Targeted Therapy in Hepatocellular Carcinoma (HCC)kaim.or.kr/pds/files/hmo/hmo_200807_08.pdf ·...
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Development of Molecular Targeted Agents in Hepatocellular carcinoma
영남대학 병원혈액종양내과
이 경 희
Dismal prognosis
More than 80% of patients presents with
advanced or unresectable disease
Supportive care
Stage
OS(%)
1yr 2yrs 3yrs
Intermediate
Advanced
80
29
65
16
50
8
case
55-yrs male, histologically proven HCC, hepatitis B(+),
ECOG PS 1, Child-Pugh score 6, macroscopic portal
vein invasion and regional L/N
Which treatment do you wants?
1. Best supportive care
2. TACE
3. Systemic cytotoxic agent
4. Hormonal therapy
5. Target agents (sorafenib)
Curative treatment for HCC
Orthotopic liver transplantation
Surgical resection
Local destruction (RF, Cryo, Alcohol)
Palliative treatment
Transarterial chemo-embolization
Systemic chemotherapy
INF
Hormonotherapy
Treatments of HCC
Barcelona Clinic Liver Cancer Staging
and Treatment Strategy
Very early
stage (0)
Early
stage (A)
Intermediate
stage (B)
Advanced
stage (C)
Terminal
stage (D)
Liver transplantation Chemoembolization New agentsResection PEI/RF
Symptomatic
treatment
Curative treatments Randomized controlled trials
Extrahepatic disease
YesNo
Associated diseases
YesNo
3 nodules ≤3cm
Increased
Normal
Single HCC
Portal pressure/
bilirubin
HCC
Adapted from Llovet JM, et al, Lancet 2003;362:1907–17
Copyright 2003, with permission from Elsevier
Treatment for Advanced HCC: Systemic
Single-Agent Chemotherapy
Authors,
year Study type Agent(s) n
PR
(%)
CR (%)
Survival
Sciarrino
et al, 1985
Retrospective Doxorubicin 109 9 1 13% at 1 year
Tan et al,
1986
Phase II Epirubicin 13 23 0 11 weeks
Hochster
et al, 1985
Phase II Epirubicin 18 17 0 ND
Pohl et al,
2001
Retrospective Epirubicin 44 7 2 16.2 months*
Yin et al,
2005
Phase II PIAF 26 15 0 6 months
Okada
et al, 1993
Phase II Cisplatin 28 15 0 ND
PR = partial response; CR = complete response
Treatment for Advanced HCC: Systemic
Single-Agent Chemotherapy (cont’d)
Authors,
year Study type Agent(s) n
PR
(%)
CR
(%) Survival
p for
difference
Lai et al,
1988
RCT Doxorubicin
vs
60 N/A N/A 10.6
weeks
0.036
No therapy 46 N/A N/A 7.5
weeks
Yeo et al,
2005
Phase III
RCT
Doxorubicin
vs
94 10.5 0 6.8
months
0.83
PIAF 94 20.9 0 8.7
months
Choi et al,
1998
RCT Doxorubicin
vs
20 6 17 14.4
weeks
ND
5-FU, methotrexate,
cyclophosphamide
+ vincristine
19 N/A N/A 6.5
weeks
PIAF = cisplatin, doxorubicin, 5-fluorouracil (5-FU) and interferon-α (IFN-α)
Treatment for Advanced HCC: Systemic
Combination Chemotherapy
Authors, year Study type Agent(s) n
PR (%) CR
(%)
Median
survival
Morstyn et al,
1983
Phase II Doxorubicin +
streptozotocin
23 9 0 3 months
Falkson et al,
1999
Phase II Doxorubicin +
clofazimine
28 0 0 7 weeks
Ikeda et al, 2005 Phase II 5-FU, mitoxantrone
+ cisplatin
51 27 0 11.6 months
Kim et al, 2006 Phase II Epirubicin,
cisplatin, UFT, and
leucovorin
53 17 0 24.6 weeks
Tanaka et al,
2007
Phase II Epirubicin
emulsified in
lipiodol
20 5 0 12.4 months
UFT = uracil-tegaful
Treatment of Advanced HCC
BCLC and practice guidelines recommend that patients with advanced HCC should be entered into clinical trials1–3
Only supportive care measures are available for patients with terminal stage disease2,3
New molecular agents that selectively target cellular signaling pathways are in development and are being investigated for single-agent therapy of advanced HCC
1. Llovet JM, et al. Lancet 2003;362:1907–17
2. Bruix J and Sherman M. Hepatology 2005;42:1208–36
3. Bruix J, et al. J Hepatol 2001;35:421–30
What’s Next?
Targeted therapies
Immunotherapy
MMG CoA reductase
COX-2 inhibitor
New cytotoxic agent
Targeting the Molecular pathways
Key pathways in hepato-carcinogenesis
Involved in cell proliferation, survival
and angiogenesis
Challenges in assessing the relevant
molecular targets in HCC
Multiple Cellular Signaling Pathways
Implicated in Pathogenesis of HCC
Cell membrane
c-MYC c-JUN
wnt Receptor
BcL-XL
BAD
ERK1/2
MEK1/2
-catenin
GSK3
GBP
DSH
HBx
Akt
mTO
R
Raf
PKC
NF-ҚB
Ras
NF-ҚB
PLC
SH
C
GrB
2
GE
F
PI3K
PTEN
p53
Survival
Transcription/translation
-catenin
HBx
RTK: FGFR
EGFR
IGF-IR
c-MET
Receptor
Adapted from Avila MA, et al. Oncogene 2006;25:3866–84
Mechanisms/
pathways
Molecular
targets
Examples of agents
Wnt/β -catenin
pathway
Wnt
β-catenin
Monoclonal antibody of Wntl and Wnt2
Small molecule inhibitors (e.g. ICG-001)
Cell cycle
regulators
CDKs Flavopiridol
Angiogenic
factors
VEGF
VEGFR
PDGFR
heparanase
Anti-VEGF monoclonal antibody
(Bevacizumab)
Tyrosine kinase inhibitors (e.g. sorafenib,
PTK787,sunitinib)
Tyrosine kinase inhibitors (e.g. sorafenib,
sunitinib)
PI-88
Molecular targets for therapy in hepatocellular carcinoma(I)
Molecular targets for therapy in hepatocellular carcinoma (II)
Mechanisms/
pathways
Molecular
targets
Examples of agents
Growth factors EGFR monoclonal antibody (e.g. cetuximab)
Tyrosine kinase inhibitor (e.g. Gefitinib
and Erlotinib)
Ras/Raf/MEK/
Erk pathway
Ras
Raf
inhibitors of farnesyl transferase
Raf kinase inhibitor (sorafenib)
PI3k/Akt/
mTOR pathway
PI3k
Akt
mTOR
Wortmannin and LY294002
alkylphospholipid perifosine
rapamycin, RAD001
CDKs = Cyclin-dependent kinases; EGFR = epidermal growth factor receptor; mTOR = mammalian target of rapamycin; PI3K = phosphatidylinositol 3-kinase; PDGER = platelet-derived growth factor receptor; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor.
Targeted agents in development for HCC:
overview
Anti-angiogenic targets Antiproliferative targets
Agents VEGF VEGFR PDGFR EGFR Raf mTOR
Bevacizumab
BMS-582664
Cediranib
Erlotinib
Gefitinib
Lapatinib
RAD001
Sorafenib
Sunitinib
Thalidomide
TSU-68
Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom, IDdB3, BioPharm Insight, MedTrack
In HCC, a net excess of pro-angiogenic factors are secreted, including
– Vascular endothelial growth factor (VEGF)
– Platelet-derived growth factor (PDGF)
– Placental growth factor
– Transforming growth factors α and β
– Basic fibroblast growth factor (FGF)
– Epidermal growth factor (EGF)
– Hepatocyte growth factor
– Angiopoietins
– Interleukin (IL)-4, IL-8
Angiogenesis and HCC
Semela D, Dufour J-F. J Hepatol 2004;41:864–80
Cell membrane
Signaling Pathways for Angiogenesis:
VEGFR and PDGFR in the Vasculature
Semela D, et al. J Hepatol 2004;41:864–80
Clauss M. Semin Thromb Hemost 2000;26:561–69
RTK: VEGFR-1
VEGFR-2
VEGFR-3
PDGFR
c-MYC c-JUN
BcL-XL
BAD
ERK1/2
MEK1/2Akt
mTOR
Raf
PKC
NF-ҚB
NF-ҚB
PLC
SHC
GrB2GEF
PI3K
PTEN
Angiogenesis
HBx
Ras
Cediranib
Bevacizumab
BMS-582664
Sorafenib
Sunitinib
Thalidomide
TSU-68
Site of action
p53
x x
x
x
x
x
x
xx
x
x
Anti-angiogenic Therapies in Development
as Single Agents for HCC
Agent MOA Phase n Inclusion criteria Status Endpoints
Bevacizumab mAb;
VEGFR
antagonist
II 50 HCC not amenable to
curative treatment
Recruiting Disease control
rate, PFS, OS
Bevacizumab mAb;
VEGF-R
antagonist
II 46 Non-metastatic,
unresectable HCC
without main portal
vein invasion
Ongoing PFS, safety
BMS-582664 Multi TKI;
VEGFR-2,
VEGFR-3,
FGFR-1,
FGFR-2
II 100 Advanced
unresectable HCC
Recruiting 6-month PFS,
tumor response,
OS
Cediranib Multi-TKI;
VEGFR-1,
VEGFR-2,
VEGFR-3
II 44 Locally advanced/
metastatic liver
cancer
Recruiting 6-month OS,
tumor response,
safety
Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom, IDdB3, BioPharm
Insight, MedTrack
MAb = monoclonal antibody; MOA = mechanism of action; TKI = tyrosine kinase inhibitor
OS = overall survival; PFS = progression-free survival
Anti-angiogenic Therapies in Development
as Single Agents for HCC (cont’d)
Agent MOA Phase n Inclusion criteria Status Endpoints
PI-88 Heparanase
inhibitor
II 343 HCC following
resection
Ongoing Recurrence rate,
recurrence-free
survival, OS
Sorafenib Multi-TKI; Raf,
PDGFR-β,
VEGFR-2/3,
KIT, Flt-3
III 602 Advanced HCC Complete OS, TTSP, TTP,
safety versus
placebo1
Sunitinib Multi-TKI;
VEGFR-2,
PDGFR-β, KIT,
Flt-3
II 34 Advanced HCC Recruiting PFS, tumor
response, OS
Thalidomide Glutamic acid
derivative;
VEGF, FGF
inhibitor
III 230 Advanced HCC
with poor liver
reserve
Recruiting OS, tumor
response, safety
TSU-68 Multi-TKI;
VEGFR, PDGF,
FGFR
I/II N/A Unresectable
HCC
Recruiting Safety/feasibility
1. Llovet J. ASCO 2007, Chicago, IL, USA
Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom, IddB3, BioPharm
Insight, MedTrack. TTSP = time to symptomatic progression; TTP = time to progression
Signaling Pathways for Cell Proliferation
and Survival: Wnt/β-Catenin
Giles RH, et al. Biochim Biophys Acta 2003;1653:1–24. Feitelson MA, et al. Surg Clin N Am 2004;84:339–54
3. De La Coste A, et al. Proc Natl Acad Sci USA. 1998;95:8847–51
Cell membrane
c-MYC c-JUN
RTK: FGFR
EGFR
IGF-IR
c-MET
Receptor
-catenin
Wnt Receptor
BcL-XL
BAD
MEK1/2
PLC
Transcription
GBP
DSH
Ras
NF-ҚB
ERK1/2
NF-ҚB
Raf
p53
PKC
mTOR
PTEN
GSK3
PI3K
-catenin
HBx
Akt
SHC
GrB2GEF
Signaling Pathways for Cell Proliferation
and Survival: PI3K
Cell membrane
p53
c-JUN
wnt Receptor
MEK1/2
Survival
Transcription/translation
PI3
K PTENDSH
GBP
GSK3
-
catenin
NF-ҚB
NF-ҚB
c-MYC
BcL-XL
HBx
mTOR
BAD
Raf
PKC
PLC
-
catenin
ERK1/2
Akt
1. Horie Y, et al. J Clin Invest 2004; 113:
1774–83; 2. Hu T-H, et al. Cancer 2003;
97:1929–40. 3. Anzola M. J Viral Hepat
2004;11:383–93
RTK: FGFR
EGFR
IGF-IR
c-MET
SHC
GrB2GEF
Ras
Site of
action
Erlotinib
Gefitinib
Lapatinib
RAD001
Sorafenib
Sunitinib
x
x x
x
xx
xxx
Receptor
Signaling Pathways for Cell Proliferation
and Survival: Raf/MEK/ERK
Cell Membrane
c-MYC c-JUN
Wnt Receptor
BcL-XL
BAD
ERK1/2
MEK1/2
-
catenin
GSK3
GBP
DSH
AktmTO
R
Raf
PKC
NF-ҚB
Ras
NF-ҚB
PLCPI3K
PTEN
p53
Survival
Transcription/Translation
-
catenin
1. Feitelson MA, et al. Surg Clin N Am 2004;84:339–54
2. Thorgeirsson S, Grisham JW. Nat Genet 2002;31:339–46
3. Wiesenauer CA, et al. J Am Coll Surg 2004;198:410–21
4. Hwang YH, et al. Hepatol Res 2004;29:113–21
RTK: FGFR
EGFR
IGF-IR
c-MET
Receptor
SH
C
GrB
2
GE
F
HBx
x x
x
x
Site of
action
Erlotinib
Gefitinib
Lapatinib
RAD001
Sorafenib
Sunitinib
x
xx
xxx
Antiproliferative Molecular-targeted
Therapies in Development for HCC
Agent MOA Phase n
Inclusion
criteria Status Endpoints
Erlotinib TKI; EGFR
inhibitor
II 80 Unresectable
HCC
Complete PFS, tumor
response,
safety
Gefitinib1 TKI; EGFR
inhibitor
II 31 Unresectable
HCC
Complete Tumor
response,
safety
Lapatinib Dual TKI;
EGFR and
HER-2/neu
II 34 Unresectable
HCC
Ongoing Tumor
response,
OS, safety
1. O’Dwyer PJ, et al. J Clin Oncol 2006; 24(Suppl.):213s (Abstract 4143)
Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom,
IDdB3, BioPharm Insight, MedTrack; HER-2 = human epidermal growth factor receptor-2
Antiproliferative Molecular-targeted
Therapies in Development for HCC (cont’d)
Agent MOA Phase n
Inclusion
criteria Status Endpoints
RAD001 Rapamycin
analog; mTOR
inhibitor
I/II 134 Advanced
HCC
Recruiting MTD, disease
control rate
Sorafenib1 Multi-TKI; Raf,
PDGFR-β,
VEGFR-1/2
KIT, Flt-3
III 602 Advanced
HCC
Complete OS, TTSP, TTP,
safety versus
placebo1
Sunitinib Multi-TKI;
VEGFR-2,
PDGFR-β, KIT,
Flt-3
II 34 Advanced
HCC
Recruiting PFS, tumor
response, OS
1. Llovet J. ASCO 2007, Chicago, IL, USA
Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom,
IDdB3, BioPharm Insight, MedTrack; MTD = maximum tolerated dose
Apoptosis Inducers and Growth Inhibitors
in Development for HCC
Agent MOA Phase n
Inclusion
criteria Status Endpoints
Arsenic
trioxide
Apoptosis
inducer
II 25 Unresectable
liver cancer
Recruiting Efficacy,
safety
Bortezomib Apoptosis
inducer; 26S
proteasome
inhibitor
II 22 Advanced
HCC
Suspended
2005
Safety, MTD
TAC-101 Retinoid;
inhibits tumor
growth
I/II 18 Advanced
HCC
Ongoing Safety, MTD
Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom,
IDdB3, BioPharm Insight, MedTrack. MTD = maximum tolerated dose
Study n Efficacy Adverse events
Sorafenib 400mg
b.i.d.1602 OS improved vs placebo (p=0.00058) Grade 3 = diarrhea (8%), hand–foot skin
reaction
Sunitinib 37.5mg
q.d.219 PR=1, SD=8 Grade 3/4 = neutropenia (21%),
lymphopenia (16%), SGOT/SGPT (16%)
Sunitinib 50mg
q.d.337 PR=1, SD=39% Grade 3/4 = thrombocytopenia (43%),
neutropenia (24%), CNS (24%), asthenia
(22%). Dose reduction in 27% pts
Thalidomide4 19 PFS rate at 6 months = 41% Grade 2/3 = constipation (50%),
somnolence (18%)
Cetuximab5 32 27 evaluable, SD (≥8 weeks) 44%,
TTP = 8.0 weeks (22.5 weeks in pts
with SD)
No serious adverse events reported
Bevacizumab6 30 24 evaluable, PR=3, SD=13 including
≥16 weeks in 7 patients)
Six pts withdrew due to variceal
bleeding
Perifisone7 11 HCC pts, 1 PR,
progression free ≥9 months
Grade 2 or higher = diarrhea (49/241),
nausea (44/241), vomiting (28/241),
fatigue (14/241)
Single-Agent Targeted Therapy:
1. Llovet et al. Presented at ASCO 2007; Refs 2–8 from J Clin Oncol 2007;25:
2. Zhu AX, et al. Abs 4637; 3. Faivre SJ , et al. Abs 3546; 4. Fazio N, et al. Abs 15076; 5. Gruenwald V, et al. Abs 4598;
6. Malka D, et al. Abs 4570; 7. Campos LT, et al. Abs 15072
Sorafenib Targets both Tumor-cell
Proliferation and Angiogenesis In Vitro
KIT/Flt-3/
RET
Angiogenesis
Raf
Endothelial cell or pericyte
Nucleus
VEGFR-2PDGFR-β
MEK
Apoptosis
Tumor cell
Proliferation
PDGF
VEGF
EGF
Survival
Wilhelm SM, et al. Cancer Res 2004;64:7099–109
Ras
Nucleus
Ras
ERK
Raf
MEK
Apoptosis
ERK
PDGF-β VEGFParacrine
stimulation
Sorafenib
X X
X X
XX
X
X
Vehicle
Sorafenib 30mg/kg
Sorafenib 100mg/kg
n=5n=5
Tumor cell death assessed by TUNEL assay
Vehicle Sorafenib 30mg/kg Sorafenib 100mg/kg
Me
an
TU
NE
L-p
os
itiv
e
are
a (
%)
10
8
6
4
2
0
*
*
n=5
*p<0.05 versus vehicle by
one-way ANOVA Dunnett’s
multiple comparison test
Sorafenib Induces Cell Death in the
PLC/PRF/5 HCC Xenograft Model
TUNEL = terminal deoxynucleotidyl
transferase biotin-deoxyuridine
5-triphosphate nick end labelling Liu L, et al. Cancer Res 2006;66:11851–8
Phase II Trial Design
Sorafenib
400mg b.i.d.
Eligibility criteria
Inoperable HCC
Child–Pugh A/B status
No previous systemic
therapy
Primary endpoints
• Tumor response
• Safety
137 patients with advanced HCC received continuous sorafenib
400mg b.i.d. in 4-week cycles
Abou-Alfa GK, et al. J Clin Oncol 2006;24:4293–300
Tumor response assessments every two cycles using modified
World Health Organization criteria
Safety assessments (NCI-CTC v2.0)
NCI CTC v2.0 = National Cancer Institute
Common-Toxicity Criteria version 2.0
Phase II Study of Sorafenib in Patients
with Advanced HCC: Tumor Response
Best response n (%)
PR 3 (2.2)
MR 8 (5.8)
SD* 46 (33.6)
PD (by radiologic assessment) 48 (35.0)
Not available for independent review 32 (23.4)
Best response (n=137) based on independent assessment
*To be classified as SD, patients needed to have SD for 16 weeks
MR = minor response
Abou-Alfa GK, et al. J Clin Oncol 2006;24:4293–300
Reproduced with permission from the American Society of Clinical Oncology
Phase II Results: Median TTP
Median TTP (independent assessment)
5.5 months (n=137)
0 100 200 300 400 500
Time from start of study treatment (days)
0
0.25
0.50
0.75
1.00
Su
rviv
al d
istr
ibu
tio
n f
un
cti
on
Median TTP (investigator assessment)
4.2 months (n=137)
0 100 200 300 400 500
Time from start of study treatment (days)
0
0.25
0.50
0.75
1.00
Su
rviv
al d
istr
ibu
tio
n f
un
cti
on
600 700 800
Abou-Alfa GK, et al. J Clin Oncol 2006;24:4293–300
Reproduced with permission from the American Society of Clinical Oncology
Phase II Results: OS
Median OS (investigator assessment)9.2 months (n=137)
0 100 200 300 400 500 600 800
1.00
0.75
0.50
0.25
0
Su
rviv
al
dis
trib
uti
on
fu
ncti
on
Time from start of study treatment (days)
700
Abou-Alfa GK, et al. J Clin Oncol 2006;24:4293–300
Reproduced with permission from the American Society of Clinical Oncology
p=0.00034
TTP according to baseline pERK status (n=33)
0 50 100 150 200 250 300 350 4000
20
40
Pati
en
ts n
ot
pro
gre
ss
ed
(%
)
60
80
100 High (2–4+)
pERK staining
intensity (n=18)
Low (0–1+)
pERK staining
intensity (n=15)
76–100% of
nuclei positive
for pERK
TTP = 178 days
6–25% of
nuclei positive
for pERK
TTP = 46 days
Phase II Biomarkers: TTP According to
Phosphorylated ERK (pERK)
Time (days)
Abou-Alfa G, et al. J Clin Oncol 2006;24:4293–300
Reproduced with permission from the American Society of Clinical Oncology
Sorafenib Improves Survival in
Hepatocellular Carcinoma:
Results of a Phase III Randomized,
Placebo-Controlled Trial
Josep M Llovet, Sergio Ricci, Vincenzo Mazzaferro, Philip Hilgard,
Jean-Luc Raoul, Stefan Zeuzem, Armando Santoro, Minghua Shan,
Marius Moscovici, Dimitris Voliotis, and Jordi Bruix,
for the SHARP Investigators Study Group
Phase III Trial Design: SHARP
Sorafenib
400mg b.i.d.
n=299
Placebo
n=303
Eligibility criteria
Advanced HCC
Child–Pugh A status
ECOG PS 0–2
Life expectancy
≥12 months
Primary
endpoints
• OS
• TTSP
Secondary endpoints
– TTP
ECOG PS = Eastern Cooperative Oncology
Group Performance Status
Ra
nd
om
izati
on
Llovet JM, et al. ASCO 2007, Chicago, IL, USA
65
87/13
88/9/3
29/1926/26
95/5
1939
66
87/13
87/10/3
27/1826/29
98/2
2141
Sorafenib Placebo
Characteristics (n=299) (n=303)
Age (median, years)
Male/Female (%)
Region (Europe/N America/others) (%)
Etiology (%)Viral Hepatitis (HCV/HBV)Alcohol/other
Child–Pugh (A/B; %)
Prior therapies (%)Surgical resectionLoco-regional therapies
Phase III SHARP Trial: Baseline
Characteristics of Patients
Llovet JM, et al. Presented at ASCO 2007, Chicago, IL, USA
18
82
54
38
8
70
30
17
83
54
39
7
70
30
BCLC stage2 (%)
Stage B (intermediate stage)
Stage C (advanced stage)
ECOG PS (%)
0
1
2
Macroscopic vascular invasion (portal
vein) and/or extrahepatic spread (%)
Present
Absent
1. Llovet JM, et al. Presented at ASCO 2007, Chicago, IL, USA; 2. Llovet JM & Bruix J.
BCLC Group. Semin Liver Dis. 1999
Phase III SHARP Trial: Baseline
Characteristics of Patients1 (cont’d)
Sorafenib Placebo
Characteristics (n=299) (n=303)
0274 241 205 161 108 67 38 12 0
Patients at risk
Sorafenib:
0276 224 179 126 78 47 25 7 2Placebo:
299
303
SorafenibMedian: 46.3 weeks (10.7 months)(95% CI: 40.9–57.9)
Su
rviv
al
pro
bab
ilit
y
Weeks
Hazard ratio (S/P): 0.69 (95% CI: 0.55–0.88)p=0.00058*
PlaceboMedian: 34.4 weeks (7.9 months)(95% CI: 29.4–39.4)
1.00
0
0.75
0.50
0.25
0 808 16 24 32 40 48 56 64 72
*O’Brien–Fleming threshold for statistical significance was p=0.0077
Phase III SHARP Trial: OS
(Intention-to-treat)
Llovet JM, et al. Presented at ASCO 2007, Chicago, IL, USA
SorafenibMedian: 24.0 weeks (5.5 months)(95% CI: 18.0–30.0)
196 126 80 50 28 14 8 2192 101 57 31 12 8 2 1
Pro
gre
ss
ion
-fre
e p
rob
ab
ilit
y
Hazard ratio (S/P): 0.58(95% CI: 0.44–0.74) p=0.000007
546 12 18 24 30 36 42 480Time (Weeks)
PlaceboMedian: 12.3 weeks (2.8 months)(95% CI: 11.7–17.1)
1.00
0
0.75
0.50
0.25
Patients at risk
Sorafenib:Placebo:
299303
Phase III SHARP Trial: TTP
(Independent Central Review)
Llovet JM, et al. Presented at ASCO 2007, Chicago, IL, USA
Phase III SHARP Trial: Response Assessment (RECIST; Independent Review)
Sorafenib
(n=299)
Placebo
(n=303)
Overall response
CR
PR
0
7 (2.3%)
0
2 (0.7%)
SD 211 (71%) 204 (67%)
PD 54 (18%) 73 (24%)
Progression-free rate at 4 months 62% 42%
Duration of treatment (median, weeks) 23 19
Llovet JM, et al. Presented at ASCO 2007
Chicago, IL, USA
RECIST = Response Evaluation Criteria In
Solid Tumors
Phase III SHARP Trial: Exploratory
Sub-group Survival Analysis
Sorafenib benefit Placebo benefit
OS Hazard ratio
ECOG PS 0
ECOG PS 1 & 2
0.5 1.0 1.50.0
Macroscopic vascular invasion
No macroscopic vascular invasion
No macroscopic VI/extrahepatic spread
Macroscopic VI and/or extrahepatic spread
No extrahepatic spread
Extrahepatic spread
Llovet JM, et al. Presented at ASCO 2007, Chicago, IL, USA
Phase III SHARP Trial: Safety Events
Drug-related adverse events (%) All Grade 3–4 All Grade 3–4
Diarrhea 39 8/– 11 2/–
Pain (abdomen) 8 2/– 3 <1/–
Weight loss 9 2/– <1 0/–
Anorexia 14 <1/– 3 <1/–
Nausea 11 <1/– 8 1/–
HFSR 21 8/– 3 <1/–
Vomiting 5 1/– 3 <1/–
Alopecia 14 0/– 2 0/–
Liver dysfunction <1 <1/– 0 0/–
Bleeding 7 <1/– 4 <1/<1
Sorafenib(n=297)
Placebo(n=302)
Treatment-emergent serious adverse events (SAE, %) 52 54
Drug-related treatment-emergent SAE (%) 13 9
Llovet JM, et al. Presented at ASCO 2007, Chicago, IL, USA
Hand–foot skin reaction
Phase III SHARP Trial: Conclusions (cont’d)
Sorafenib is the first systemic therapy to demonstrate
prolonged survival in patients with HCC
Sorafenib may become the new reference standard
for systemic therapy of patients with HCC
Sunitinib is being investigated in different
phase II trials in HCC
Design Country;
clinicaltrials.gov identifier
European/Asian, open-label study of sunitinib in
patients with unresectable HCC
France, Korea;
NCT00247676
Open-label, first-/second-line sunitinib in locally
advanced, unresectable or metastatic HCC
United States;
NCT00361309
Continuous sunitinib treatment in patients with
unresectable HCC
Switzerland; NCT00514228
Sunitinib and chemoembolization in patients with
unresectable HCC
United States;
NCT00524316
Open-label study of sunitinib in patients with
metastatic and/or surgically unresectable HCC
United States;
NCT00495625
Sunitinib and capecitabine for the treatment of
unresectable or metastatic HCC
United States
Open-label study of sunitinib in patients with
metastatic and/or surgically unresectable HCC
Italy, Denmark
www.ClinicalTrials.gov. Accessed December 2007
Phase II study to determine single-agent efficacy and
safety of sunitinib in patients with unresectable HCC
Phase II, European/Asian, open-label study of sunitinib in
patients with unresectable HCC who had not received prior
systemic treatment
Primary endpoints: Objective response rate (defined by RECIST)
Secondary endpoints: Clinical benefit rate (CR + PR + SD),
duration of response, time to tumor progression, overall survival,
exploratory measures of antitumor activity, safety
Faivre et al. Eur J Cancer 2007;5:270 (Abstract 3535)
RECIST=Response Evaluation Criteria in Solid Tumors
Continue as
long as
clinical
benefit
Unresectable
HCC
Sunitinib 50 mg/day
4 weeks on 2 weeks off
Results demonstrate sunitinib activity in
patients with unresectable HCC
Best response, n
(%)
Asia
(n=16)
Europe
(n=21)
Total
(N=37)
CR 0 0 0
PR 1 (6.3) 0 1 (2.7)
SD
>3 months 4 (25.0) 9 (42.9) 13 (35.1)
>6 months 3 (18.8) 5 (23.8) 8 (21.6)
PD 8 (50.0) 5 (23.8) 13 (35.1)
Clinical benefit rate (PR + SD >3 months) was 37.8% (n=14)
Faivre et al. Eur J Cancer 2007;5:270 (Abstract 3535)
Density Density
Prior to sunitinib After sunitinib
Decrease in tumor density, n=26
n (%)
Induction of necrosis, n=21
n (%)
15% 21 (81)* 13 (62)
30% 16 (62) 10 (48)
*Choi criteria
Sunitinib decreases tumor density and 3-
dimensional measurement of tumor necrosis in
unresectable HCC
Faivre et al. Eur J Cancer 2007;5:270 (Abstract 3535)
Phase II study to determine single-agent efficacy
and safety of sunitinib in patients with advanced HCC
Phase II, open-label single-center study of first- and second-line
treatment with sunitinib in patients with advanced HCC
Primary endpoint: PFS of patients with advanced HCC treated
with sunitinib
Secondary endpoints: safety, preliminary efficacy (based on
response rate, duration of response, and OS), exploratory
measures of antitumor activity Zhu et al. AACR-NCI-EORTC 2007 (oral presentation)
Stage 2:
Additional 17 patients
enrolled if >8 patients
achieved PFS >3 months
Stage 1:
Advanced
HCC (N=17)
Sunitinib 37.5 mg/day
4 weeks on
2 weeks off
Median PFS and OS in patients with
advanced HCC
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5
1.00
0.75
0.50
0.25
0
Time (Months)
Median OS = 10 months
(95% CI: 7.5–not estimable)
Zhu et al. AACR-NCI-EORTC 2007 (oral presentation)
1.00
0.75
0.50
0.25
0
Time (Months)
Median PFS = 4 months
(95% CI: 2.8–7.0)
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5
Pro
ba
bil
ity
Sunitinib treatment caused a change in
angiogenic biomarkers: VEGF and soluble
VEGFR2
pg
/ml
0
5000
10000
15000
Day 1 Day 15
pg
/ml
0
400
800
1200
1600
Day 1 Day 15
14/15 patients had a decrease in
sVEGFR2 at day 15
14/18 patients had an increase
in VEGF at day 15
Zhu et al. AACR-NCI-EORTC 2007 (oral presentation)
Summary of Recent Phase II Studies With Epidermal Growth Factor Receptor Inhibitors in Hepatocellular Carcimoma
Study Regimen
No.of
patients RR, %
Median
PFS/TTP,
mo
PFS at 6
mo, %
Median
survival,
mo
Philip2005 Erlotinib 38 9 3.2 32 13
Thomas 2007 Erlotinib 40 0 3.1 28 6.3
O’Dwyer 2006 Gefitinib 31 3 2.8 NR 6.5
Ramanathan 2006 Lapatinib 30 5 2.3 NR 6.2
Zhu 2007 Cetuximab 30 0 1.36 3 9.6
Gruenwald 2007 Cetuximab 32 0 1.87 NR NR
Louafi 2007 Cetuximab-
GEMOX
43 23 4.5 NR 9.2
RR indicates response rate; PFS, progression-free survival; TTP, time to tumor progression;
NR, not reported; GEMOX, gemcitabine and oxaliplatin.
Unresectable
DS : 33/38 (87%)
PR : 9%, SD :
50%
OS : 13 Months
Phase II study of Erlotinib (OSI-774) in patients with advanced HCC
JCO 23:6657-6663, 2005
A phase II open-label study of cetuximab in unresectable HCC
(ASCO 2007, Abs #4598)
GEMOX + Cetuximab
(ASCO 2007, Abs #4594)
GEMOX + Cetuximab
(ASCO 2007, Abs #4594)
Summary of Recent Phase I/II Studies With Bevacizumab-based Regimens in Hepatocellular Carcinoma
Study Regimen No. of patients
RR, % Median PFS/TTP, mo
PFS at 6 mo, %
Median survival, mo
Schwartz 2006 Bevacizumab 25 8 6.5 NR NR
Malka 2007 Bevacizumab 24 12.5 NR NR NR
Zhu 2006 GEMOX-B 33 20 5.3 48 9.6
Sun 2007 CAPEOX-B 30 10 5.4 40 NR
Hsu 2007 Capecitabine-bevacizumab
25 16 4.1 34 10.7
Thomas 2007 Bevacizumab-erlotinib
34 21 9 75(at 4 mo) 19
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.
Phase II Combination Targeted Therapy:
Study n Efficacy Adverse events
Bevacizumab +
capecitabine1
45 25 patients had 6 months therapy:
ORR = 16%
DCR (ORR + SD) = 60%
Median OS/PFS 10.7/4.1 months
6-month PFS rate = 34%
Grade 3: HFSR (n=2)
Cetuximab +
gemcitabine +
oxaliplatin2
43 35 evaluable patients:
ORR = 23%; DCR = 65%
Grade 4: thrombocytopenia (n=1);
grade 3: thrombocytopenia (21%),
neutropenia (19%), acneiform rash
(19%)
Bevacizumab +
capecitabine +
oxaliplatin3
30 30 evaluable patients:
DCR = 89%
Mean PFS = 5.4 months
6-month PFS rate = 40%
Grade 2–3:
peripheral neuropathy (33%);
hand-foot syndrome reaction (11%)
Bevacizumab +
erlotinib4
29 27 evaluable patients:
CR = 1; PR = 5
SD (16 weeks) = 9
1 early death; grade 3–4:
hypertension (n=5), fatigue (n=4)
and GI bleeding (n=3)
References 1–4 from J Clin Oncol 2007; 25 (Supp):
1. Hsu C, et al. Abstract 15190; 2. Louafi S, et al. Abstract 4594
3. Sun W, et al. Abstract 4574; 4. Thomas MB, et al. Abstract 4567
Ongoing Trials of Molecular-targeted Therapies
in Combination Regimens for HCC
Combination Phase n Inclusion criteria Status Endpoints
Bevacizumab +
capecitabine
II 100 Advanced/
metastatic liver
cancer
In progress PFS rate at 27 weeks
Bevacizumab +
erlotinib
II 21 Unresectable HCC Recruiting PFS rate at 27 weeks,
tumor response rate
Bevacizumab +
erlotinib
II 40 Unresectable HCC Recruiting PFS rate at 16 weeks,
response rate, OS
Bevacizumab +
oxaliplatin +
gemcitabine
II 30 Unresectable HCC In progress TTP, tumor response,
safety
Bortezomib +
doxorubicin
II 40 Unresectable HCC Recruiting Objective response
rate, OS, TTP, safety
Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom,
IDdB3, BioPharm Insight, MedTrack
Ongoing Trials of Molecular-targeted Therapies
in Combination Regimens for HCC (cont’d)
Combination Phase n
Inclusion
criteria Status Endpoints
Bevacizumab +
dexamethasone
+ floxuridine
II 55 Unresectable
HCC
Initiated Tumor response,
safety
Thalidomide +
UFUR
II 41 Advanced
HCC
Recruiting Tumor response, PFS,
6-month PFS rate, OS
Sorafenib +
UFUR
II 50 Unresectable
and/or
metastatic
HCC
Recruiting PFS, 6-month PFS rate,
tumor response rate,
OS
Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom,
IDdB3, BioPharm Insight, MedTrack; UFUR = Tegafur/uracil
Ongoing Trials of Molecular-targeted Therapies
Combined with Current Modalities
Combination Phase n
Inclusion
criteria Status Endpoints
Bevacizumab +
TACE
II 30 Unresectable
HCC
Recruiting Neovessel
formation, tumor
progression
Bevacizumab +
TACE
II 40 Unresectable
HCC
Initiated 1-year tumor
response, OS,
safety
Celecoxib +
erlotinib as
adjuvant
I/II 50 Unresectable
HCC
Ongoing OS, disease-free
survival, safety,
MTD
Chemoembolization
+/- bevacizumab
II 30 Unresectable
HCC
Recruiting PFS, safety,
response rate
Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom,
IDdB3, BioPharm Insight, MedTrack
Ongoing Trials of Molecular-targeted Therapies
Combined with Current Modalities (cont’d)
Combination Phase n
Inclusion
criteria Status Endpoints
PI-88 as
adjuvant to
curative
therapy
III N/A HCC Planned Tumor non-recurrence,
time to recurrence, OS
Gefitinib
adjuvant to
resection
II 40 Resectable
HCC
Recruiting Identification of
biomarkers,
recurrence-free
survival
Thalidomide +
radiotherapy
I/II 19 Locally
advanced
HCC
Recruiting Tolerability, feasibility
Sorafenib +
TACE with
doxorubicin
I N/A Unresectable
HCC
Recruiting MTD, dose-limiting
toxicity
Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom,
IDdB3, BioPharm Insight, MedTrack
Schematic illustration of potential future trial designs in advanced hepatocellular carcinoma. HCC indicates hepatocellular carcinoma; BSC, best supportive care.
Potential Future Trial Designs in Advanced HCC
A
B
C
Randomized :
1st-line
Randomized :
1st-line
Randomized :
2nd-line
(sorafenib-refractory)
New agent
Sorafenib
New agent + sorafenib
Orngoing sorafenib or BSC
Sorafenib
New agent
Overall Summary
Treatment options in advanced HCC are limited
Pathogenesis of HCC involves multiple signaling
pathways
Sorafenib is the first systemic therapy to demonstrate
prolonged survival in patients with HCC
Sorafenib may become the new reference standard for
systemic therapy of patients with HCC
Future Directions
Developing more effective systemic therapies
To identify key relevant molecular targets for
therapeutic intervention
Understanding of the clinical and molecular
predictors of sorafenib-mediated clinical
benefits and mechanisms of resistance
Examined in the adjuvant setting after RFA,
TACE, surgical resection, liver transplantation
case
55-yrs male, histologically proven HCC, hepatitis B(+),
ECOG PS 1, Child-Pugh A, macroscopic portal vein
invasion and regional L/N
Which treatment do you wants?
1. Best supportive care
2. TACE
3. Systemic cytotoxic agent
4. Hormonal therapy
5. Target agents (sorafenib)