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Keywords:

  • hepatocellular carcinoma;
  • targeted therapy;
  • sorafenib;
  • antiangiogenesis

Abstract

  1. Top of page
  2. Abstract
  3. Key Pathways in Hepatocarcinogenesis–Defining the Targets
  4. Antivascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor Agents
  5. Anti-EGFR Agents
  6. Challenges in HCC Clinical Trial Design in the Post-Sorafenib Era
  7. Future Directions
  8. REFERENCES

It is well appreciated that hepatocellular carcinoma (HCC) represents one of the most challenging malignancies of worldwide importance. In fact, HCC is the fifth most common cancer and the third most common cause of cancer-related death globally. The incidence rates for HCC in the U.S. and Western Europe have been rising. Unresectable or metastatic HCC carries a poor prognosis, and systemic therapy with cytotoxic agents provides marginal benefit. Because of the poor track record of systemic therapy in HCC, there has been a sense of nihilism for this disease in the oncology community for decades. However, with the arrival of newly developed, molecularly targeted agents and the success of some of these agents in other traditionally challenging cancers, such as renal cell carcinoma, there has been renewed interest in developing novel systemic therapy in HCC. At the recent Annual Meeting of the American Society of Clinical Oncology, results of a phase 3, randomized, placebo-controlled trial were presented in which sorafenib demonstrated improved survival in patients with advanced HCC. This landmark study represents the first agent that has demonstrated an improved overall survival benefit in this disease and sets the new standard for first-line treatment of advanced HCC. For this review, the author concisely summarized the current status of molecularly targeted agents that are under clinical development in advanced HCC. Cancer 2008. © 2007 American Cancer Society.

It is well appreciated that hepatocellular carcinoma (HCC) represents one of the most challenging malignancies of worldwide importance. In fact, HCC is the fifth most common cancer and the third most common cause of cancer-related death globally.1 The incidence rates for HCC in the U.S. and Western Europe have been rising.2, 3 Unresectable or metastatic HCC carries a poor prognosis, and systemic therapy with cytotoxic agents provides marginal benefit.4, 5 Because of the poor track record of systemic therapy in HCC, there has been a sense of nihilism for this disease in the oncology community for decades. However, with the arrival of newly developed, molecularly targeted agents and the success of some of these agents in other traditionally challenging cancers, such as renal cell carcinoma, there has been renewed interest in developing novel systemic therapy in HCC. In the recent Annual Meeting of the American Society of Clinical Oncology (ASCO), results of a phase 3, randomized, placebo-controlled trial were presented in which sorafenib demonstrated improved survival in patients with advanced HCC.6 This landmark study represents the first agent that has demonstrated an improved overall survival (OS) benefit in this disease and sets the new standard for the first-line treatment of advanced HCC. In this review, I have attempted to summarize concisely the current status of molecularly targeted agents that are under clinical development in advanced HCC.

Key Pathways in Hepatocarcinogenesis–Defining the Targets

  1. Top of page
  2. Abstract
  3. Key Pathways in Hepatocarcinogenesis–Defining the Targets
  4. Antivascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor Agents
  5. Anti-EGFR Agents
  6. Challenges in HCC Clinical Trial Design in the Post-Sorafenib Era
  7. Future Directions
  8. REFERENCES

Improved understanding of the mechanisms of hepatocarcinogenesis, coupled with the arrival of many newly developed, molecularly targeted agents, has provided the opportunity to study some of these novel agents in advanced HCC. Among the key pathways in carcinogenesis proposed by Hanahan and Weinberg,7 alterations are observed in nearly every carcinogenic pathway in HCC. Several excellent reviews have summarized the state of knowledge of the most common and important molecular aberrations in HCC.8–11 There are several perceived challenges in assessing the relevant molecular targets in HCC. First, despite many aberrant alterations observed in HCC, it remains difficult to assess which pathway is pathogonomotic for HCC. Second, it is well known that HCC is heterogeneous and has different underlying etiologies. Therefore, it is conceivable that the relevant significance of molecular alterations may differ depending on the underlying risk factors. Third, the animal models used to study HCC, in general, have limitations, in that they cannot recapitulate many of the key features observed in human hepatocarcinogenesis. Last, many of the molecular changes observed in HCC may be attributed to underlying cirrhosis or to dysplastic nodules. Of all the newly developed, molecularly targeted agents, those that target angiogenesis and epidermal growth factor (EGF) receptor (EGFR) pathways have gained the most experience in advanced HCC and are the focus of this review (Fig. 1).

thumbnail image

Figure 1. Key pathways in carcinogenesis and molecularly targeted agents under development in advanced hepatocellular carcinoma. VEGF indicates vascular endothelial growth factor; PDGFR, platelet-derived growth factor receptor; EGFR, epidermal growth factor receptor; PI3K, phosphoinositide-3 kinase; AKT, protein kinase B; STAT, signal transducer and activator of transcription; mTOR, mammalian target of rapamycin; HIF-1α, hypoxia-inducible factor-1 α; GRB2, growth factor receptor-bound protein 2; SOS, son of sevenless; Mek, mitogen-activated protein kinase/extracellular signal-regulated kinase.

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Antivascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor Agents

  1. Top of page
  2. Abstract
  3. Key Pathways in Hepatocarcinogenesis–Defining the Targets
  4. Antivascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor Agents
  5. Anti-EGFR Agents
  6. Challenges in HCC Clinical Trial Design in the Post-Sorafenib Era
  7. Future Directions
  8. REFERENCES

Tumor angiogenesis is a complex and dynamic process involving factors that are essential for the development of new tumor blood vessels, tumor growth, and metastasis. HCCs are vascular tumors, and increased levels of vascular endothelial growth factor (VEGF) and microvessel density have been observed.12–15 High VEGF expression has been associated with inferior survival.16–18 Therefore, inhibition of angiogenesis represents a potential therapeutic target in HCC, and several antiangiogenic agents have entered clinical studies in HCC.

Sorafenib

Given the complex, diverse signaling pathways involved in hepatocarcinogenesis, molecularly targeted agents that have multiple modes of action and thereby target multiple signaling pathways/effectors concurrently appear to be very attractive. Sorafenib (BAY 43-9006; Nexavar, Bayer Pharmaceuticals, West Haven, Conn) is an oral multikinase inhibitor that blocks tumor cell proliferation by targeting the Raf/mitgen-activated protein kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) signaling pathway and exerts an antiangiogenic effect by targeting the tyrosine kinases (TKs) VEGF receptor 2 (VEGFR-2), VEGFR-3, and platelet-derived growth factor receptor β (PDGFR-β).19, 20 In preclinical models, evidence of dose-dependent activity against a wide range of tumor types, including HCC, was observed.20, 21 Sorafenib exhibited growth-inhibitory effects, induction of apoptosis, and down-regulation of the antiapoptotic protein Mcl-1 through an Raf/MEK/ERK-independent mechanism. In tumor xenograft models, sorafenib inhibited tumor growth in a dose-dependent manner; and, at a dose of 100 mg/kg, it produced partial tumor regression in 50% of treated mice.

In a phase 2 study in patients with advanced, inoperable HCC (n = 137), single-agent sorafenib given at a dose of 400 mg twice daily induced a partial response (PR) in 2.2% of patients, a minor response in 5.8% of patients, and stable disease (SD) that lasted ≥4 months in 34% of patients.22 In that study, the median time to progression (TTP) was 4.2 months, and the median OS was 9.2 months. Tumor necrosis was observed in some patients with increased tumor size. Sorafenib was fairly tolerated. Grade 3 and 4 drug-related toxicities included fatigue (9.5%), diarrhea (8%), and hand-foot skin reaction (5.1%). Treatment was discontinued because of adverse events in only 7% of patients. In a small group of patients (n = 33), pretreatment tumor phosphorylated ERK (pERK) levels were correlated with the TTP and patients who had tumors that expressed more intense pERK staining had a longer TTP. Whether this marker will prove to be predictive of response needs to be validated in future larger studies.

Encouraged by the strong rationale for the mechanism of action of sorafenib, preclinical data indicating its action against HCC, and early evidence of antitumor activity from the phase 2 study, the international, phase 3, placebo-controlled ‘Sorafenib HCC Assessment Randomized Protocol’ (SHARP) trial was conducted.6 For that study, 602 patients with advanced HCC who had received no prior systemic therapy were evaluated and randomized to receive either sorafenib 400 mg twice daily (n = 299) or placebo (n = 303). The key eligibility criteria included biopsy-proven HCC, an Eastern Cooperative Oncology Group performance status from 0 to 2, Child-Pugh Class A cirrhosis, the presence of measurable disease, and the receipt no prior regimen. The primary objectives of the study were OS and the time to symptomatic progression, which were determined by using the Functional Assessment in Cancer Hepatobiliary Symptom Index Time to Symptom Progression (FSHI-8-TSP) scoring system. The secondary objective was time to tumor progression. The study had an impressive accrual rate and completed enrollment within 13 months. Of the patients enrolled, approximately 50% had either hepatitis C virus or hepatitis B virus as underlying etiology, and 26% had alcohol-related cirrhosis. Patients with underlying Child-Pugh Class A cirrhosis accounted for 95% and 98% of patients in the sorafenib and placebo groups, respectively. On the basis of the presentation at the 2007 Annual Meeting of the ASCO, the efficacy data are summarized in Table 1. Similar to prior phase 2 experience, only 7 patients (2.3%) achieved a PR according to Response Evaluation Criteria in Solid Tumors (RECIST) in the sorafenib arm. The median OS was 46 weeks in sorafenib-treated patients compared with 34 weeks in patients who received placebo, indicating a 44% increase in OS (hazard ratio, 0.69; P = .00058). The median TTP was 24 weeks in sorafenib-treated patients compared with 12 weeks in patients who received placebo, indicating a 73% prolongation in the TTP (hazards ratio, 0.58; P = .000007).

Table 1. Phase III Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol Trial
VariableSorafenib (n = 299)Placebo (n = 303)HRP
  1. HR indicates hazards ratio; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; TTP, time to tumor progression; OS, overall survival; FSHI8-TSP, the Functional Assessment in Cancer Hepatobiliary Symptom Index Time to Symptom Progression scoring system.

Overall response, no. (%)
 CR00  
 PR7 (2.3)2 (0.7)  
 SD211 (71)204 (67)  
 PD54 (18)73 (24)  
Progression-free rate at 4 mo, %6242  
TTP, wk2412.30.58.000007
OS, wk46.334.40.69.00058
Time to symptom progression (FSHI8-TSP)   .77

Sorafenib represents the first agent that has shown improved OS benefits in patients with advanced HCC, and it has validated the use of molecularly targeted agents in this disease. Several unusual aspects of study design were used in the SHARP trial. The control arm used best supportive care, which would have been difficult for enrollment in the U.S., as reflected by the low accrual rate in North America of only 9%. In addition to OS, the study used another primary endpoint of the time to symptomatic progression, which had not been validated in HCC in prior studies and did not reach statistical difference in the SHARP study. Patients were continued on treatment until both radiographic progression and progression according to the FSHI-8-TSP were achieved. Because symptomatic progression was defined by using an instrument that had not been validated, this may have resulted in some patients remaining on the study for a longer time than would have been the case if a more standard endpoint of radiographic progression alone had been used. The toxicity profiles seemed to be more favorable than prior experience with sorafenib in other studies, raising concern regarding toxicity grading and compliance. In addition, until the final publication of the study, we still are waiting for the ongoing analyses and clarification of some aspects of the study. Given the seemingly balanced number of patients with SD in both arms and the low response rate according to RECIST criteria, it would be informative to know how many patients have achieved minor responses in both arms. The numbers of patients requiring dose reduction of sorafenib were not presented. No information on the changes in serum α-fetoprotein levels was provided, raising the ongoing debate regarding the value of this marker in HCC. Despite these limitations, the SHARP study does establish the first new standard for the treatment of advanced HCC.

However, it also leaves several unanswered questions and presents new challenges in this field. Because most patients enrolled had underlying Child-Pugh Class A cirrhosis, it remains uncertain what would be the relative safety and tolerability for sorafenib in patients with worsening underlying cirrhosis. What are the molecular and clinical predictors of clinical benefits of sorafenib? What are the potential mechanisms of action that lead to the sorafenib-mediated clinical benefits? Is this because of the VEGFR blockage or inhibition of the Raf/MEK/ERK signaling pathway? How should we incorporate quality-of-life and symptomatic improvement assessment in future studies? Would sorafenib be beneficial in the adjuvant setting after transarterial chemoembolization (TACE), radiofrequency ablation (RFA), surgical resection, or liver transplantation? How do we rationally combine other biologic and cytotoxic agents with sorafenib to further improve efficacy?

Sunitinib

Sunitinib (SU11248, Sutent,; Pfizer, Inc., New York, NY) is a rationally designed small molecule that inhibits members of the split-kinase domain family of receptor TKs (RTKs) including VEGFR types 1 and 2 (fms-related TK 1 [FLT1] and the FLK1 kinase insert domain receptor [FLK1/KDR]); PDGFR-α and PDGFR-β, the stem cell factor receptor c-KIT, and the FLT3 and RET kinases.23–25 Inhibition of these RTKs blocks signal transduction, thereby affecting many of the processes involved in tumor growth, progression, metastasis, and angiogenesis.7 Preclinical studies in various tumor cell lines have demonstrated that the antiangiogenic effects of sunitinib are mediated through VEGFR and PDGFR-β, and sunitinib also has a direct antitumor effect through KIT and Flt3 in diseases in which these pathways are biologically relevant.26, 27 Preclinical models have indicated a more potent angiogenic effect through the inhibition of both VEGFR on endothelial cells and PDGFR on pericytes compared with the inactivation of endothelial cells alone.28 Clinically, sunitinib has good oral bioavailability, linear pharmacokinetics, and a prolonged half-life for the parent compound SU11248 (approximately 40 hours) and its active N-desethyl metabolite SU012662 (approximately 80 hours). Sunitinib has been approved for the treatment of renal cell carcinoma and gastrointestinal stromal tumor and has shown antitumor activity in several other malignancies.

Two independent phase 2 studies have examined the tolerability and efficacy of sunitinib in patients with advanced HCC. We treated patients with advanced HCC by using sunitinib at 37.5 mg orally once daily on a standard 4-weeks-on/2-weeks-off regimen (6-weeks cycle).29 The primary endpoint of the study was progression-free survival (PFS). Of the 26 patients enrolled, 1 patient had a PR response of 10 months' duration, and an additional 10 patients (38.5%) had SD that lasted ≥12 weeks. The median PFS in this cohort was 4.1 months. We also assessed changes in angiogenic parameters, including tumor permeability, using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and plasma angiogenic markers measured by enzyme-linked immunoadsorbent assay (ELISA) and Meso-Scale Discovery multiplex ELISA. Tumor permeability (Ktrans) decreased by an average of 38% after 2 weeks of treatment with sunitinib among the 20 patients who were analyzed. The majority of patients had decreased levels of soluble VEGFR2 and increased placental growth factor (PlGF) and VEGF levels from baseline to Day 15 after sunitinib treatment. Sunitinib administered at this dose schedule can be given safely, with close monitoring, to the majority of patients with advanced HCC. Adverse events generally were manageable, and the most common adverse events included neutropenia, lymphopenia, thrombocytopenia, elevation of transaminases, fatigue, and skin rash.

In another European/Asian phase 2 study, sunitinib was administered at a dose of 50 mg daily for 4 weeks every 6 weeks to patients with unresectable HCC.30 The primary endpoint of the study was the overall response rate according to RECIST criteria. Of the 37 patients enrolled, 1 patient had a confirmed PR, and 39% of patients had SD as their best response. Grade 3 and 4 toxicities included thrombocytopenia (43%), neutropenia (24%), central nervous system symptoms (24%), asthenia (22%), and hemorrhage (14%). Dose reductions were required in 27% of patients. Four patients developed grade 5 events, including ascites, edema, bleeding, drowsiness, and hepatic encephalopathy. Preliminary pharmacokinetic (PK) data do not suggest any differences in drug exposure between patients with underlying Child-Pugh Class A or Class B cirrhosis.

It is interesting to note that tumor necrosis was observed in a significant number of patients after sunitinib treatment in both studies. How to quantify the degree of tumor necrosis and to assess whether tumor necrosis indeed correlates with clinical efficacy remain to be defined in future studies. On the basis of the preliminary experience, sunitinib appears to have more toxicities and side effects in patients with HCC compared with prior experiences in other tumor types. How to define the optimal tolerable treatment dose schedule, select the right population to treat, and confirm the efficacy of sunitinib in larger studies remain some of the challenges in future development of this agent in HCC.

Bevacizumab

Bevacizumab (Avastin; Genentech, Inc., South San Francisco, Calif), a recombinant, humanized monoclonal antibody that targets VEGF, has emerged as an important therapeutic agent in several malignancies.31 In addition to its direct antiangiogenic effects, bevacizumab may enhance chemotherapy administration by “normalizing” tumor vasculature and decreasing the elevated interstitial pressure in tumors.32, 33 Several studies have explored the use of bevacizumab either as a single agent or in combination with cytotoxic or molecularly targeted agents in patients with advanced HCC (Table 2).

Table 2. Summary of Recent Phase I/II Studies With Bevacizumab-based Regimens in Hepatocellular Carcinoma
StudyRegimenNo. of patientsRR, %Median PFS/TTP, moPFS at 6 mo, %Median survival, mo
  1. RR indicates response rate; PFS, progression-free survival; TTP, time to tumor progression; NR, not reported; GEMOX-B, gemcitabine, oxaliplatin, bevacizumab; CAPEOX-B, capecitabine, oxaliplatin, bevacizumab.

Schwartz 200634Bevacizumab2586.5NRNR
Malka 200735Bevacizumab2412.5NRNRNR
Zhu 200636GEMOX-B33205.3489.6
Sun 200737CAPEOX-B30105.440NR
Hsu 200738Capecitabine-bevacizumab25164.13410.7
Thomas 200739Bevacizumab-erlotinib3421975 (at 4 mo)19

Schwartz et al. reported their preliminary experience using single-agent bevacizumab in HCC in a phase 1 study.34 Two dosages of bevacizumab, 5 mg/kg and 10 mg/kg administered intravenously once every 2 weeks, were tested in patients with HCC who had no overt extrahepatic metastases or invasion of major blood vessels. Of the initial 25 patients who were evaluable for efficacy, 2 patients had a PR, and 18 patients had SD. The median TTP was 6.5 months (range, 3.9–24.2 months). Malka et al. recently reported their early experience using bevacizumab as a single agent in HCC in a phase 2 study.35 Among the 24 patients who were evaluable for efficacy, 3 patients (12.5%) had a PR, and 7 patients (29%) had SD that lasted at least 16 weeks.

The combination of bevacizumab with cytotoxic agents also was evaluated in 3 phase 2 studies. We completed a phase 2 study using bevacizumab in combination with gemcitabine and oxaliplatin (GEMOX-B) in patients with advanced HCC.36 For Cycle 1 (14 days), bevacizumab at a dose of 10 mg/kg was administered intravenously alone on Day 1. For Cycle 2 and subsequent cycles (28 days), bevacizumab at a dose of 10 mg/kg was administered onDays 1 and 15, and gemcitabine at a dose of 1000 mg/m2 was delivered intravenously as a dose-rate infusion at 10 mg/m2/minute followed by oxaliplatin at a dose of 85 mg/m2 as a 2-hour intravenous infusion on Days 2 and 16 of every cycle. This regimen had moderate antitumor activity in HCC with an overall response rate of 20% in evaluable patients. An additional 27% of patients had SD with a median duration of 9 months (range, 4.5–13.7 months). The median OS was 9.6 months, the median PFS was 5.3 months, and the PFS rate at 3 months and 6 months approached 70% and 48%, respectively. Sun et al. recently reported their experience of using bevacizumab in combination with capecitabine and oxaliplatin in patients with advanced HCC.37 In a 21-day cycle, bevacizumab (5 mg/kg) and oxaliplatin (130 mg/m2) were administered intravenously on Day 1, and capecitabine (825 mg/m2, twice daily) was administered on Days 1 through 14. Of the evaluable patients, 3 patients (11%) had a PR, and 21 patients had SD (78%). The mean PFS was 5.4 months, and the PFS rates at 3 months and 6 months were 70%, and 40%, respectively. In another early report, the combination of bevacizumab and capecitabine was evaluated in a phase 2 study.38 Capecitabine was given at a dose of 800 mg/m2 orally twice daily on Days 1 through 14, and bevacizumab was given at a dose of 7.5 mg/kg intravenously on Day 1 of each 21-day cycle. Of the 25 patients who were evaluable for efficacy and safety, the overall response rate was 16% (95% confidence interval [95% CI], 4.5–36.1%), and the disease control rate (complete response [CR] + PR + SD) was 60% (95% CI, 38.7–78.9%). The median OS was 10.7 months (95% CI, 5.3–14.7 months), and the median PFS was 4.1 months (95% CI, 1.6–6.2 months). The PFS rates at 3 months and 6 months were 64% (95% CI, 45.2–82.8%) and 34% (95% CI, 15.1–53.2%), respectively.

Thomas et al. reported their early phase 2 experience using the combination of bevacizumab and erlotinib in patients with advanced HCC.39 Bevacizumab was given at a dose of 10 mg/kg intravenously once every 14 days, and erlotinib was given at a dose of 150 mg orally daily. Of the 34 patients who were evaluable for efficacy, 1 patient had a confirmed CR, and 6 patients had a PR, for a 21% response rate. The median PFS was 9 months, and the median OS 19 months. The encouraging results from that early study should be confirmed cautiously by an independent study in the future.

Despite the initial safety concerns for bevacizumab use in this population, in particular the risks for gastrointestinal bleeding and thrombosis, the safety profiles from the phase 2 studies described above appeared to be favorable overall. Bevacizumab-related side effects, including hypertension, bleeding, and proteinuria, were observed and generally were manageable. Rare occurrence of small bowel perforation was encountered. Early changes of bevacizumab-induced alterations in angiogenic parameters, including computed tomography perfusion and DCE-MRI scan parameters and circulating endothelial cells (CECs), also were observed. However, whether changes in any of these parameters correlate with treatment response and clinical efficacy remains to be explored in future studies. On the basis of the phase 1 and 2 study experiences detailed above, bevacizumab appears to have antitumor activity in HCC either as a single agent or in combination with other cytotoxic agents or erlotinib with tolerable safety profiles. However, because of the nonrandomized nature, small sample size, and patient selection bias inherent in single-arm studies, the relative contributions, if any, from chemotherapy regimens (either GEMOX, capecitabine, or capecitabine-oxaliplatin) or erlotinib remain unknown and warrant further investigations. Whether bevacizumab eventually will prove to be beneficial and how it compares with sorafenib will require additional assessment and validation in future large, randomized phase 2/3 studies.

AZD2171

AZD2171 (cediranib; AstraZeneca Pharmaceuticals, U.K.) is a potent, oral, pan-VEGFR TK inhibitor with activity against PDGFRs and c-Kit. AZD2171 is a potent inhibitor of both KDR (50% inhibitory concentration [IC50] <0.002 μM) and Flt-1 (IC50 = 0.005 μM) and demonstrates activity against c-kit, PDGFRβ, and Flt-4 at nanomolar concentrations.40 Alberts et al. reported their early experience of the toxicity and efficacy of AZD2171 from a North Central Cancer Treatment Group phase 2 study in patients with advanced HCC.41 AZD2171 was given at a dose of 45 mg orally once daily using a 28-day treatment cycle. Twenty-eight patients have been accrued, and 19 patients were evaluable for toxicity. Of these, 16 patients (84%) developed grade 3 toxicity. Fatigue, hypertension, and anorexia accounted for the majority of adverse events. Despite a lack of grade 4 events, a high rate of refusal of further treatment was encountered and apparently was related to the high rate of grade 3 fatigue. Patients received a median of 1 cycle of treatment (range, 1–8 cycles) on study. A dose reduction of AZD2171 was planned in an ongoing study.

PTK787

PTK787/ZK222584 (Vatalanib; Novartis, East Hanover, NJ) is an oral angiogenesis inhibitor that targets all known VEGFR TKs, including VEGFR-1/flt-1, VEGFR-2/KDR, and VEGFR-3/Flt-4, PDGFR, and c-kit, with a higher selectivity for VEGFR-2.42, 43 Koch et al. reported the early experience of an open-label, multicenter, phase 1 study to characterize the safety, tolerability, and PK profile of PTK787 administered once daily at a dose from 750 mg to 1250 mg in patients with unresectable HCC.44 Patients were stratified into 3 groups with mild, moderate, and severe hepatic dysfunction, respectively, based on total bilirubin and aspartate/alanine aminotransferase levels. The maximal tolerated dose of PTK787 was defined as 750 mg daily. Among the patients in all 3 groups, 18 patients were evaluable for efficacy. No CR or PR was observed. Nine patients had a best response of SD, and 9 patients had progressive disease.

Anti-EGFR Agents

  1. Top of page
  2. Abstract
  3. Key Pathways in Hepatocarcinogenesis–Defining the Targets
  4. Antivascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor Agents
  5. Anti-EGFR Agents
  6. Challenges in HCC Clinical Trial Design in the Post-Sorafenib Era
  7. Future Directions
  8. REFERENCES

Increasing evidence has highlighted the importance of EGFR/human EGFR1 (EGFR/HER1) and its ligands EGF and transforming growth factor-α (TGF-α) in hepatocarcinogenesis. The expression of several EGF family members, specifically EGF, TGF-α, and heparin binding-EGF, as well as the EGFR, has been described in several HCC cell lines and in tissue.45–50 Morimitsu et al. examined the expression of TGF-α and its receptor, EGFR, in HCC and adjacent nontumorous livers from 25 Japanese patients using immunohistochemistry.51 TGF-α was detected in 24 of 25 HCCs (96%) and in 23 of 24 (96%) available adjacent nontumorous livers. EGFR was detected in 16 of 25 HCCs (64%) and in 17 of 24 (71%) adjacent nontumorous liver tissues. Studies have supported the theory of an autocrine, paracrine, and endocrine mechanism of TGF-α and EGFR/HER1 on the proliferation of human HCC.52 Multiple strategies to target EGFR signaling pathways have been developed, and 2 classes of anti-EGFR agents have established clinical activity in cancer: monoclonal antibodies, which competitively inhibit extracellular endogenous ligand binding, and small molecules, which inhibit the intracellular TK domain.

EGFR TK inhibitors

Two phase 2 clinical studies have evaluated the safety and efficacy of erlotinib (Tarceva) given at a dose of 150 mg daily in patients with advanced HCC (Table 3).53, 54 In the study by Philip et al., 3 of 38 patients (9%) had a PR, and 12 patients (32%) were progression free at 6 months.53 The median OS for this cohort was 13 months. In another report by Thomas et al., 17 of 40 patients (43%) achieved PFS at 16 weeks, and the PFS rate at 24 weeks was 28%.54 No PR or CR was observed in this study. The median time to failure, which was defined as either disease progression or death, was 13.3 weeks. The median OS was 25.0 weeks (95% CI, 17.9–42.3 weeks) from the date erlotinib therapy was initiated. In Eastern Cooperative Oncology Group Study E1203, gefitinib given at 250 mg daily was examined in a single-arm phase 2 study.55 A 2-stage design was used, and 31 patients were accrued to the first stage. One patient had a PR, and 7 patients had SD. The median PFS was 2.8 months (95% CI, 1.5–3.9 months), and the median OS was 6.5 months (95% CI, 4.4–8.9 months). The criterion for second-stage accrual was not met, and the authors concluded that gefitinib as a single agent was not active in patients with advanced HCC. Lapatinib, a selective dual inhibitor of both EGFR and HER-2/NEU TKs, also demonstrated modest activity in HCC in a preliminary report.56 Among the first 17 patients with advanced HCC, 2 patients had a confirmed PR, and an additional 8 patients had SD. However, the PFS was only 2.3 months in this cohort.

Table 3. Summary of Recent Phase II Studies With Epidermal Growth Factor Receptor Inhibitors in Hepatocellular Carcinoma
StudyRegimenNo. of patientsRR, %Median PFS/TTP, moPFS at 6 mo, %Median survival, mo
  1. RR indicates response rate; PFS, progression-free survival; TTP, time to tumor progression; NR, not reported; GEMOX, gemcitabine and oxaliplatin.

Philip 200553Erlotinib3893.23213
Thomas 200754Erlotinib4003.1286.3
O'Dwyer 200655Gefitinib3132.8NR6.5
Ramanathan 200656Lapatinib3052.3NR6.2
Zhu 200757Cetuximab3001.3639.6
Gruenwald 200758Cetuximab3201.87NRNR
Louafi 200759Cetuximab-GEMOX43234.5NR9.2

Monoclonal antibodies against EGFR

Cetuximab, a chimeric monoclonal antibody against EGFR, was tested in 2 phase 2 studies in patients with advanced HCC.57 In our study, 30 patients with advanced HCC were enrolled. The initial dose of cetuximab was 400 mg/m2 given intravenously followed by weekly intravenous infusions at 250 mg/m.2 No responses were observed. Five patients had SD (median time, 4.2 months; range, 2.8–4.2 months). The median OS was 9.6 months (95% CI, 4.3–12.1 months), and the median PFS was 1.4 months (95% CI, 1.2–2.6 months). Cetuximab trough concentrations were not altered notably in patients with Child-Turcotte-Pugh (CTP) Class A and CTP Class B cirrhosis. Gruenwald et al. reported their preliminary experience of cetuximab in a similarly designed study in patients with HCC.58 Of the 32 patients who were enrolled, 27 patients were evaluable for efficacy. No responses were observed, and the median TTP for all patients was 8 weeks.

The combination of cetuximab with GEMOX was evaluated in a phase 2 study.59 All patients received cetuximab at an initial dose of 400 mg/m2 followed by 250 mg/m2 weekly, gemcitabine at a dose of 1000 mg/m2 on Day 1, and oxaliplatin at a dose of 100 mg/m2 on Day 2 repeated every 14 days until disease progression or limiting toxicity. Of the 43 patients who were enrolled, 35 patients were evaluable for efficacy with a response rate of 23%. Given the known antitumor activity of GEMOX in prior phase 2 studies and the lack of activity of cetuximab as a single agent, the relative contribution of cetuximab to this regimen remains to be defined.

Challenges in HCC Clinical Trial Design in the Post-Sorafenib Era

  1. Top of page
  2. Abstract
  3. Key Pathways in Hepatocarcinogenesis–Defining the Targets
  4. Antivascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor Agents
  5. Anti-EGFR Agents
  6. Challenges in HCC Clinical Trial Design in the Post-Sorafenib Era
  7. Future Directions
  8. REFERENCES

The SHARP study has established sorafenib as the new reference standard for the treatment of advanced HCC. Because of this important study, it has sparked more interest in the development of other agents in HCC. In addition, it has generated further challenges in future trial designs. Several potential phase 2/3 study designs in advanced HCC are illustrated in Figure 2. The tested new agent/regimen can be compared directly with sorafenib or the combination of the tested agent and sorafenib can be compared with sorafenib alone, and the new agent/regimen can be tested in the sorafenib-refractory population. Because of the aggressive nature of HCC and underlying cirrhosis, we should continue to focus on testing the promising agents/regimens in patients who have relatively preserved hepatic function and good performance status. Because most patients who have HCC have underlying cirrhosis with impaired hepatic function, we should assess the safety and toxicity profiles of the newer agents/regimens carefully in this population. We should continue with our efforts to develop and validate an HCC-specific quality-of-life measurement. The efficacy and safety profiles of any new agents/regimens should be examined vigorously in phase 2, preferably in randomized phase 2 studies, before rushing for large phase 3 studies, to ensure the optimal use of patient resources. While testing the newer molecularly targeted agents in HCC, it is imperative to incorporate imaging studies and surrogate markers in an attempt to understand the potential mechanisms of action of these agents.

thumbnail image

Figure 2. Schematic illustration of potential future trial designs in advanced hepatocellular carcinoma. HCC indicates hepatocellular carcinoma; BSC, best supportive care.

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Future Directions

  1. Top of page
  2. Abstract
  3. Key Pathways in Hepatocarcinogenesis–Defining the Targets
  4. Antivascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor Agents
  5. Anti-EGFR Agents
  6. Challenges in HCC Clinical Trial Design in the Post-Sorafenib Era
  7. Future Directions
  8. REFERENCES

Despite the important, positive results of improved OS with sorafenib in the SHARP study, the benefits are modest. Therefore, developing more effective systemic therapies for patients with HCC remains a challenge. Future research should continue to unravel the mechanism of hepatocarcinogenesis and to identify key relevant molecular targets for therapeutic intervention. We should have a better understanding of the clinical and molecular predictors of sorafenib-mediated clinical benefits and mechanisms of resistance. The development and approval of other molecularly targeted agents in this disease should be expedited. The role of sorafenib and other promising agents should be examined in the adjuvant setting after RFA, TACE, surgical resection, or selective settings in liver transplantation in an attempt to improve further the outcomes of these patients. Hopefully, we will continue to witness meaningful progress for the development of molecularly targeted agents in HCC in the coming years.

REFERENCES

  1. Top of page
  2. Abstract
  3. Key Pathways in Hepatocarcinogenesis–Defining the Targets
  4. Antivascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor Agents
  5. Anti-EGFR Agents
  6. Challenges in HCC Clinical Trial Design in the Post-Sorafenib Era
  7. Future Directions
  8. REFERENCES
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