The quest for medical treatments for patients with advanced stage hepatocellular carcinoma (HCC) has met repeated road blocks with failed therapies. These failures have been well documented in a number of reviews and in the American Association for the Study of Liver Diseases HCC practice guidelines. A major breakthrough in systemic treatment occurred with the advent of targeted therapies that block specific cancer-promoting signaling pathways. For HCC, the era of molecular targeted therapy began with the SHARP trial. In this phase III trial, sorafenib, an inhibitor of RAF serine-threonine kinases and the receptor tyrosine kinase activity of vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor beta (PDGF-B), or placebo was administered to patients with Child-Pugh class A cirrhosis and mainly advanced HCC, compatible with stage C disease according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Sorafenib-treated subjects experienced an extension in median survival compared with placebo-treated subjects of about 3 months, accompanied by tumor stabilization due to delayed tumor progression. These results suggest that sorafenib acts mainly as a cytostatic agent. This pivotal study led to approval of sorafenib by regulatory agencies in the United States and the European Union in 2007 and cemented sorafenib as the standard first-line treatment for advanced stage HCC. The clinical success of sorafenib provided the first proof of concept that targeting up-regulated molecular signaling pathways and angiogenesis in HCC can be efficacious. This achievement spawned the clinical development of already approved targeted agents in other malignancies and new molecular targeted therapies for advanced HCC.
platelet-derived growth factor receptor
Response Evaluation Criteria in Solid Tumors
vascular endothelial growth factor receptor
Development and Progression of Cancer
The development and progression of cancer is a multistep, complex process that involves acquiring hallmark features to sustain tumor growth. Conceptually, this framework was revisited as our understanding of the mechanistic underpinnings of cancer has improved over the last decade (Fig. 1). The prior hallmarks included sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. The updated framework now includes genome instability, inflammation, reprogramming of energy metabolism, and evading immune destruction. Although our knowledge of the molecular pathways necessary for tumor growth and progression continues to evolve, new targets continue to be identified for drug development. A number of drugs targeting specific signal transduction pathways showed promising results in early phase clinical studies that led to phase II and III clinical trials in advanced HCC. The current treatment strategies of these trials include: (1) single agents that inhibit novel targets; (2) multiple targeted agents combined to inhibit the same or different molecular pathways; (3) combining targeted agents with conventional chemotherapy; and (4) combining molecular targeted agents with liver-directed therapies (treatment stage migration). Table 1 summarizes the planned, ongoing, and completed clinical trials for advanced HCC. A brief overview of recent failures and ongoing clinical studies with emerging molecular targeted agents along with future perspectives is discussed below.
|First-line||Sorafenib versus placebo||Phase III: approved (2007)|
|Sorafenib versus sunitinib||Phase III: halted (2010)|
|Sorafenin versus brivanib||Phase III: failed|
|Sorafenib versus linifanib||Phase III: halted (2011)|
|Sorafenib ± erlotinib||Phase III: failed|
|Sorafenib versus bevacizumab ± erlotinib||Phase II: ongoing|
|Sorafenib ± doxorubicin||Phase III: ongoing|
|Second-line||Brivanib versus placebo||Phase III: failed|
|Ramucirumab versus placebo||Phase III: ongoing|
|Bevacizumab ± erlotinib versus placebo||Phase II: ongoing|
|Everolimus versus placebo||Phase III: ongoing|
Current Treatment for Advanced HCC: Sorafenib and Lessons Learned
Sorafenib targets both the tumor compartment by inhibiting Raf kinase proliferative signaling and tumor angiogenesis by blocking the VEGF and PDGF receptor tyrosine kinases. Preclinical studies have shown that Raf kinase signaling and tumor angiogenesis together play an important role in the evolution of HCC, lending a molecular rationale for the use of sorafenib in this malignancy. This knowledge along with the early signal of efficacy in a phase II study (median overall survival of 9.2 months) led to the phase III SHARP registration trial.[1, 5] The SHARP trial compared single-agent sorafenib with placebo in patients with advanced HCC and Child-Pugh class A cirrhosis, the majority of whom had either only chronic HCV (approximately 30%) or alcoholic liver disease (26%) as the cause of their cirrhosis. Treatment with sorafenib significantly improved overall survival (10.7 months) compared with placebo (7.9 months), with a hazard ratio of 0.69 (P < 0.001) that was both statistically and clinically significant. Further, the time to radiological progression was significantly longer in those patients treated with sorafenib (5.5 months) compared with patients receiving placebo (2.8 months). In terms of tumor responses, only seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST), while no patients had a complete response. Single-agent sorafenib versus placebo was also evaluated in a second phase III trial (the Asia-Pacific trial) for patients with advanced HCC. The Asia-Pacific trial largely confirmed the survival benefit of sorafenib (6.5 months) over placebo (4.2 months) with a hazard ratio of 0.68 (P = 0.014), but not to the same degree as seen in the SHARP trial (Table 2). Both of these phase III trials demonstrate a modest improvement in median overall survival for sorafenib compared with placebo in patients with advanced HCC.
|Endpoint||SHARP Trial||Asia-Pacific Trial|
|Sorafenib||Placebo||HR (95% CI)||P||Sorafenib||Placebo||HR (95% CI)||P|
|OS, months||10.7||7.9||0.69 (0.55-0.87)||<0.001||6.5||4.2||0.68 (0.50-0.93)||0.014|
|TTP, months||5.5||2.8||0.58 (0.45-0.74)||<0.001||2.8||1.4||0.57 (0.42-0.79)||<0.001|
|Response rate, %||2||1||—||NS||3.3||1.3||—||NS|
Sunitinib is an oral tyrosine kinase inhibitor that targets receptor kinases that include vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, platelet-derived growth factor receptor (PDGFR)-a/b, c-KIT, FLT3, and RET kinases. In contrast to sorafenib, sunitinib has more potent activity against VEGFR-1 and VEGFR-2. Initial single-arm phase II trials with sunitinib in advanced HCC showed modest antitumor activity.[8, 9] A randomized phase III study comparing sunitinib (37.5 mg daily) with sorafenib (400 mg twice daily) in patients with advanced HCC found a higher incidence of serious adverse events in the sunitinib arm before its early termination by an independent data monitoring committee. In addition to higher toxicity, the sunitinib arm was also inferior to sorafenib, with a significantly shorter median overall survival (7.9 months) versus sorafenib (10.2 months) with a hazard ratio of 1.30 (P = 0.001). Based on these findings, sunitinib does not have clinical activity in HCC.
Brivanib is a dual inhibitor of VEGFR and fibroblast growth factor receptor signaling pathways. In a single-arm phase II trial studying the safety and efficacy of brivanib in patients with advanced HCC (n = 55), brivanib demonstrated a median overall survival of 10 months as a first-line treatment with tolerable adverse effects. Brivanib also demonstrated activity as a second-line agent in sorafenib-refractory patients with advanced HCC with a median overall survival of 9.8 months (n = 46). These promising phase II studies led to the phase III clinical development of brivanib. Unfortunately, in the phase III study in patients with advanced HCC as a second-line agent, brivanib failed to improve overall survival compared with best supportive care. A recent press release by Bristol-Meyers Squibb also reported that the phase III study comparing brivanib to sorafenib in advanced HCC also failed to meet its primary survival objective. As such, brivanib does not have clinical activity in HCC.
Additional Anti-angiogenic Agents
Linifanib (ABT-869) is another VEGF and PDGF inhibitor that was studied in a phase II study with advanced HCC (n = 44). The study reported an objective response rate of 6.8% that was only noted in patients with Child-Pugh class A cirrhosis. Patients with Child-Pugh class A cirrhosis received linifanib at 0.25 mg/kg daily and achieved a median overall survival of 10.4 months. The favorable survival led to a phase III trial comparing linifanib with sorafenib, which was terminated recently based on the recommendation of an independent data monitoring committee. Ramucirumab (IMC-1121B) is a human monoclonal antibody that binds to VEGFR-2 and was evaluated in a phase II study in patients (n = 43) with advanced HCC. As a single agent in sorafenib-naïve patients with HCC, it demonstrated a tumor response rate of 10% and was associated with gastrointestinal bleeding (9%; grade 3/4), hypertension (14%; grade 3/4), infusion-related reactions (5%; grade 3), and a median overall survival of 12.0 months. Ramucirumab is under evaluation in a phase III study as a second-line treatment in patients with advanced HCC who fail first-line treatment with sorafenib (the REACH study). Several other VEGF inhibitors are in the early stages of clinical development and have not entered phase III trials, including bevacizumab, cediranib, and axitinib. In general, the recent failures with inhibitors of the VEGF pathway such as sunitinib and brivanib raise concern about continuing to target this pathway. Going forward, a key to the ongoing clinical development of anti-VEGF therapies will be identifying markers that predict patients most likely to benefit from treatment and ensuring that anti-RAF activity is present with agents.
Epidermal Growth Factor Receptor Inhibitors
Although a number of epidermal growth factor receptor inhibitors have been evaluated in single-arm phase II studies, only erlotinib has shown modest antitumor activity. In a single-arm phase II trial monotherapy in patients with advanced HCC (n = 38), erlotinib demonstrated a median overall survival of 13 months. A phase III study (the SEARCH trial) evaluating the combination of erlotinib with sorafenib versus single-agent sorafenib failed to meet primary end-point of overall survival. Results demonstrated that the addition of erlotinib to sorafenib did not improve overall survival, compared with sorafenib alone. Another compelling combination occurs when using erlotinib and bevacizumab together. This combination when tested in a single-arm phase II trial in patients with advanced HCC (n = 40) demonstrated an impressive median survival of 15.6 months. This clinically meaningful result has led to a phase II randomized study of bevacizumab and erlotinib compared to sorafenib monotherapy as a first-line treatment and as a second-line treatment for advanced HCC.
Mammalian Target of Rapamycin Inhibitors
Mammalian target of rapamycin is a key protein kinase that regulates cell growth, proliferation, metabolism and angiogenesis in many cancers including HCC. Everolimus has shown good tolerability with promising efficacy in early phase I-II studies in heavily pretreated HCC cohort with an overall survival of 8.4 months. These results have led to the phase III (EVLOLVE-1 trial) comparing the efficacy and safety of everolimus 7.5 mg daily with that of placebo in patients with advanced HCC that have progressed after sorafenib or who are sorafenib intolerant. However, the potential role of everolimus combination therapy in HCC will be a challenge. The incidence of adverse events with single-agent everolimus appears to be higher in HCC cohorts versus other solid malignancies likely due to the presence of cirrhosis. Future clinical studies looking to combine everolimus with other agents for advanced HCC should carefully select the combination to maximize antitumor synergism and minimize the overlap of safety profiles.
Hepatocyte Growth Factor/c-Met Inhibitors
Hepatocyte growth factor and its high-affinity receptor c-Met are involved in tumor cell migration, invasion, proliferation, and angiogenesis. Tivantinib (ARQ 197) is an oral inhibitor of the tyrosine kinase receptor c-Met and has shown promise in phase 1 HCC studies as monotherapy and in combination with sorafenib. The recent results observed with the randomized phase II trial comparing tivantinib (n = 71) with placebo (n = 36) in patients with advanced HCC who failed one prior systemic therapy met its primary endpoint of improving TTP. Tivantinib treatment has a manageable safety profile and significantly benefited second-line HCC patients. A randomized phase III study with tivantinib as a second-line treatment is planned. Cabozantinib (XL 184) is a dual inhibitor of c-Met, and VEGFR-2 was also evaluated in a randomized dose discontinuation trial that showed antitumor activity and a safety profile similar to other VEGFR inhibitors.
Sorafenib and Conventional Chemotherapy
Prior to the benefits of sorafenib demonstrated by the phase III SHARP trial, a randomized phase II trial of patients with advanced HCC to treatment with sorafenib plus doxorubicin versus doxorubicin alone was performed. This study was halted once the survival benefit of sorafenib was established, making sorafenib the standard of care for advanced HCC. In this study, sorafenib plus doxorubicin, when compared with doxorubicin monotherapy, improved median time to progression (6.4 months versus 2.8 months; P = 0.02) and overall survival (13.7 months versus 6.5 months; hazard ratio, 0.49; P = 0.006). Presently, a large phase III trial (CALGB 80802) comparing single-agent sorafenib versus sorafenib plus doxorubicin to further explore the synergy of this combination is ongoing.
While a major advancement in the management of advanced HCC has been the clinical success of the oral multikinase inhibitor sorafenib, nearly 5 years after this major milestone sorafenib remains the standard of care for advanced HCC. The wave of molecular-targeted agents will certainly change the current landscape of treatment to one where targeted therapies will be used in the adjuvant setting and combined with locoregional treatments. However, a key focus during these trials needs to be advances in genomic and molecular profiling to identify subset of patients most likely to benefit and biomarkers predictive of response and that anticipate resistance. Critical to the success of future treatments will be our ability to incorporate the individual's genetic/epigenetic background, molecular profile of tumors, and predictive biomarkers in the design of clinical trials. Designing trials where treatment is tailored to clearly defined patients will expedite discovery and clinical development of new treatment approaches in a cost-effective manner.