Future developments
AASLD-JNCI guidelines in HCC
Trial design
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-71.
HCC trial design strategy recommended by
AASLD expert panel
Early clinical
research phase
Phase 1/2 study
Randomized phase 2
Advanced clinical
research phase
Combined phase 2–3
Phase 3
study

Combined phase 1/2 studies in cirrhotic patients will capture liver-specific
toxic effects of new drugs

Randomized phase 2 trials are pivotal in HCC research because they enable
reliable comparison with standard of care

Phase 3 studies remain the main source of evidence in HCC research

Phase 2/3 studies may be appropriate in very specific circumstances, where
the drug proposed would require fast-track assessment
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-71.
Endpoints in clinical trials recommended by
AASLD expert panel
Recommended primary and secondary endpoints
Survival
Time from randomization to death. Patients alive at the end of follow-up are censored
•Primary endpoint in phase 3 studies assessing primary treatments
•Primary/secondary endpoint in phase 2/3 studies assessing adjuvant or neoadjuvant
treatments
•Secondary endpoint in phase 2 studies assessing primary treatments
Time to recurrence
(TTR)*
Time from randomization to recurrence. Evidence of recurrence should follow the
RECIST amendments. Once evidence of HCC recurrence is confirmed, TTR will be
defined as the time that recurrence was first suspected
•Primary/secondary endpoint in phase 2/3 studies assessing adjuvant or neoadjuvant
treatments
Time to progression*
Time from randomization to radiological progression. Definition of progression is
based on the RECIST amendments. Deaths during follow-up without evidence of
radiological progression are censored
•Primary endpoint in phase 2 studies assessing primary treatments
•Secondary endpoint in phase 3 studies assessing primary treatments
Time to local
recurrence*
Time from randomization to local radiological progression. Definition of progression is
based on the RECIST amendments. Deaths during follow-up without evidence of
radiological progression are censored
•Secondary endpoint in studies assessing locoregional therapies
*Time to progression and time to local recurrence can vary considerably if evaluation interval varies among studies or between
study arms of an individual study.
RECIST = Response Evaluation Criteria in Solid Tumors.
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-71.
Endpoints in clinical trials recommended by
AASLD expert panel
Recommended primary and secondary endpoints
Tertiary endpoints†
Cancer-specific
death
Time from randomization to HCC-related death. Patients alive at the end of followup are censored
•Competing risk analysis is recommended to assess this endpoint
Time to symptomatic
progression
Time from randomization to deterioration of symptoms as assessed by a
standardized questionnaire
•No reliable questionnaires have been thoroughly validated in HCC research
Disease-free survival
Composite endpoint. Time from randomization to either recurrence or death.
Patients alive and free of recurrence at the end of follow-up are censored
•Vulnerable endpoint in HCC research
Progression-free
survival
Composite endpoint. Time from randomization to either radiological progression or
death. Patients alive and free of progression at the end of follow-up are censored
•Vulnerable endpoint in HCC research
Response rate
Definition of response is based on the RECIST amendments
† Tertiary
endpoints include composite endpoints that are vulnerable in HCC research, such as disease-free and
progression-free survival, that are difficult to measure with standard tools, such as time to symptomatic progression, or that
are not time-to-event endpoints, such as response rate or disease control rate.
RECIST = Response Evaluation Criteria in Solid Tumors.
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-71.
Other recommendations of AASLD expert
panel on HCC trial design
 Target population
• selection of the target population should be based on the
Barcelona Clinic Liver Cancer staging system
• new drugs should be tested in patients with well preserved liver
function (Child–Pugh A class)
 Control arm in clinical trials
• patients assigned to the control arm should receive standard-ofcare therapy, namely TACE for patients with intermediate-stage
disease and sorafenib for patients with advanced-stage disease
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-71.
Conventional and proposed trial design in HCC trials
Trial phase and
component
Conventional design
New proposed design
Study population
All cancers
HCC by Barcelona Clinic Liver Cancer
(BCLC) Child–Pugh A
Study design
Phase 1
Phase 1/2
Aim
Dose defining
Safety
Dose defining
Safety
Endpoint
Toxic effects
Maximum tolerated dose,
pharmacokinetics
Dose defining
Toxic effects
Maximum tolerated dose and/or optimal
biological dose
Study population
Unresectable HCC
Child–Pugh A and B
HCC by BCLC Child–Pugh A
Study design
Single arm
Randomized phase 2
Single arm*
Aim
Antitumor activity, safety
Antitumor activity, safety
Endpoint
Response rate
Toxicity
Time to progression
Survival, toxicity
Phase 1
Phase 2
*Large single-arm phase 2 studies might only be considered when a contemporary historical control arm has been well
characterized within other trials, and thus, inclusion criteria can be reproduced.
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.
Conventional and proposed trial design in HCC
trials
Trial phase and
component
Conventional design
New proposed design
Study population
Unresectable HCC
Child–Pugh A and B
HCC by BCLC
Child–Pugh A
Study design**
Randomized controlled trial
Randomized controlled trial
Combined phase 2/3
Aim
Clinical outcome
Clinical outcome
Endpoint
Survival
Response
Progression-free survival,
disease-free survival
Survival
Time to progression (TTP)
Recurrence***
Phase 3*
*Large single-arm phase 2 studies might only be considered when a contemporary historical control arm has been well
characterized within other trials, and thus, inclusion criteria can be reproduced.
** Consider phase 2/3 studies for fast-track approval with strong interim analysis.
*** Time to recurrence as primary endpoint in adjuvant trials.
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.
Selected targeted therapies under evaluation in
advanced HCC: first-line therapy
Target
population
Aim
Comparison Phase
Status
Location
Advanced HCC1
Improve sorafenib
first line
Sorafenib +/–
erlotinib
Phase 3
Recruiting
Global
Advanced HCC2
Compare with
sorafenib first line
Sorafenib vs
linifanib
Phase 3
Recruiting
Global
Advanced HCC3
Compare with
sorafenib first line
Sorafenib vs
brivanib
Phase 3
Recruiting
Regional/US
Advanced HCC4
Compare with
sorafenib first line
Sorafenib vs
erlot + beva*
Phase 2
Recruiting
Global
Advanced HCC5
Improve sorafenib
first line
Sorafenib +/–
everolimus
Phase 1/2 Active
Global
Advanced HCC6
Compare with
sorafenib first line
Sorafenib vs
sunitinib
Phase 3
Terminated
Global
Advanced HCC7,8
Compare with
sorafenib first line
Sorafenib vs
BIBF
Phase 2
Recruiting
Regional/Asia
Advanced HCC9
Compare with
sorafenib first line
Sorafenib vs
Dovitinb
Phase 2
Recruiting
Asia
*Erlotinib + Bevacizumab
Available from: http://www.clinicaltrials.gov. Last accessed March 2011
1. SEARCH trial: NCT00901901. 2. NCT01009593. 3. BRISK FL trial: NCT00858871.
4. NCT00881751. 5. NCT00828594. 6. NCT00699374. 7. NCT01004003. 8. NCT00987935. 9. NCT01232296
Selected targeted therapies under evaluation in
advanced HCC: Second-line therapy
Target
population
Aim
Comparison Phase
Status
Location
Advanced HCC1
Second line after
sorafenib
Brivanib vs
placebo
Phase 3
Recruiting
Global
Advanced HCC2
Second line after
sorafenib
Ramucirumab
vs placebo
Phase 3
Recruiting
Global
Advanced HCC3
Second line therapy
ADI-PEG 20
vs placebo
Phase 3
Not yet
open
US
Advanced HCC4
Second line after
sorafenib
Everolimus vs
placebo
Phase 3
Recruiting
Global
Advanced HCC5
Second line therapy
ARQ 197 vs
placebo
Phase 2
Recruiting
Europ/US
Advanced HCC6
Second line after
sorafenib
OSI-906 vs
placenbo
Phase 2
Recruiting
Europ/US
Advanced HCC7
Second line after
sorafenib
TAC-101 vs
placenbo
Phase 1/2 Terminated
Italy
Available from: http://www.clinicaltrials.gov. Last accessed March 2011
1. BRISK PS trial: NCT00825955 and BRISK-APS trial: NCT01108705. 2. REACH trial: NCT01140347.
3. NCT01287585 4. EVOLVE-1 trial: NCT01035229. 5. NCT00988741. 6. NCT01101906. 7. NCT00687596.
Molecular therapies tested in HCC
Regimen
Phase
Sample
size
Response
rate (%)
Sorafenib
3
300
2.3
Sorafenib
3
271
Sorafenib +
doxorubicin
2b
47
Sunitinib
2
Sunitinib
Progression-free
survival/time to
progression
(months)
Median
survival
(months)
Reference
5.5 (T)
10.7 (vs 7.9
placebo
Llovet et al.
2.8 (T)
6.5 (vs 4.2
placebo)
Cheng et al.
4
8.6 (T)
13.7 (vs 6.5
placebo)
Abou-Alfa et al.
37
2.7
5.2 (P)
11.2
Faivre et al.
2
34
2.9
3.9 (P)
9.8
Zhu et al.
Erlotinib
2
38
9
3.2 (P)
13
Philip et al.
Erlotinib
2
40
0
3.1 (P)
6.3
10.75
Thomas et al.
Gefitinib
2
31
3
2.8 (P)
6.5
O’Dwyer et al.
Cetuximab
2
30
0
1.4 (P)
9.6
Zhu et al.
Cetuximab
2
32
0
1.87 (T)
–
Gruenwald et al.
Adapted from Finn RS. Clin Cancer Res. 2010;16:390-7.
Molecular therapies tested in HCC
Regimen
Phase
Sample
size
Respons
e rate
(%)
Progression-free
survival/time to
progression
(months)
Median Reference
survival
(months)
Bevacizumab
2
46
13
6.9 (P)
12.4
Siegel et al.
Bevacizumab
+ erlotinib
2
40
25
9 (P)
15.65
Thomas et al.
Bevacizumab
+ gem+oxa*
2
30
5.3 (P)
9.6
Zhu et al.
Brivanib
2
First-line
55
2.8 (T)
10
Raoul et al.
Sec-line
46
2.7 (T)
9.8
Finn et al.
Linifanib
2
44
6,8
3,7 (T)
9,7
Toh et al.
Lapatinib
2
40
5
2,3 (P)
6,2
Ramanathan et
al
Lapatinib
2
26
0
1.9 (P)
12.6
Bekaii-Saab et al.
*gem=gemcitabine; Oxa=oxaliplatin
Adapted from Finn RS. Clin Cancer Res. 2010;16:390-7. Toh et al JCO 2009;27: 222s:abstr 4581; Ramanathan et al. Cancer Chem. Pharm. 2009;64:777-83
Sorafenib as adjuvant Treatment in the prevention Of
Recurrence of hepatocellular carcinoMa (STORM)

Phase III, randomized, double-blind, placebo-controlled study of
sorafenib +/- erlotinib in advanced metastatic patients

International (Europe, Americas, Asia-Pacific)
Advanced/
metastatic
Disease
Eligibility criteria
 Child-Pugh A
 PS 0 or 1
Randomization
 n=700
Stratification
 ECOG PS
 Geographic region
 MVI/EHS
DCR = disease control rate; PRO = patient-reported outcome.
Sorafenib 400 mg bid +
erlotinib 150 mg daily
Sorafenib 400 mg
b.i.d. + placebo
Endpoint
Primary
OS
Secondary
TTP
DCR
PRO
Safety
http://clinicaltrials.gov/; NCT00901901.
Sorafenib as adjuvant Treatment in the prevention Of
Recurrence of hepatocellular carcinoMa (STORM)

Phase III, randomized, double-blind, placebo-controlled study of
sorafenib as adjuvant treatment of HCC after surgical resection of local
ablation

International (Europe, Americas, Asia-Pacific, Japan)
Prior treatment
 Resection
 RFA
 PEI
Eligibility criteria
 Child-Pugh
score 5–7
 Intermediate/high
risk of recurrence
Randomization
 n=1,100
Stratification
 Prior curative
treatment
 Geographical region
Sorafenib
400 mg bid
Placebo
Endpoints
 RFS
 OS
 Biomarkers
 Other
RFA = radiofrequency ablation;
PEI = percutaneous ethanol injection; RFS: recurrence-free survival.
http://clinicaltrials.gov/; NCT00692770.
Sorafenib or Placebo in combination with TACE in
hepatocellular carcinoma (SPACE)

Phase II, randomized, double-blind, placebo-controlled study of TACE
plus sorafenib vs TACE plus placebo
Eligibility criteria
 BCLC B
 ECOG PS 0
 Child-Pugh Class A
without ascite
 No extrahepatic
spread
 No macrovascular
invasion
n=300
R
A
N
D
O
M
I
Z
E
DC-Beads-TACE
+ Sorafenib 400 mg bid
DC-Beads-TACE
+ Placebo
Endpoints
Primary
 TTP
Secondary
 OS
 Time to untreatable
progress
 Time To Vascular
Invasion
 Time To Extrahepatic
Spread
1:1
TACE = transarterial chemoembolization;
TTP = time to progression; OS = overall survival.
http://clinicaltrials.gov
Signaling Pathways Provide Rationale for
Combination Treatment Strategies
RTK: PDGFR FGFR
VEGFR EGFR
IGFIR c-MET
Cell Membrane
HBx
GEF
PTEN
PI3K
Receptor
Wnt Receptor
X X
GrB2
SHC
Ras
DSH
PLC
X
Akt
Raf
MEK
mTOR
BAD
GBP
PKC
X
GSK3
Catenin
BcL-XL
c-MYC
X Gefitinib
X Everolimus
c-JUN
Catenin
p53
X
X Erlotinib
X Lapatinib
ERK
NF-κB
NF-κB
Site of
action
Survival
Transcription/Translation
X Sorafenib
X Sunitinib
Anzola M. J Virol Hepat. 2004; 11: 383-393; Avila MA, et al. Oncogene 2006; 25: 3866-3884; Clauss M. Semin Thromb Hemost 2000; 26: 561-569.
Molecular targets and targeted agents in HCC
Bevacizumab
AMG 386
VEGF
Ang1/2
HGF
PDGF
EGF
FGF
Ramucirumab
MEDI-575
Cetuximab
E70807
Sorafenib*
Sunitinib
Vatalanib
Cediranib
Pazopanib
Linifanib
Tie2
PDGFR
Regorafenib
Sorafenib* is the only drug approved for HCC
Gefitinib
ARQ 197
Erlotinib
Brivanib
VEGFR
BIBF 1120
SU6688
FGFR
C-Met
EGFR
Forentinib
XL 184
Adapted from Tanaka S, Arii S. Cancer Sci. 2009;100:1-8
Adapted from Tanaka S, Arii S. J Gastroenterol 2011; in press *published online 25 Feb 2011
Molecular targets and targeted agents in HCC
GF
RASSF1A
Ras
SOS
PTEN
Grb2
PI3K
RTK
Sorafenib*
Raf
IKK
Akt
Regorafenib
AZD8055
AZD6244
PDK1
mTOR
Sirolimus
Everolimus
MEK
eIF4E
4E-BP1
p70S6K
ERK
Sorafenib* is the only drug approved for HCC
Adapted from Tanaka S, Arii S. J Gastroenterol 2011; in press *published online 25 Feb 2011.
Molecular targets and targeted agents in HCC
Agent
Classification
Target
Sorafenib (Nexavar, BAY43-9006; Bayer)
Small-molecule
VEGFR2, VEGFR3, PDGFR-b, Flt-3, c-KIT tyrosine kinase, Raf
serine-threonine kinase
Regorafenib ( BAY73-4506; Bayer)
Small-molecule
VEGFR2, VEGFR3, PDGFR-b, Flt-3, c-KIT, Tie2 tyrosine kinase,
Raf serine-threonine kinase
Sunitinib (Sutent, SU11248; Pfizer)
Small-molecule
VEGFR1 VEGFR2, PDGFRs, Flt-3, c-KIT tyrosine kinase
Brivanib (BMS-582664; Bristol-Myers
Squibb)
Small-molecule
VEGFR2, VEGFR3, FGFR tyrosine kinase
BIBF 1120 (Vargatef; Boehringer Ingelheim)
Small-molecule
VEGFR2, PDGFR-b, FGFR tyrosine kinase
SU6688 (TSU-68; Taiho)
Small-molecule
VEGFR2, PDGFR-b, FGFR tyrosine kinase
Vatalanib (PTK787/ZK222584; Novartis)
Small-molecule
VEGFR1, VEGFR2, VEGFR3,PDGFR-b, c-KIT tyrosine kinase
Cediranib (AZD2171; AstraZeneca)
Small-molecule
VEGFR1, VEGFR2, VEGFR3, PDGFRs, c-KIT tyrosine kinase
Pazopanib (Votrient, GW786034;
GlaxoSmithKline)
Small-molecule
VEGFR-1, VEGFR-2, VEGFR-3, PDGFRs, c-KIT tyrosine kinase
Linifanib (ABT-869; Abbott)
Small-molecule
VEGFR-2, PDGFR-b, CSF-1R tyrosine kinase
E7080 (Eisai)
Small-molecule
VEGFR3, VEGFR2, VEGFR1 tyrosine kinase
Foretinib (XL880, GSK1363089;
GlaxoSmithKline)
Small-molecule
VEGFR-2, c-MET tyrosine kinase
XL184 (BMS907351; Bristol-Myers Squibb)
Small-molecule
VEGFR-2, c-MET tyrosine kinase
ARQ 197 (Daiichi Sankyo)
Small-molecule
c-MET tyrosine kinase
Bevacizumab (Avastin; Roche/Genentech)
Monoclonal antibody
VEGF-A (neutralization)
Ramucirumab (IMC-1121B; Eli Lilly)
Monoclonal antibody
Monoclonal antibody VEGFR-2 (neutralization)
MEDI-575 (AstraZeneca)
Monoclonal antibody
PDGFR-a (neutralization)
AMG 386 (Amgen)
Antibody-type peptide
Angiopoietin-1, angiopoietin-2 (neutralization)
Adapted from Tanaka S, Arii S. J Gastroenterol 2011; in press *published online 25 Feb 2011.
Subway map HCC pathways
Dufour JF et al. J Hepatol. 2007; 47(6): 860-7
HCC transcriptome classification
BIOLOGICAL PATHWAYS
GROUPS
TREATMENTS
Developmental
and imprinting
genes,IGF2
Cell Cycle
Nucleus pore
Stress and
immune
response
Amino acid
metabolism
E-cadherin
Dufour J-F and Jonson P. J Hepatology 2009. J Hepatol. [Epub ahead of print]
Molecular classification of HCC
HCC genomic-based classification
• 3 HCC subtypes were
observed, S1–S3
• distinguished by
molecular phenotype
• correlated with tumor
size, cellular
differentiation, and
serum α-fetoprotein
levels
Published
subclasse
In a meta-analysis of 603
HCC patients
Clinical
phenotype

Molecular
pathways
S1
IFN = interferon; EpCAM = epithelial cell adhesion molecule.
S2
TGF-ß
Wnt
E2F1
S3
MYC
AKT
Retained hepatocyte-like
phenotype
p53
IFN
Poor Survival
Good Survival
Proliferation
late TGF-ß
CTNNB1
EpCAM (+)
Moderately/poorly
differentiated
Well differentiated
Large tumor
Smaller tumor
AFT
Hoshida Y, et al. Cancer Res. 2009;69:7385-92.
Outcome prediction in HCC
Model of HCC prognosis combining clinical and genomic data
In patients with early stage tumors, survival is mostly determined by genomic data coded
in non-tumoral cirrhotic tissue (‘field effect’), because it determines the risk of liver
dysfunction and development of a de novo HCC

As cancer progresses, genomic data from the tumor increases its prediction capacity
because cancer-related death limits survival in patients with advanced disease
Relative prognostic impact
of molecular data from
tumor and adjacent tissue
Clinical stage
(BCLC algorithm)

Very early
(Stage 0)
Early
(Stage A)
Intermediate
(Stage B)
Advanced
(Stage C)
Single nodule < 2 cm,
no vascular invasion,
PST 0
Single nodule, 3 nodules < 3 cm,
no macrovascular invasion,
PST 0
Multiple nodules,
no macrovascular invasion,
PST 0
Macrovascular invasion,
extrahepatic spread (N1, M1),
PST 1–2
De novo
tumor
Liver
dysfunction
Intrahepatic
dissemination
Tumor
biology
Others
Tumor
Adjacent
tissue
© 2010 American Association for Cancer Research`
Villanueva A, et al. Clin Cancer Res. 2010;16:4688-94.
Translational research in HCC