculogenesis, angiogenesis (sprouting and intussusceptive models), and co-option.8,9 Angiogenesis is the specific process of new blood vessel formation from preexisting blood vessels.10 Angiogenic signals activate blood vessel endothelial cells, leading to sequential degradation of the vessel basement membrane, proliferation of endothelial cells, vessel sprouting, stromal cell recruitment, targeting, and new vessel luminzation. Folkman pioneered the concept of antiangiogenic therapy, a therapeutic approach in which blockade of angiogenic stimuli might result in antitumor efficacy.11 The signaling molecule VEGF is a critical regulator of angiogenesis and is overexpressed in HCC and many malignancies.9 Many other mediators participate in the angiogenic process, including fibroblast growth factor (FGF), angiopoietin (Ang)21/2, platelet-derived growth factor (PDGF), tumor growth factor (TGF)-b, matrix metalloproteinases, integrins, other cellular elements, and stromal cells.10 Numerous studies have indicated that VEGF/VEGF receptor (VEGFR) and other angiogenic factors are abundantly expressed on HCC cell lines and tumor specimens and are present in excess in the circulating blood of patients with this disease.12 These findings often correspond with more aggressive disease biology and worse clinical outcomes.13,14
Corresponding author: Ghassan K. Abou-Alfa, MD, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 300 East 66th St, New York, NY 10065; Fax: (212) 396-5561; [email protected] Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York. DOI: 10.1002/cncr.28850, Received: March 12, 2014; Revised: April 3, 2014; Accepted: April 23, 2014, Published online Month 00, 2014 in Wiley Online Library (wileyonlinelibrary.com)
Cancer
Month 00, 2014
1
Review Article
Sorafenib blocks new blood vessel formation and cell proliferation, leading to tumor cell apoptosis in vitro.15,16 Its antitumor activity is multifactorial and may be mediated by blockade of VEGFR2/VEGFR3, plateletderived growth factor receptor-beta (PDGFR-b), and/or other receptor tyrosine kinases.9 The drug also inhibits the RAF kinases, key constituents of the mitogenactivated protein kinase (MAPK) pathway.17 Sorafenib has activity in patients with advanced HCC and was licensed by the US Food and Drug Administration for this indication in 2007 after a pivotal, multicenter, doubleblind, placebo-controlled, randomized phase 3 study of sorafenib versus best supportive care in patients with advanced HCC, called the SHARP trial.6 Patients were selected mostly from the Western hemisphere and had no more than Child-Pugh class A liver function. The HCC etiologic factors of hepatitis C virus (HCV) infection, hepatitis B virus (HBV) infection, and alcohol were identified in most participants and well distributed at 28%, 18%, and 26%, respectively. Overall survival (OS) and time to symptomatic disease progression were the coprimary endpoints of the study. Sorafenib rarely caused tumor shrinkage (2% overall response rate); however, the agent led to stable disease in 71% of patients. This cytostatic effect translated into a median OS of 10.7 months in the sorafenib arm versus 7.9 months in the cohort receiving best supportive care (hazard ratio [HR], 0.69; 95% confidence interval [95% CI], 0.55-0.87). Pretreatment and on-treatment serum levels of VEGF, VEGFR, and Ang-2 were not predictive of response.18 This observation is not unexpected given that the complexity and redundancy of angiogenic pathways makes it difficult to ascribe the antitumor activity to blockade of VEGF signalling alone. The Asia-Pacific study assessed the activity of sorafenib in comparison with best supportive care in patients with advanced HCC from Asia.7 As expected and in contrast to SHARP, the Asia-Pacific study was comprised mostly of patients with HBV-related HCC (73% of the study population). A greater percentage of patients also had poorer Eastern Cooperative Oncology Group performance status and a higher disease burden. Despite these dissimilarities, the trial confirmed that sorafenib led to a statistically significant improvement in disease control, time to radiographic disease progression, and OS when compared with best supportive care (6.5 months for sorafenib vs 4.2 months for placebo; HR, 0.69 [95% CI, 0.50-0.93]). The magnitude of the OS benefit to sorafenib on the Asia-Pacific study was not as substantial as that observed 2
on the SHARP study. Minor differences in the study population might explain this difference. It is interesting to note that in an unplanned subset analysis of the SHARP study, patients with HBV-related HCC (N 5 60) who were treated with sorafenib had a modest prolongation in median OS over placebo (9.7 months vs 6.1 months)19 In contrast, patients with HCV-related HCC (N 5 167) who were treated with sorafenib appeared to derive greater clinical benefit, with substantial improvements in OS noted over placebo (14.0 months vs 7.4 months). Retrospective analysis of an initial phase 2 study of sorafenib observed similar etiologic-dependent trends in survival,20,21 and the recently reported phase 3 study of firstline sunitinib versus sorafenib indicates that there are differential outcomes relative to disease cause and ethnic origin (median OS of 18.3 months for patients with HCVassociated HCC living outside of Asia vs 7.9 months for patients with HBV-associated HCC living in Asia).22 A hypothesis requiring further investigation is that etiologic factors might affect prognosis and/or influence the responsiveness of liver cancer to sorafenib. Etiologicdependent genomic differences in HCC have been observed in several molecular studies.23-25 Activating CTNNB1 mutations are more common in HCV-related compared with HBV-related HCC, and these mutations are associated with a particular WNT gene expression profile.24,26,27 Sorafenib modulates this transciptomic signature and leads to HCC growth suppression in preclinical models.27 HCV has also been shown to upregulate CRAF, a known sorafenib target.28 In vitro data have suggested that sorafenib inhibits HCV viral replication directly. This observation may have important clinical implications and is being tested prospectively on an ongoing phase 3 study of doxorubicin and sorafenib versus sorafenib alone.29 Thus, it is plausible that patient outcomes with sorafenib might be dependent on the specific factors that lead to the development of HCC. These observations suggest that the stratification of clinical trials based on HCC etiologic factors will be important for drug development. However, it should be stressed that sorafenib remains a life-prolonging therapy for patients with HCC, irrespective of etiologic factors. Potential Limitations To Antiangiogenic Therapy
Several agents believed to be more precise and/or more potent inhibitors of angiogenic pathways than sorafenib have been tested extensively in patients with HCC. Sunitinib,22 brivanib,30 and linifanib31 all failed to improve on sorafenib in large, randomized, phase 3 clinical studies, either due to inactivity, toxicity, or both (Table 1). One Cancer
Month 00, 2014
HCC-Targeted Therapy/Harding and Abou-Alfa
TABLE 1. Results of Randomized Phase 3 Studies Evaluating Multi-targeted Receptor Tyrosine Kinase Inhibitors Versus Sorafenib in Patients With Advanced HCC SUN1170 HCC
Study Arm Median OS, mo OS HR (95% CI) TTP, mo TTP HR (95% CI) Response CR PR SD Toxic death rate
BRISK-FL
Linifanib
Sunitinib N 5 530
Sorafenib N 5 544
Brivanib N 5 578
Sorafenib N 5 577
Linifanib
7.9
10.2
9.5
9.9
9.1
1.30 (1.13-1.50) 4.1
1.06 (0.93-1.22) 3.8
4.2
1.13 (0.98-1.31) < 1.0% 6.2% 43.8% 18.5%
4.1 1.01 (0.88-1.16)
