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Sorafenib for the treatment of hepatocellular carcinoma across geographic regions Expert Rev. Clin. Pharmacol. 2(2), 129–136 (2009)
Chiun Hsu, Ying‑Chun Shen and Ann Lii Cheng† † Author for correspondence Departments of Oncology and Internal Medicine, National Taiwan University Hospital, Taiwan Tel.: +88 622 312 3456 ext. 67251 Fax: +88 622 371 1174 [email protected]
www.expert-reviews.com
Sorafenib is an oral multikinase inhibitor targeting Raf, VEGF receptor, PDGF receptor, c-kit, Flt‑3 and rearranged during transfection (RET). Two randomized, placebo-controlled trials for Western and Asian patients, respectively, demonstrated that sorafenib significantly prolongs overall survival and time to progression in patients with advanced hepatocellular carcinoma (HCC). These have become the reference treatment for future clinical trials of advanced HCC. Sorafenib is well tolerated in patients with Child–Pugh liver function class A, but limited data are available in Child–Pugh class B and C patients. Clinical trials are ongoing to test the efficacy of sorafenib‑based combination therapy and sorafenib adjuvant therapy for HCC. Keywords : hepatocellular carcinoma • molecular targeted therapy • sorafenib
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide and its incidence continues to increase [1] . Most patients with HCC have underlying cirrhosis caused by chronic hepatitis B virus (HBV), hepatitis C virus (HCV) infection or alcoholic liver disease. The etiologies of the underlying cirrhosis have distinct geographic variations: HBV infection occurs in most Asian and African countries, chronic hepatitis C infection or alcoholic liver disease occurs in Western countries and in Japan [2,3] . The different etiologies have been found to be associated with different genetic and epigenetic aberrations, which may have important implications in patient prognosis and in new drug development [4–6] . Curative surgery is feasible in only approximately 20–30% of patients because of advanced tumor stage and impaired liver function at diagnosis [7] . These situations also limit the usefulness of other local treatment strategies, such as percutaneous alcohol injection, radiofrequency ablation and transarterial chemoembolization. Therefore, effective systemic therapy is urgently needed for patients with advanced HCC. Objective response rates to single-agent cytotoxic therapies, even in highly selected patients, are usually less than 10%, and no survival benefit has been observed [8–10] . Recent advances in elucidating the molecular mechanisms of hepato carcinogenesis have provided opportunities to 10.1586/17512433.2.2.129
develop molecular targeted therapy for advanced HCC [11] . Agents targeting tumor angiogenesis, the Raf/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway and the EGF receptor (EGFR) pathway have shown promising anti-tumor activity in patients with advanced HCC. The most successful example is the multikinase inhibitor sorafenib, which has shown survival benefit in two randomized, placebo-control trials [12,13] . Introduction to sorafenib
Sorafenib was developed by a new drug-discovery program aimed at agents targeting the Raf/ MAPK/ERK signaling pathway [14] . The lead compounds identified by high-throughput screening were optimized by combinatory chemistry approaches to improve the potency of Raf kinase inhibition. In addition to wild-type B-raf (IC50 at 6 nM), sorafenib also inhibits the kinase activity of mutant Raf V600E , VEGF receptors (VEGFRs), PDGF receptors (PDGFRs), c-kit, Flt-3 and rearranged during transfection (RET) (IC50 < 100 nM). Preclinical studies showed that sorafenib can inhibit tumor growth in various tumor models with wild-type or mutant Raf kinases [15] . The role of Raf/MAPK/ERK signaling in carcinogenesis of HCC has been extensively studied. Aberrant expression and activation of Raf/ MAPK/ERK signaling were demonstrated in
© 2009 Expert Reviews Ltd
ISSN 1751-2433
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Hsu, Shen & Cheng
Table 1. Comparison of the published Phase I trials of sorafenib. Study
Patients (n)
Dosing schedule
Dose ranges
Pharmacokinetic parameters Patients (n)
AUC0–12 (mg × h/l)
Cmax (mg/h)
Western trials Clark et al.
19
7 days on/7 days off
100–800 mg b.i.d.
4‡
56.6 (90.5)
6.2 (106.7)
Awada et al.
44
21 days on/7 days off
50–800 mg b.i.d.
5
76.5
10.0
Moore et al.
41
28 days on/ 7 days off
50 mg/4 days– 600 mg b.i.d.
3
47.8 (24.0)
5.4 (41.0)
Strumberg et al.
69
Continuous dosing
100–600 mg b.i.d.
5§
71.7 (43)
9.35 (44)
Minami et al.
31
Continuous dosing
100–600 mg b.i.d.
6¶
36.7 (73)
4.91 (76)
Furuse et al.
27
Continuous dosing
200–400 mg b.i.d.
6¶#
33.5 (60.1)
4.7 (66.1)
‡
‡
Japanese trials
Data are expressed as geometric mean values. Percentage coefficient of variation, if available, is expressed in parentheses. Based on pharmacokinetic sampling performed on the final day of dosing in cycle one. Based on pharmacokinetic sampling after multiple dosing. ¶ Based on pharmacokinetic sampling performed on day 14 of cycle one. # Data from patients with normal liver function reserves (Child–Pugh class A). ** Based on serum lipase study. b.i.d.: Twice daily; Gr: Grade; NA: Not available. * ‡ §
human HCC tumor tissue and were correlated with large tumor size, advanced tumor stage and poor survival [16–18] . Multiple mechanisms may account for the increased activity of the Raf/ MAPK/ERK signaling pathway in HCC. For example, the hepatitis B HBx protein and the hepatitis C core protein can induce activation of Raf/MAPK/ERK signaling, which in turn is involved in many critical steps of hepatocarcinogenesis, including increased cell proliferation, increased invasive potential and induction of inflammatory responses [19–21] . Moreover, downregulation of endogenous inhibitors of the Raf/MAPK/ERK pathway, such as the Raf kinase inhibitor protein (RKIP) and the sprouty-related protein with Ena/vasodilator-stimulated phosphoprotein homology-1 domain (Spred), has been found in HCC tumor tissue. This downregulation was correlated with activation of MAPK/ ERK signaling, increased cancer cell proliferation and increased invasive potential [22,23] . This evidence indicates that the Raf/ MAPK/ERK signaling pathway is an important target for new drug development for HCC. Chemistry
The tosylate salt of sorafenib is used for clinical development. Sorafenib tosylate is insoluble in aqueous medium but soluble in polyethylene glycol (PEG)400. Sorafenib tosylate in its solid form is stable at room temperature for prolonged periods. The drug product of sorafenib for clinical use is a 200‑mg coated tablet. Pharmacodynamics
Sorafenib has been demonstrated to inhibit tumor growth in a wide range of preclinical models [15] . In some models, such as the HT-29 colon cancer (with BRAF mutation) and the MDA-MB-231 breast cancer (with BRAF and k-ras mutations) models, the anti-tumor 130
effects of sorafenib were correlated with the inhibitory effects on Raf/MAPK/ERK signaling activity. In others, such as the A549 lung cancer and the Colo-205 colon cancer models, the anti-tumor effects of sorafenib were not associated with inhibition of Raf/ MAPK/ERK activity, suggesting that other mechanisms may play an important role in tumor growth inhibition. Inhibition of tumor angiogenesis was considered another key anti-tumor mechanism of sorafenib, presumably through its inhibition of VEGFR and PDGFR activities [24,25] . In addition, sorafenib can induce tumor cell apoptosis by regulating the expression of several apoptosis regulatory proteins, such as the myeloid cell leukemia-1 (mcl-1), cFLIP and the apoptosis-inducing factor (AIF) [26–29] . The in vivo pharmacodynamic effects of sorafenib have been evaluated in two Phase I trials by measuring sorafenib-induced inhibition of pERK in patients’ peripheral blood lymphocytes, using an in vitro model of phorbol myristate acetate (PMA) stimulation [30,31] . In the study by Strumberg et al., almost complete inhibition of PMA-induced ERK phosphorylation was observed on day 21 of a continuous dosing schedule. However, in the study by Minami et al., no significant change of pERK was seen after the same dosing schedule. The latter trial also used PET to evaluate the metabolic activity of tumor cells after sorafenib treatment [31] . In 23 patients who had serial PET examination, the median maximum standardized uptake values (SUVmax) was significantly decreased after sorafenib treatment (from 16.2 at baseline to 11.2 at the first examination after the start of treatment). A 25% or greater decrease in SUVmax was found in 11 patients. In addition, a higher trough concentration of sorafenib on day 28 was associated with a larger decrease in SUVmax. These pharmacodynamic parameters warrant further investigation in larger clinical trials. Expert Rev. Clin. Pharmacol. 2(2), (2009)
Sorafenib for hepatocellular carcinoma
Drug Profile
Table 1. Comparison of the published Phase I trials of sorafenib (cont.). Adverse events Fatigue All
≥Gr3
Anorexia All
≥Gr3
Diarrhea All
≥Gr3
Rash/ Hand–foot desquamation skin reaction
Ref. Nausea
Alopecia
All
≥Gr3
All
≥Gr3
All
≥Gr3
All
≥Gr3
Pancreatitis All
≥Gr3
Western trials 11
0
11
0
0
0
32
11
NA
NA
11
0
0
0
NA
NA
[32]
52
9
39
5
18
2
36
5
43
11
14
2
30
0
NA
NA
[33]
44
7
29
0
32
0
15
0
22
10
22
0
17
0
NA
NA
[34]
39
6
42
0
55
9
26
0
23
6
30
0
16
3
NA
4.3
[30]
0
36
3.2
61
0
39
0
10
0
26
0
11**
6.5**
[31]
55.6
3.2
48.4
6.4
38.7
6.4
NA
NA
16.1
0
88.9
63
[35]
Japanese trials 10
3.2
26
3.2
0
19.4 0
**
**
Data are expressed as geometric mean values. Percentage coefficient of variation, if available, is expressed in parentheses. ‡ Based on pharmacokinetic sampling performed on the final day of dosing in cycle one. § Based on pharmacokinetic sampling after multiple dosing. ¶ Based on pharmacokinetic sampling performed on day 14 of cycle one. # Data from patients with normal liver function reserves (Child–Pugh class A). ** Based on serum lipase study. b.i.d.: Twice daily; Gr: Grade; NA: Not available. *
Pharmacokinetics & metabolism
Since sorafenib is metabolized by the CYP enzymes (mainly Six single-agent Phase I studies of sorafenib, four from Western CYP3A4) in the liver, it is important to see whether sorafenib is countries and two from Japan, have been published (Table 1) [30–35] . safe in patients with impaired liver function reserves. The Japanese Japanese patients appeared to have lower plasma Cmax and AUC Phase I trial for HCC patients and a Western Phase II trial for values than their Western counterparts. Although ethnic difference HCC patients compared the pharmacokinetic parameters between in expression of cytochrome P450 (CYP), the enzymes responsi- patients with Child–Pugh A and B cirrhosis (Table 2) [35,39] . In the ble for the metabolism of sorafenib, have been reported [36] , the Western trial, patients with Child B cirrhosis had higher AUC and ethnic difference of the pharmacokinetics of sorafenib cannot be Cmax than patients with Child A cirrhosis, while in the Japanese explained by this factor [37,38] . Moreover, the difference in pharma- trial, patients with Child B cirrhosis had lower AUC and Cmax. cokinetic parameters found in these Phase I trials did not correlate These variations were not considered significant because they were with the incidence and severity of sorafenib-related adverse events. not associated with difference in adverse events between Child A Significant interpatient variability of pharmacokinetic parameters and Child B patients in either trial. between the studies was found. The plasma half-life Table 2. Comparison of safety and pharmacokinetic profiles between of sorafenib ranged from 20 hepatocellular carcinoma patients with Child–Pugh A or B cirrhosis. to 30 h. Drug accumulation Study Patients (n) Pharmacokinetic parameters after multiple dosing was AUC Cmax (mg/l) Tmax (h) found and the concentration (mg × h/l) reached a steady state after 14 days of treatment. The Abou-Alfa et al.* most common dose-limiting Child A 14 25.4 (38.2) 4.9 (38.7) 1.0 (0–12) toxicity included skin rash/ Child B 8 30.3 (82.1) 6.0 (73.8) 0.5 (0–8) desquamation, hand–foot skin reaction, diarrhea and Furuse et al.‡ fatigue. The Japanese trials Child A 6 28.9 (86.8) 3.3 (113.5) 8 (6–24) reported a high incidence Child B 5 20.7 (72.1) 4.0 (79.1) 24 (4–24) of grade 3 or 4 elevation of * AUC0–8 was reported because blood samples at 12 h were not available for most patients. All data were based on pancreatic amylase or lipase. pharmacokinetic sampling after one cycle (28 days) of treatment. This biochemical abnormal- ‡AUC0–12 and Cmax were reported based on pharmacokinetic sampling after 28 days of treatment. Tmax data were based on pharmacokinetic sampling after day 1 doses. ity was not associated with The values of percentage coefficient of variation for AUC and Cmax and the ranges of Tmax are given in parentheses. Data from [35,39]. symptoms of pancreatitis. www.expert-reviews.com
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Hsu, Shen & Cheng
Another pharmacokinetic study specifically addressed the safety issue of sorafenib in patients with liver or kidney dysfunction [40] . Patients with refractory solid tumors or hematological malignancy were divided into cohorts of normal function or mild/moderate/ severe/very severe organ dysfunction based on bilirubin and albumin levels and creatinine clearance. The apparent oral clearance of sorafenib was not significantly different among the cohorts. However, patients with elevated bilirubin levels had lower tolerance to sorafenib treatment. These data suggest that conventional pharmacokinetic parameters may not accurately reflect the difference of sorafenib metabolism in patients with impaired liver function reserves. Clinical efficacy Phase I & II studies
In the Phase I studies for patients with advanced solid tumors, partial response (according to Response Evaluation in Solid Tumors [RECIST]) was demonstrated in two patients with renal cell carcinoma, one with HCC and one with non-small-cell lung cancer [30–34] . Prolonged disease stabilization was demonstrated in patients with renal cell carcinoma, HCC, colon cancer and lung cancer. In the Phase I trial for HCC patients, one partial response was documented in 27 evaluable patients and the overall survival and time to progression were 15.6 and 4.9 months, respectively [35] . No clear dose–response relationship was shown in these Phase I studies. The 400 mg twice daily, continuous‑dosing regimen was selected for further clinical development.
One Phase II trial for patients with advanced HCC was reported [39] . This study used a three-stage design and recruited patients with inoperable HCC and Child–Pugh liver function class A or B. Patient recruitment stopped at the second interim analysis because the preset efficacy end point (six or more responders in 97 subjects) was not met. In 137 evaluable patients, three (2.2%) achieved partial response, eight (5.8%) had minor response and 46 (33.6%) had stable disease for more than 16 weeks. The median time to progression and overall survival were 4.2 and 9.2 months, respectively. The levels of phosphorylated ERK in tumor cells were evaluated by immunohistochemistry in 33 patients with tumor specimens available. Patients with high phosphorylated ERK staining in tumor cells (n = 18) had significantly longer time to progression than those with low intensity (n = 15). The RNA expression patterns in blood cells were evaluated by microarray in 31 patients. A panel of 18 genes were identified to have predictive value on tumor progression status. The usefulness of these biomarkers must be validated in large-scale trials. Phase III studies
Two randomized, placebo-controlled trials of sorafenib for the treatment of advanced HCC have been reported [12,13] . The first trial (the Sorafenib Hepatocarcinoma Assessment Randomized Protocol [SHARP] trial) was performed primarily in Europe and in America with the primary end point of overall survival. The second trial was designed originally as a bridging study
Table 3. Phase III trials of sorafenib versus placebo for patients with advanced hepatocellular carcinoma. Parameter
SHARP trial [12]
Asian–Pacific trial [13]
Sorafenib (n = 299)
Placebo (n = 303)
Sorafenib (n = 150)
Placebo (n = 76)
Median age (years)
65
66
51
52
Hepatitis virus status (HBV/HCV; %)
19/29
18/27
71/11
78/4
Sex (male; %)
87
87
85
87
Barcelona clinic liver cancer stage (B/C; %)
18/82
17/83
4/96
4/96
ECOG PS (0/1/2; %)
54/38/8
54/39/7
25/69/5
28/67/5
Extrahepatic spread (%)
53
50
69
68
Macroscopic vascular invasion (%)
36
41
36
34
Lung metastasis (%)
22
19
52
45
Overall survival (months) (95% CI)
10.7 (9.4–13.3)
7.9 (6.8–9.1)
6.5 (5.6–7.5)
4.2 (3.7–5.5)
Hazard ratio (95% CI)
0.69 (0.55–0.87)
Time to progression (months) (95% CI)
5.5 (4.1–6.9)
Hazard ratio (95% CI)
0.58 (0.45–0.74)
Time to symptomatic progression (months) (95% CI)
4.1 (3.5–4.8)
Hazard ratio (95% CI)
1.08 (0.88–1.31)
Baseline characteristics
Treatment efficacy 0.68 (0.53–0.93) 2.8 (2.7–3.9)
2.8 (2.6–3.6)
1.4 (1.3–1.5)
0.57 (0.42–0.79) 4.9 (4.2–6.3)
3.5 (2.8–4.2)
3.4 (2.4–4.1)
0.90 (0.67–1.22)
ECOG: Eastern Cooperative Oncology Group; HBV: Hepatitis B virus; HCV: Hepatitis C virus; PS: Performance status; SHARP: Sorafenib HCC Assessment Randomized Protocol Trial.
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to evaluate the overall efficacy and safety of sorafenib in the Asian–Pacific population. Both trials recruited HCC patients whose tumors were not eligible for or had progressed after surgery or locoregional therapy, and those who had a Child–Pugh liver function of class A and an Eastern Cooperative Oncology Group (ECOG) performance score of 2 or lower. The treatment regimen was the same (sorafenib 400 mg twice daily). Both trials stopped early because per-protocol interim analysis indicated significant survival benefit of sorafenib versus placebo. Comparison of these two Phase III trials is listed in Table 3. Patients in the Asian–Pacific trial were younger and had more symptomatic diseases (ECOG score 1 or 2) and extrahepatic metastases. Despite these differences in the baseline prognostic features, the overall treatment efficacy of sorafenib, in terms of hazard ratios of overall survival and time to progression, was similar between these two trials. The survival time of patients in the Asian–Pacific trial was significantly shorter than that of the SHARP trial, reflecting the poor prognostic features of the Asian patients. Geographic areas (Asian vs non-Asian) should be used as a stratification factor in future randomized trials of HCC [41] . Exploratory subgroup analysis of the SHARP trial indicated that sorafenib treatment prolonged survival regardless of patient age, performance status, tumor burden (vascular invasion or extrahepatic spread) and prior anti-tumor therapy (Table 4) [42–46] .
Drug Profile
liver function class. However, patients with Child–Pugh B class had higher rate of elevated bilirubin (18 vs 40%), encephalopathy (2 vs 11%) and worsening ascites (11 vs 18%) than patients with Child–Pugh A class [47] . In the Phase III SHARP trial, the incidence of serious hepatobiliary events was similar between the sorafenib (11%) and placebo groups (9%). Regulatory affairs
Sorafenib was approved for the treatment of advanced HCC by the EMEA in October 2007 and by the US FDA in November 2007. In the most recent practice guidelines recommended by the US National Comprehensive Cancer Network, sorafenib is listed as a treatment option for HCC patients who are inoperable by performance status or comorbidity (local disease only) and who do not present with cancer-related symptoms [101] . Sorafenib has also been approved for the treatment of HCC by several Asian countries, including Korea, China, Singapore and Thailand. Conclusion
Sorafenib has a proven survival benefit for patients with advanced HCC across geographic regions. It has become the reference treatment for future clinical trials of systemic therapy for advanced HCC.
Safety & tolerability
Expert commentary & five-year view
Sorafenib is generally well tolerated. The most common sorafenibinduced adverse events include diarrhea, fatigue, hand–foot skin reaction and rash/desquamation. These events occured in 20–40% of patients, most of which were grade 1 or 2. The most common causes of dose interruption or reduction in previous sorafenib trials were hand–foot skin reaction, rash and diarrhea. In the Phase II trial of sorafenib for HCC, the incidence of all adverse events and serious adverse events was similar between patients with Child–Pugh A (n = 98) and Child–Pugh B (n = 38)
Advanced HCC has been considered a huge unmet medical need, especially in countries endemic for chronic viral hepatitis. Sorafenib represents a successful first step toward better treatment for this difficult disease. Although sorafenib is generally well tolerated, it should be used with caution in patients with impaired liver function reserves. Combination therapy to improve the therapeutic efficacy of sorafenib has been pursued [48] . A randomized Phase II trial of sorafenib plus doxorubicin versus doxorubicin alone reported
Table 4. Exploratory subgroup analysis of the Sorafenib HCC Assessment Randomized Protocol Trial. HCV (n = 178)
Alcohol (n = 159)
Prior resection/ ablation (n = 158)
Prior TACE (n = 176)
PS
MVI/EHS
0 (n = 325)
1–2 (n = 277)
No (n = 181)
Yes (n = 421)
Overall survival (months) Sorafenib
14.0
10.3
11.9
11.9
13.3
8.9
14.5
8.9
Placebo
7.9
8.0
8.8
9.9
8.8
5.6
10.2
6.7
HR (95% CI)
0.58 (0.39–0.91)
0.76 (0.50–1.16)
0.79 (0.51–1.22)
0.75 (0.49–1.14)
0.68 (0.50–0.95)
0.71 (0.52–0.96)
0.52 0.77 (0.35–0.85) (0.60–0.99)
Time to progression (months) Sorafenib
7.7
5.5
5.5
5.8
5.5
5.3
9.6
4.1
Placebo
2.8
3.9
2.7
4.0
2.9
2.8
4.3
2.7
HR (95% CI)
0.44 (0.25–0.76)
0.64 (0.40–1.03)
0.62 (0.39–0.98)
0.57 (0.36–0.91)
0.55 (0.40–0.77)
0.61 (0.42–0.88)
0.40 0.64 (0.23–0.70) (0.48–0.84)
EHS: Extrahepatic spread; HCV: Hepatitis C virus; HR: Hazard ratio; MVI: Macroscopic vascular invasion; PS: Performance status; TACE: Transcatheter arterial chemoembolization.
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Drug Profile
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superior median overall survival (13.7 vs. 6.5 months) and time to progression (8.6 vs 4.8 months) in patients receiving sorafenib plus doxorubicin compared with doxorubicin alone [49] . These results should be interpreted with caution because of the lack of a sorafenib-alone arm and the high incidence of adverse events related to doxorubicin. An alternative approach is to combine sorafenib with small, frequent, uninterrupted doses of cytotoxic chemotherapy, usually referred to as ‘metronomic chemotherapy’ [50] . Results from a Phase II study combining sorafenib with oral tegafur/uracil indicated promising anti-tumor activity and good patient tolerance [51] . Further exploration of this concept is warranted. The success of the sorafenib trials has also spurred interest in the development of novel molecular targeted therapy for the treatment of advanced HCC [11] . Agents targeting pathways that may play roles in hepatocarcinogenesis, such as the angiogneic signaling pathways, the EGFR pathway or the PI3K/Akt/mTOR pathway, are under clinical development. A Phase III trial is ongoing to compare the efficacy of sorafenib with another multi kinase inhibitor sunitinib, which has shown anti-tumor activity in Phase II trials for advanced HCC [52,53] . Preliminary results of combining the anti-VEGF antibody bevacizumab with the EGFR inhibitor erlotinib produced a response rate of 20% and a median overall survival of 15.5 months [54] . In addition to trials for advanced HCC, clinical trials of molecular targeted therapy as adjuvant therapy after curative treatment (surgery or References
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Financial & competing interests disclosure
Ann Lii Cheng is a consultant of Bayer Schering Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Sorafenib is an oral multikinase inhibitor targeting Raf, VEGF receptors, PDGF receptors, c-kit, Flt-3 and RET. • Sorafenib is the first molecular targeted therapy approved by the US FDA and the EMEA for the treatment of advanced hepatocellular carcinoma. • Similar efficacy of sorafenib, in terms of hazard ratios of overall survival and time to progression, has been observed in Western and Asian patients with advanced hepatocellular carcinoma. • Sorafenib is well tolerated in patients with Child–Pugh liver function class A. Limited safety data are available to guide dosing in Child–Pugh class B and C patients.
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•• First randomized, placebo-controlled trial that demonstrated a survival benefit for sorafenib in patients with advanced-stage hepatocellular carcinoma. 13
Cheng AL, Kang YK, 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, placebocontrolled trial. Lancet Oncol. 10, 25–34 (2009).
•• Randomized, placebo-controlled trial demonstrating sorafenib was equally effective in Asian–Pacific patients with advanced-stage hepatocellular carcinoma. 14
Wilhelm S, Carter C, Lynch M et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat. Rev. Drug Dis. 5, 835–844 (2006).
•
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Sorafenib for hepatocellular carcinoma
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Huynh H, Nguyen TT, Chow KH et al. Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)MAPK in hepatocellular carcinoma: its role in tumor progression and apoptosis. BMC Gastroenterol. 8, 3–19 (2003). Schmitz KJ, Wohlschlaeger J, Lang H et al. Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection. J. Hepatol. 48, 83–90 (2008). Erhardt A, Hassan M, Heintges T, Haussinger D. Hepatitis C virus core protein induces cell proliferation and activates ERK, JNK, and p38 MAP kinases together with the MAP kinase phosphatase MKP-1 in a HepG2 Tet-Off cell line. Virology 292, 272–284 (2002). Chung TW, Lee YC, Kim CH. Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/ AKT pathways: involvement of invasive potential. FASEB J. 18, 1123–1125 (2004). Bataller R, Paik YH, Lindquist JN, Lemasters JJ, Brenner DA. Hepatitis C virus core and nonstructural proteins induce fibrogenic effects in hepatic stellate cells. Gastroenterology 126, 529–540 (2004). Lee HC, Tian B, Sedivy JM, Wands JR, Kim M. Loss of Raf kinase inhibitor protein promotes cell proliferation and migration of human hepatoma cells. Gastroenterology 131, 1208–1217 (2006). Yoshida T, Hisamoto T, Akiba J et al. Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors. Oncogene 25, 6056–6066 (2006). Chang YS, Adnane J, Trail PA et al. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother. Pharmacol. 59, 561–574 (2007). Liu L, Cao Y, Chen C et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces
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tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 66, 11851–11858 (2006). 26
27
Schulze-Bergkamen H, Fleischer B, Schuchmann M et al. Suppression of Mcl-I via RNA interference sensitizes human hepatocellular carcinoma cells toward apoptosis induction. BMC Cancer 6, 232–245 (2006). Rosato RR, Almenara JA, Coe S, Grant S. The multikinase inhibitor sorafenib potentiates TRAIL lethality in human leukemia cells in association with Mcl-1 and cFLIPL down-regulation. Cancer Res. 67, 9490–9500 (2007).
28
Panka DJ, Wang W, Atkins MB, Mier JW. The Raf inhibitor BAY 43-9006 (Sorafenib) induces caspase-independent apoptosis in melanoma cells. Cancer Res. 66, 1611–1619 (2006).
29
Kim SH, Ricci S, El-Deiry WS. Mcl-1: a gateway to trail sensitization. Cancer Res. 68, 2062–2064 (2008).
30
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Strumberg D, Richly H, Hilger RA et al. Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J. Clin. Oncol. 23, 965–972 (2005). Minami H, Kawada K, Ebi H et al. Phase I and pharmacokinetic study of sorafenib, an oral multikinase inhibitor, in Japanese patients with advanced refractory solid tumors. Cancer Sci. 99, 1492–1498 (2008). Clark JW, Eder JP, Ryan D et al. Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin. Cancer Res. 11, 5472–5480 (2005). Awada A, Hendlisz A, Gil T et al. Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br. J. Cancer 92, 1855–1861 (2005). Moore M, Hirte HW, Siu L et al. Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann. Oncol. 16, 1688–1694 (2005). Furuse J, Ishii J, Nakachi K Suzuki E, Shimizu S, Nakajima K. Phase I study of sorafenib in Japanese patients with hepatocellular carcinoma. Cancer Sci. 99, 159–165 (2008).
Drug Profile
36
Yamaori S, Yamazaki H, Iwano S et al. Ethnic differences between Japanese and Caucasians in the expression levels of mRNAs for CYP3A4, CYP3A5 and CYP3A7: lack of co-regulation of the expression of CYP3A in Japanese livers. Xenobiotica 35, 69–83 (2005).
37
Tateishi T, Watanabe M, Moriya H, Yamaguchi S, Sato T, Kobayashi S. No ethnic difference between Caucasian and Japanese hepatic samples in the expression frequency of CYP3A5 and CYP3A7 proteins. Biochem. Pharmacol. 57, 935–939 (1999).
38
Myrand SP, Sekinguchi K, Man MZ et al. Pharmacokinetics/genotype associations for major cytochrome P450 enzymes in native and first- and third-generation Japanese populations: comparison with Korean, Chinese, and Caucasian populations. Clin. Pharmacol. Ther. 84, 347–361 (2008).
39
Abou-Alfa GK, Schwartz L, Ricci S et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J. Clin. Oncol. 24, 4293–4300 (2006).
40
Miller AA, Murry DJ, Owzar K et al. Pharmacokinetic (PK) and Phase I study of sorafenib (S) for solid tumors and hematologic malignancies in patients with hepatic or renal dysfunction (HD or RD): CALGB 60301. J. Clin. Oncol. 25(18 Suppl.), 3538 (2007).
41
Hsu C, Shen YC, Hu FC, Cheng AL. Geographic difference in clinical trial practice for advanced hepatocellular carcinoma (HCC): implications on trial design of global scale. Ann. Oncol. 19(Suppl. 6), 0–10 (2008).
42
Craxi A, Porta C, Sangiovanni A et al. Efficacy and safety of sorafenib in patients with alcohol-related hepatocellular carcinoma: a sub-analysis from the SHARP trial. J. Clin. Oncol. 26(Suppl.) (2008) (Abstract 15591).
43
Bolondi L, Caspary W, Bennouna J et al. Clinical benefit of sorafenib in hepatitis C patients with hepatocellular carcinoma (HCC): subgroup analysis of the SHARP trial. Presented at: 2008 ASCO Gastrointestinal Cancers Symposium, Orlando, FL, USA, 25–27 January 2008 (Abstract 129).
44
Sherman M, Mazzaferro V, Amadori D et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma and vascular invasion or extrahepatic spread: a subanalysis from the SHARP trial. J. Clin. Oncol. 26(Suppl.) (2008) (Abstract 4584).
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46
47
48
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Raoul J, Santoro A, Beaugrand M et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to ECOG performance status: a subanalysis from the SHARP trial. J. Clin. Oncol. 26(Suppl.) (2008) (Abstract 4587). Galle P, Blanc J, Van Laethem JL et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma and prior anti-tumor therapy: a subanalysis from the SHARP trial. J. Hepatol. 48(Suppl. 2), S372 (2008). Abou-Alfa GK, Amadori D, Santoro A et al. Is sorafenib (S) safe and effective in patients (pts) with hepatocellular carcinoma (HCC) and Child-Pugh B (CPB) cirrhosis? J. Clin. Oncol. 26(Suppl.) (2008) (Abstract 4518). Dal Lago L, D’Hondt V, Awada A. Selected combination therapy with sorafenib: a review of clinical data and perspectives in advanced solid tumors. Oncologist 13, 845–858 (2008). Abou-Alfa GK, Johnson P, Knox J et al. Preliminary results from a Phase II, randomized, double-blind study of sorafenib plus doxorubicin versus placebo plus doxorubicin in patients with advanced hepatocellular carcinoma. Presented at: 14th European Cancer
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Shen YC, Shao YY, Hsu CH et al. Phase II study of sorafenib plus tegafur/ uracil (UFT) in patients with advanced hepatocellular carcinoma (HCC). J. Clin. Oncol. 26(Suppl.) (2008) (Abstract 15664).
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DePrimo SE, Cheng AL, Lanzalone S et al. Circulating biomarkers of sunitinib in patients with unresectable hepatocellular carcinoma (HCC): analysis of correlations with outcome and tumor imaging parameters. J. Clin. Oncol. 26(Suppl.) (2008) (Abstract 4593).
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Zhu AX, Sahani DV, di Tomaso E et al. Sunitinib monotherapy in patients with advanced hepatocellular carcinoma (HCC): insights from a multidisciplinary Phase II study. J. Clin. Oncol. 26(Suppl.) (2008) (Abstract 4521).
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Website 101
National Comprehensive Cancer Network: practice guidelines in oncology, v.2.2008 – hepatobiliary cancers www.nccn.org (Accessed 6th November 2008)
Affiliations •
Chiun Hsu Departments of Oncology and Internal Medicine, National Taiwan University Hospital, Taiwan Tel.: +88 622 312 3456 ext. 67789 Fax: +88 622 371 1174 [email protected]
•
Ying-Chun Shen Departments of Oncology and Medical Research, National Taiwan University Hospital, Taiwan and National Center of Excellence for General Clinical Trial and Research, National Taiwan University Hospital, Taiwan Tel.: +88 622 312 3456 ext. 67011 Fax: +88 622 371 1174 [email protected]
•
Ann-Lii Cheng Departments of Oncology and Internal Medicine, National Taiwan University Hospital, Taiwan Tel.: +88 622 312 3456 ext. 67251 Fax: +88 622 371 1174 [email protected]
Expert Rev. Clin. Pharmacol. 2(2), (2009)
Sorafenib for the treatment of hepatocellular carcinoma across geographic regions Expert Rev. Clin. Pharmacol. 2(2), 129–136 (2009)
Chiun Hsu, Ying‑Chun Shen and Ann Lii Cheng† † Author for correspondence Departments of Oncology and Internal Medicine, National Taiwan University Hospital, Taiwan Tel.: +88 622 312 3456 ext. 67251 Fax: +88 622 371 1174 [email protected]
www.expert-reviews.com
Sorafenib is an oral multikinase inhibitor targeting Raf, VEGF receptor, PDGF receptor, c-kit, Flt‑3 and rearranged during transfection (RET). Two randomized, placebo-controlled trials for Western and Asian patients, respectively, demonstrated that sorafenib significantly prolongs overall survival and time to progression in patients with advanced hepatocellular carcinoma (HCC). These have become the reference treatment for future clinical trials of advanced HCC. Sorafenib is well tolerated in patients with Child–Pugh liver function class A, but limited data are available in Child–Pugh class B and C patients. Clinical trials are ongoing to test the efficacy of sorafenib‑based combination therapy and sorafenib adjuvant therapy for HCC. Keywords : hepatocellular carcinoma • molecular targeted therapy • sorafenib
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide and its incidence continues to increase [1] . Most patients with HCC have underlying cirrhosis caused by chronic hepatitis B virus (HBV), hepatitis C virus (HCV) infection or alcoholic liver disease. The etiologies of the underlying cirrhosis have distinct geographic variations: HBV infection occurs in most Asian and African countries, chronic hepatitis C infection or alcoholic liver disease occurs in Western countries and in Japan [2,3] . The different etiologies have been found to be associated with different genetic and epigenetic aberrations, which may have important implications in patient prognosis and in new drug development [4–6] . Curative surgery is feasible in only approximately 20–30% of patients because of advanced tumor stage and impaired liver function at diagnosis [7] . These situations also limit the usefulness of other local treatment strategies, such as percutaneous alcohol injection, radiofrequency ablation and transarterial chemoembolization. Therefore, effective systemic therapy is urgently needed for patients with advanced HCC. Objective response rates to single-agent cytotoxic therapies, even in highly selected patients, are usually less than 10%, and no survival benefit has been observed [8–10] . Recent advances in elucidating the molecular mechanisms of hepato carcinogenesis have provided opportunities to 10.1586/17512433.2.2.129
develop molecular targeted therapy for advanced HCC [11] . Agents targeting tumor angiogenesis, the Raf/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway and the EGF receptor (EGFR) pathway have shown promising anti-tumor activity in patients with advanced HCC. The most successful example is the multikinase inhibitor sorafenib, which has shown survival benefit in two randomized, placebo-control trials [12,13] . Introduction to sorafenib
Sorafenib was developed by a new drug-discovery program aimed at agents targeting the Raf/ MAPK/ERK signaling pathway [14] . The lead compounds identified by high-throughput screening were optimized by combinatory chemistry approaches to improve the potency of Raf kinase inhibition. In addition to wild-type B-raf (IC50 at 6 nM), sorafenib also inhibits the kinase activity of mutant Raf V600E , VEGF receptors (VEGFRs), PDGF receptors (PDGFRs), c-kit, Flt-3 and rearranged during transfection (RET) (IC50 < 100 nM). Preclinical studies showed that sorafenib can inhibit tumor growth in various tumor models with wild-type or mutant Raf kinases [15] . The role of Raf/MAPK/ERK signaling in carcinogenesis of HCC has been extensively studied. Aberrant expression and activation of Raf/ MAPK/ERK signaling were demonstrated in
© 2009 Expert Reviews Ltd
ISSN 1751-2433
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Drug Profile
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Table 1. Comparison of the published Phase I trials of sorafenib. Study
Patients (n)
Dosing schedule
Dose ranges
Pharmacokinetic parameters Patients (n)
AUC0–12 (mg × h/l)
Cmax (mg/h)
Western trials Clark et al.
19
7 days on/7 days off
100–800 mg b.i.d.
4‡
56.6 (90.5)
6.2 (106.7)
Awada et al.
44
21 days on/7 days off
50–800 mg b.i.d.
5
76.5
10.0
Moore et al.
41
28 days on/ 7 days off
50 mg/4 days– 600 mg b.i.d.
3
47.8 (24.0)
5.4 (41.0)
Strumberg et al.
69
Continuous dosing
100–600 mg b.i.d.
5§
71.7 (43)
9.35 (44)
Minami et al.
31
Continuous dosing
100–600 mg b.i.d.
6¶
36.7 (73)
4.91 (76)
Furuse et al.
27
Continuous dosing
200–400 mg b.i.d.
6¶#
33.5 (60.1)
4.7 (66.1)
‡
‡
Japanese trials
Data are expressed as geometric mean values. Percentage coefficient of variation, if available, is expressed in parentheses. Based on pharmacokinetic sampling performed on the final day of dosing in cycle one. Based on pharmacokinetic sampling after multiple dosing. ¶ Based on pharmacokinetic sampling performed on day 14 of cycle one. # Data from patients with normal liver function reserves (Child–Pugh class A). ** Based on serum lipase study. b.i.d.: Twice daily; Gr: Grade; NA: Not available. * ‡ §
human HCC tumor tissue and were correlated with large tumor size, advanced tumor stage and poor survival [16–18] . Multiple mechanisms may account for the increased activity of the Raf/ MAPK/ERK signaling pathway in HCC. For example, the hepatitis B HBx protein and the hepatitis C core protein can induce activation of Raf/MAPK/ERK signaling, which in turn is involved in many critical steps of hepatocarcinogenesis, including increased cell proliferation, increased invasive potential and induction of inflammatory responses [19–21] . Moreover, downregulation of endogenous inhibitors of the Raf/MAPK/ERK pathway, such as the Raf kinase inhibitor protein (RKIP) and the sprouty-related protein with Ena/vasodilator-stimulated phosphoprotein homology-1 domain (Spred), has been found in HCC tumor tissue. This downregulation was correlated with activation of MAPK/ ERK signaling, increased cancer cell proliferation and increased invasive potential [22,23] . This evidence indicates that the Raf/ MAPK/ERK signaling pathway is an important target for new drug development for HCC. Chemistry
The tosylate salt of sorafenib is used for clinical development. Sorafenib tosylate is insoluble in aqueous medium but soluble in polyethylene glycol (PEG)400. Sorafenib tosylate in its solid form is stable at room temperature for prolonged periods. The drug product of sorafenib for clinical use is a 200‑mg coated tablet. Pharmacodynamics
Sorafenib has been demonstrated to inhibit tumor growth in a wide range of preclinical models [15] . In some models, such as the HT-29 colon cancer (with BRAF mutation) and the MDA-MB-231 breast cancer (with BRAF and k-ras mutations) models, the anti-tumor 130
effects of sorafenib were correlated with the inhibitory effects on Raf/MAPK/ERK signaling activity. In others, such as the A549 lung cancer and the Colo-205 colon cancer models, the anti-tumor effects of sorafenib were not associated with inhibition of Raf/ MAPK/ERK activity, suggesting that other mechanisms may play an important role in tumor growth inhibition. Inhibition of tumor angiogenesis was considered another key anti-tumor mechanism of sorafenib, presumably through its inhibition of VEGFR and PDGFR activities [24,25] . In addition, sorafenib can induce tumor cell apoptosis by regulating the expression of several apoptosis regulatory proteins, such as the myeloid cell leukemia-1 (mcl-1), cFLIP and the apoptosis-inducing factor (AIF) [26–29] . The in vivo pharmacodynamic effects of sorafenib have been evaluated in two Phase I trials by measuring sorafenib-induced inhibition of pERK in patients’ peripheral blood lymphocytes, using an in vitro model of phorbol myristate acetate (PMA) stimulation [30,31] . In the study by Strumberg et al., almost complete inhibition of PMA-induced ERK phosphorylation was observed on day 21 of a continuous dosing schedule. However, in the study by Minami et al., no significant change of pERK was seen after the same dosing schedule. The latter trial also used PET to evaluate the metabolic activity of tumor cells after sorafenib treatment [31] . In 23 patients who had serial PET examination, the median maximum standardized uptake values (SUVmax) was significantly decreased after sorafenib treatment (from 16.2 at baseline to 11.2 at the first examination after the start of treatment). A 25% or greater decrease in SUVmax was found in 11 patients. In addition, a higher trough concentration of sorafenib on day 28 was associated with a larger decrease in SUVmax. These pharmacodynamic parameters warrant further investigation in larger clinical trials. Expert Rev. Clin. Pharmacol. 2(2), (2009)
Sorafenib for hepatocellular carcinoma
Drug Profile
Table 1. Comparison of the published Phase I trials of sorafenib (cont.). Adverse events Fatigue All
≥Gr3
Anorexia All
≥Gr3
Diarrhea All
≥Gr3
Rash/ Hand–foot desquamation skin reaction
Ref. Nausea
Alopecia
All
≥Gr3
All
≥Gr3
All
≥Gr3
All
≥Gr3
Pancreatitis All
≥Gr3
Western trials 11
0
11
0
0
0
32
11
NA
NA
11
0
0
0
NA
NA
[32]
52
9
39
5
18
2
36
5
43
11
14
2
30
0
NA
NA
[33]
44
7
29
0
32
0
15
0
22
10
22
0
17
0
NA
NA
[34]
39
6
42
0
55
9
26
0
23
6
30
0
16
3
NA
4.3
[30]
0
36
3.2
61
0
39
0
10
0
26
0
11**
6.5**
[31]
55.6
3.2
48.4
6.4
38.7
6.4
NA
NA
16.1
0
88.9
63
[35]
Japanese trials 10
3.2
26
3.2
0
19.4 0
**
**
Data are expressed as geometric mean values. Percentage coefficient of variation, if available, is expressed in parentheses. ‡ Based on pharmacokinetic sampling performed on the final day of dosing in cycle one. § Based on pharmacokinetic sampling after multiple dosing. ¶ Based on pharmacokinetic sampling performed on day 14 of cycle one. # Data from patients with normal liver function reserves (Child–Pugh class A). ** Based on serum lipase study. b.i.d.: Twice daily; Gr: Grade; NA: Not available. *
Pharmacokinetics & metabolism
Since sorafenib is metabolized by the CYP enzymes (mainly Six single-agent Phase I studies of sorafenib, four from Western CYP3A4) in the liver, it is important to see whether sorafenib is countries and two from Japan, have been published (Table 1) [30–35] . safe in patients with impaired liver function reserves. The Japanese Japanese patients appeared to have lower plasma Cmax and AUC Phase I trial for HCC patients and a Western Phase II trial for values than their Western counterparts. Although ethnic difference HCC patients compared the pharmacokinetic parameters between in expression of cytochrome P450 (CYP), the enzymes responsi- patients with Child–Pugh A and B cirrhosis (Table 2) [35,39] . In the ble for the metabolism of sorafenib, have been reported [36] , the Western trial, patients with Child B cirrhosis had higher AUC and ethnic difference of the pharmacokinetics of sorafenib cannot be Cmax than patients with Child A cirrhosis, while in the Japanese explained by this factor [37,38] . Moreover, the difference in pharma- trial, patients with Child B cirrhosis had lower AUC and Cmax. cokinetic parameters found in these Phase I trials did not correlate These variations were not considered significant because they were with the incidence and severity of sorafenib-related adverse events. not associated with difference in adverse events between Child A Significant interpatient variability of pharmacokinetic parameters and Child B patients in either trial. between the studies was found. The plasma half-life Table 2. Comparison of safety and pharmacokinetic profiles between of sorafenib ranged from 20 hepatocellular carcinoma patients with Child–Pugh A or B cirrhosis. to 30 h. Drug accumulation Study Patients (n) Pharmacokinetic parameters after multiple dosing was AUC Cmax (mg/l) Tmax (h) found and the concentration (mg × h/l) reached a steady state after 14 days of treatment. The Abou-Alfa et al.* most common dose-limiting Child A 14 25.4 (38.2) 4.9 (38.7) 1.0 (0–12) toxicity included skin rash/ Child B 8 30.3 (82.1) 6.0 (73.8) 0.5 (0–8) desquamation, hand–foot skin reaction, diarrhea and Furuse et al.‡ fatigue. The Japanese trials Child A 6 28.9 (86.8) 3.3 (113.5) 8 (6–24) reported a high incidence Child B 5 20.7 (72.1) 4.0 (79.1) 24 (4–24) of grade 3 or 4 elevation of * AUC0–8 was reported because blood samples at 12 h were not available for most patients. All data were based on pancreatic amylase or lipase. pharmacokinetic sampling after one cycle (28 days) of treatment. This biochemical abnormal- ‡AUC0–12 and Cmax were reported based on pharmacokinetic sampling after 28 days of treatment. Tmax data were based on pharmacokinetic sampling after day 1 doses. ity was not associated with The values of percentage coefficient of variation for AUC and Cmax and the ranges of Tmax are given in parentheses. Data from [35,39]. symptoms of pancreatitis. www.expert-reviews.com
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Drug Profile
Hsu, Shen & Cheng
Another pharmacokinetic study specifically addressed the safety issue of sorafenib in patients with liver or kidney dysfunction [40] . Patients with refractory solid tumors or hematological malignancy were divided into cohorts of normal function or mild/moderate/ severe/very severe organ dysfunction based on bilirubin and albumin levels and creatinine clearance. The apparent oral clearance of sorafenib was not significantly different among the cohorts. However, patients with elevated bilirubin levels had lower tolerance to sorafenib treatment. These data suggest that conventional pharmacokinetic parameters may not accurately reflect the difference of sorafenib metabolism in patients with impaired liver function reserves. Clinical efficacy Phase I & II studies
In the Phase I studies for patients with advanced solid tumors, partial response (according to Response Evaluation in Solid Tumors [RECIST]) was demonstrated in two patients with renal cell carcinoma, one with HCC and one with non-small-cell lung cancer [30–34] . Prolonged disease stabilization was demonstrated in patients with renal cell carcinoma, HCC, colon cancer and lung cancer. In the Phase I trial for HCC patients, one partial response was documented in 27 evaluable patients and the overall survival and time to progression were 15.6 and 4.9 months, respectively [35] . No clear dose–response relationship was shown in these Phase I studies. The 400 mg twice daily, continuous‑dosing regimen was selected for further clinical development.
One Phase II trial for patients with advanced HCC was reported [39] . This study used a three-stage design and recruited patients with inoperable HCC and Child–Pugh liver function class A or B. Patient recruitment stopped at the second interim analysis because the preset efficacy end point (six or more responders in 97 subjects) was not met. In 137 evaluable patients, three (2.2%) achieved partial response, eight (5.8%) had minor response and 46 (33.6%) had stable disease for more than 16 weeks. The median time to progression and overall survival were 4.2 and 9.2 months, respectively. The levels of phosphorylated ERK in tumor cells were evaluated by immunohistochemistry in 33 patients with tumor specimens available. Patients with high phosphorylated ERK staining in tumor cells (n = 18) had significantly longer time to progression than those with low intensity (n = 15). The RNA expression patterns in blood cells were evaluated by microarray in 31 patients. A panel of 18 genes were identified to have predictive value on tumor progression status. The usefulness of these biomarkers must be validated in large-scale trials. Phase III studies
Two randomized, placebo-controlled trials of sorafenib for the treatment of advanced HCC have been reported [12,13] . The first trial (the Sorafenib Hepatocarcinoma Assessment Randomized Protocol [SHARP] trial) was performed primarily in Europe and in America with the primary end point of overall survival. The second trial was designed originally as a bridging study
Table 3. Phase III trials of sorafenib versus placebo for patients with advanced hepatocellular carcinoma. Parameter
SHARP trial [12]
Asian–Pacific trial [13]
Sorafenib (n = 299)
Placebo (n = 303)
Sorafenib (n = 150)
Placebo (n = 76)
Median age (years)
65
66
51
52
Hepatitis virus status (HBV/HCV; %)
19/29
18/27
71/11
78/4
Sex (male; %)
87
87
85
87
Barcelona clinic liver cancer stage (B/C; %)
18/82
17/83
4/96
4/96
ECOG PS (0/1/2; %)
54/38/8
54/39/7
25/69/5
28/67/5
Extrahepatic spread (%)
53
50
69
68
Macroscopic vascular invasion (%)
36
41
36
34
Lung metastasis (%)
22
19
52
45
Overall survival (months) (95% CI)
10.7 (9.4–13.3)
7.9 (6.8–9.1)
6.5 (5.6–7.5)
4.2 (3.7–5.5)
Hazard ratio (95% CI)
0.69 (0.55–0.87)
Time to progression (months) (95% CI)
5.5 (4.1–6.9)
Hazard ratio (95% CI)
0.58 (0.45–0.74)
Time to symptomatic progression (months) (95% CI)
4.1 (3.5–4.8)
Hazard ratio (95% CI)
1.08 (0.88–1.31)
Baseline characteristics
Treatment efficacy 0.68 (0.53–0.93) 2.8 (2.7–3.9)
2.8 (2.6–3.6)
1.4 (1.3–1.5)
0.57 (0.42–0.79) 4.9 (4.2–6.3)
3.5 (2.8–4.2)
3.4 (2.4–4.1)
0.90 (0.67–1.22)
ECOG: Eastern Cooperative Oncology Group; HBV: Hepatitis B virus; HCV: Hepatitis C virus; PS: Performance status; SHARP: Sorafenib HCC Assessment Randomized Protocol Trial.
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Sorafenib for hepatocellular carcinoma
to evaluate the overall efficacy and safety of sorafenib in the Asian–Pacific population. Both trials recruited HCC patients whose tumors were not eligible for or had progressed after surgery or locoregional therapy, and those who had a Child–Pugh liver function of class A and an Eastern Cooperative Oncology Group (ECOG) performance score of 2 or lower. The treatment regimen was the same (sorafenib 400 mg twice daily). Both trials stopped early because per-protocol interim analysis indicated significant survival benefit of sorafenib versus placebo. Comparison of these two Phase III trials is listed in Table 3. Patients in the Asian–Pacific trial were younger and had more symptomatic diseases (ECOG score 1 or 2) and extrahepatic metastases. Despite these differences in the baseline prognostic features, the overall treatment efficacy of sorafenib, in terms of hazard ratios of overall survival and time to progression, was similar between these two trials. The survival time of patients in the Asian–Pacific trial was significantly shorter than that of the SHARP trial, reflecting the poor prognostic features of the Asian patients. Geographic areas (Asian vs non-Asian) should be used as a stratification factor in future randomized trials of HCC [41] . Exploratory subgroup analysis of the SHARP trial indicated that sorafenib treatment prolonged survival regardless of patient age, performance status, tumor burden (vascular invasion or extrahepatic spread) and prior anti-tumor therapy (Table 4) [42–46] .
Drug Profile
liver function class. However, patients with Child–Pugh B class had higher rate of elevated bilirubin (18 vs 40%), encephalopathy (2 vs 11%) and worsening ascites (11 vs 18%) than patients with Child–Pugh A class [47] . In the Phase III SHARP trial, the incidence of serious hepatobiliary events was similar between the sorafenib (11%) and placebo groups (9%). Regulatory affairs
Sorafenib was approved for the treatment of advanced HCC by the EMEA in October 2007 and by the US FDA in November 2007. In the most recent practice guidelines recommended by the US National Comprehensive Cancer Network, sorafenib is listed as a treatment option for HCC patients who are inoperable by performance status or comorbidity (local disease only) and who do not present with cancer-related symptoms [101] . Sorafenib has also been approved for the treatment of HCC by several Asian countries, including Korea, China, Singapore and Thailand. Conclusion
Sorafenib has a proven survival benefit for patients with advanced HCC across geographic regions. It has become the reference treatment for future clinical trials of systemic therapy for advanced HCC.
Safety & tolerability
Expert commentary & five-year view
Sorafenib is generally well tolerated. The most common sorafenibinduced adverse events include diarrhea, fatigue, hand–foot skin reaction and rash/desquamation. These events occured in 20–40% of patients, most of which were grade 1 or 2. The most common causes of dose interruption or reduction in previous sorafenib trials were hand–foot skin reaction, rash and diarrhea. In the Phase II trial of sorafenib for HCC, the incidence of all adverse events and serious adverse events was similar between patients with Child–Pugh A (n = 98) and Child–Pugh B (n = 38)
Advanced HCC has been considered a huge unmet medical need, especially in countries endemic for chronic viral hepatitis. Sorafenib represents a successful first step toward better treatment for this difficult disease. Although sorafenib is generally well tolerated, it should be used with caution in patients with impaired liver function reserves. Combination therapy to improve the therapeutic efficacy of sorafenib has been pursued [48] . A randomized Phase II trial of sorafenib plus doxorubicin versus doxorubicin alone reported
Table 4. Exploratory subgroup analysis of the Sorafenib HCC Assessment Randomized Protocol Trial. HCV (n = 178)
Alcohol (n = 159)
Prior resection/ ablation (n = 158)
Prior TACE (n = 176)
PS
MVI/EHS
0 (n = 325)
1–2 (n = 277)
No (n = 181)
Yes (n = 421)
Overall survival (months) Sorafenib
14.0
10.3
11.9
11.9
13.3
8.9
14.5
8.9
Placebo
7.9
8.0
8.8
9.9
8.8
5.6
10.2
6.7
HR (95% CI)
0.58 (0.39–0.91)
0.76 (0.50–1.16)
0.79 (0.51–1.22)
0.75 (0.49–1.14)
0.68 (0.50–0.95)
0.71 (0.52–0.96)
0.52 0.77 (0.35–0.85) (0.60–0.99)
Time to progression (months) Sorafenib
7.7
5.5
5.5
5.8
5.5
5.3
9.6
4.1
Placebo
2.8
3.9
2.7
4.0
2.9
2.8
4.3
2.7
HR (95% CI)
0.44 (0.25–0.76)
0.64 (0.40–1.03)
0.62 (0.39–0.98)
0.57 (0.36–0.91)
0.55 (0.40–0.77)
0.61 (0.42–0.88)
0.40 0.64 (0.23–0.70) (0.48–0.84)
EHS: Extrahepatic spread; HCV: Hepatitis C virus; HR: Hazard ratio; MVI: Macroscopic vascular invasion; PS: Performance status; TACE: Transcatheter arterial chemoembolization.
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Drug Profile
Hsu, Shen & Cheng
superior median overall survival (13.7 vs. 6.5 months) and time to progression (8.6 vs 4.8 months) in patients receiving sorafenib plus doxorubicin compared with doxorubicin alone [49] . These results should be interpreted with caution because of the lack of a sorafenib-alone arm and the high incidence of adverse events related to doxorubicin. An alternative approach is to combine sorafenib with small, frequent, uninterrupted doses of cytotoxic chemotherapy, usually referred to as ‘metronomic chemotherapy’ [50] . Results from a Phase II study combining sorafenib with oral tegafur/uracil indicated promising anti-tumor activity and good patient tolerance [51] . Further exploration of this concept is warranted. The success of the sorafenib trials has also spurred interest in the development of novel molecular targeted therapy for the treatment of advanced HCC [11] . Agents targeting pathways that may play roles in hepatocarcinogenesis, such as the angiogneic signaling pathways, the EGFR pathway or the PI3K/Akt/mTOR pathway, are under clinical development. A Phase III trial is ongoing to compare the efficacy of sorafenib with another multi kinase inhibitor sunitinib, which has shown anti-tumor activity in Phase II trials for advanced HCC [52,53] . Preliminary results of combining the anti-VEGF antibody bevacizumab with the EGFR inhibitor erlotinib produced a response rate of 20% and a median overall survival of 15.5 months [54] . In addition to trials for advanced HCC, clinical trials of molecular targeted therapy as adjuvant therapy after curative treatment (surgery or References
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Financial & competing interests disclosure
Ann Lii Cheng is a consultant of Bayer Schering Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Sorafenib is an oral multikinase inhibitor targeting Raf, VEGF receptors, PDGF receptors, c-kit, Flt-3 and RET. • Sorafenib is the first molecular targeted therapy approved by the US FDA and the EMEA for the treatment of advanced hepatocellular carcinoma. • Similar efficacy of sorafenib, in terms of hazard ratios of overall survival and time to progression, has been observed in Western and Asian patients with advanced hepatocellular carcinoma. • Sorafenib is well tolerated in patients with Child–Pugh liver function class A. Limited safety data are available to guide dosing in Child–Pugh class B and C patients.
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Affiliations •
Chiun Hsu Departments of Oncology and Internal Medicine, National Taiwan University Hospital, Taiwan Tel.: +88 622 312 3456 ext. 67789 Fax: +88 622 371 1174 [email protected]
•
Ying-Chun Shen Departments of Oncology and Medical Research, National Taiwan University Hospital, Taiwan and National Center of Excellence for General Clinical Trial and Research, National Taiwan University Hospital, Taiwan Tel.: +88 622 312 3456 ext. 67011 Fax: +88 622 371 1174 [email protected]
•
Ann-Lii Cheng Departments of Oncology and Internal Medicine, National Taiwan University Hospital, Taiwan Tel.: +88 622 312 3456 ext. 67251 Fax: +88 622 371 1174 [email protected]
Expert Rev. Clin. Pharmacol. 2(2), (2009)
