Hepatocellular carcinoma: current and evolving therapies

1
 New drugs for Hepatocellular Carcinoma
Jordi Bruix Head, BCLC Group, Liver Unit
Hospital Clínic, University of Barcelona
2
BCLC Staging and Treatment Strategy
HCC
Stage D
Stage A - C
Stage 0
PST gt2, Child-Pugh C
PST 0-2, Child-Pugh A-B
PST 0, Child-Pugh A
Very early stage (0) Singlelt 2cm.
Terminal stage (D)
Early stage ( A) Single or 3 nodules lt 3cm, PS 0
Intermediate stage ( B) Multinodular, PS 0
Advanced stage (C) Portal invasion, N1,M1, PS
1-2
Single
3 nodules lt3cm
Portal pressure/ bilirubin
Portal invasion, N1,M1
Associated diseases
Increased
No
Yes
No
Yes
Liver Transplantation (CLT / LDLT)
PEI/RF
Chemoembolization
Resection
?
Sympt. Treat. (20)
Curative Treatments (30) 50 - 75 at 5
years
Non-curative treatments (50) 3 year survival
10-40
Sem Liv Dis 1999 to JNCI 2008
3
Treatment of advanced HCC
Phase II/III studies with systemic treatments
Treatments Studies
N Objective response
Systemic chemotherapy Doxorubicin as single
agent Phase II/III gt1000 10-18 Doxorubicin
combination (PIAF) Phase II/III 144 26 Cisplatin
Phase II 48 10 Epirubicin Phase II
62 11 Mitoxantrone Phase II 118 16
5-FU,Paclitaxel, iridotecan, gemcitabine Phase
II/III .... lt10 Anti-androgen Phase
III 376 lt10 Interferon Phase
III 60 lt10 Tamoxifen Phase III gt1000 lt
5 Octreotide Phase III 60 lt5 Seocalcitol
Phase III 746 lt5
4
The hepatocarcinogenic process
Signalling pathways molecular targets for new
therapies.
Wnt pathway
EGFR pathway
Raf/MAPK pathway
Akt pathway
Jat/Stat pathway
Hanahan. Cell 2000.
5
Molecular targeted therapies in HCC
Growth factors receptor pathway
GROWTH FACTORS (EGF, VEGF, PDGF)
Targets and agents EGFR
TKI Erlotinib, Lapatinib
Gefitinib Ab Cetuximab VEGF
TKI Sorafenib Ab
Bevacizumab RAF
TKI Sorafenib mTOR
Rapamycin Proteasome inhibitors

Bortezomib
IGF-1 / IGF-2
Erlotinib
Bevacizumab
IGFBP3
Cetuximab
EGFR VEGFR PDGFR
IGFR-I
Sorafenib
PIP2
p85
PTEN
p110
PI3K
RAS
PIP3
Akt
Sorafenib
RAF
CELL SURVIVAL CELL CYCLE
TSC
MEK
Rapamycin
mTOR
ERK
p70S6
4E-BP1
TRANSLATION (Cap-Dependent)
Translation (5 TOP)
PROLIFERATION
6
Targeted agents in development for HCC overview
Agent Anti-angiogenic targets Anti-angiogenic targets Anti-angiogenic targets Antiproliferative targets Antiproliferative targets Antiproliferative targets Developmental status
Agent VEGF VEGFR PDGFR EGFR Raf mTOR Developmental status
Bevacizumab ? Phase II ongoing
Brivanib ? Phase II recruiting
Cediranib ? Phase II recruiting
Erlotinib ? Phase II complete
Gefitinib ? Phase II complete
Cetuximab ?
Lapatinib ? Phase II ongoing
RAD001 ? Phase I/II recruiting
Sorafenib ? ? ? Phase III complete
Sunitinib ? ? Phase II ongoing
Thalidomide ? Phase III recruiting
TSU-68 ? ? Phase I/II recruiting
Phase II complete
Sources Trial Trove, ClinicalTrials.gov (NCI),
Evaluate Pharma, IMS Knowledge Link, Espicom,
IDdB3, BioPharm Insight, MedTrack
Sorafenib and sunitinib also have
antiproliferative effects through multi-tyrosine
kinase inhibition
7
Molecular targeted therapies for EGFR pathway
Erlotinib Phase II studies in HCC
Erlotinib (n38)

• Characteristics of patients
• Child A/B 27/11
• PST 0/1-2 10/28
• EGFR-1 in 88
• Treatment 150 mg/d
• Outcomes
• Response rate
• 3 PR, 50 SD (3.8 mo)
• Toxicity (G3-4) 8 pts.
• Median TTP 3.2 mo
• Median survival 13 mo

Philip et al. J Clin Oncol 2005
8
Erlotinib plus bevacizumab in patients with
unresectable advanced HCC

• Patients (n29) received bevacizumab 10mg/kg
  every 14 days plus erlotinib 150mg orally daily
• RR (RECIST) in 27
• - CR one patient (4)
• PR five patients (19)
• SD at 16 weeks nine patients (33)
• SD at 8 weeks five patients (19)
• Grade 34 toxicities transaminase elevation (1),
  hyperkalaemia (1), acne (1), diarrhoea (2),
  proteinuria (2), gastrointestinal bleeding (3),
  fatigue (4), and hypertension (5).
• Median Survival 19.5 months. (2009 MS 15months)

Thomas MB, et al. ASCO 2007, JCO 2009
9
Erlotinib plus bevacizumab in patients with
unresectable advanced HCC

• Patients (n29) received bevacizumab 10mg/kg
  every 14 days plus erlotinib 150mg orally daily
• RR (RECIST) in 27
• - CR one patient (4)
• PR five patients (19)
• SD at 16 weeks nine patients (33)
• SD at 8 weeks five patients (19)
• Grade 34 toxicities transaminase elevation (1),
  hyperkalaemia (1), acne (1), diarrhoea (2),
  proteinuria (2), gastrointestinal bleeding (3),
  fatigue (4), and hypertension (5).
• Median Survival 19.5 months. (2009 MS 15months)

Thomas MB, et al. ASCO 2007, JCO 2009
10
Molecular targeted therapies for VEGF
Bevacizumab (5-10 mg/Kg /2 weeks) in HCC
Phase II (n46)
Characteristics of patients Age
21-81 Gender (M/F) 38/8 Child-Pugh
(A/B) 34/12 CLIP (0-4)
2/19/15/8/1 ECOG (0/1/2)
19/23/2 Tumor stage ? Adverse events
(grade 3-4) Transient ischemic accident
1 Arterial hypertension 7 Hepatic
arterial thrombosis 1 Hemoperitoneum
1 Gastrointestinal bleeding 5 (1
death) Clinical Outcomes Response rate 1CR,
5 PR Median PFS 6.9 months Median survival
12.4 months
Baseline
16 weeks after
ASCO 2005, JCO 2008
11
Molecular targeted therapies for VEGF
Bevacizumab (5-10 mg/Kg /2 weeks) in HCC
Phase II (n46)
Characteristics of patients Age
21-81 Gender (M/F) 38/8 Child-Pugh
(A/B) 34/12 CLIP (0-4)
2/19/15/8/1 ECOG (0/1/2)
19/23/2 Tumor stage ? Adverse events
(grade 3-4) Transient ischemic accident
1 Arterial hypertension 7 Hepatic
arterial thrombosis 1 Hemoperitoneum
1 Gastrointestinal bleeding 5 (1
death) Clinical Outcomes Response rate 1CR,
5 PR Median PFS 6.9 months Median survival
12.4 months
Baseline
16 weeks after
ASCO 2005, JCO 2008
12
Sunitinib in patients with unresectable HCC

• Patients (n37) received sunitinib 50mg daily for
  4 weeks of every 6-week treatment cycle.
• Major (50) tumour necrosis was noted in 46 of
  patients
• Response (RECIST)
• partial response (PR) one patient (3)
• stable disease (SD) gt3 months 13 patients (35)
• SD gt6 months eight patients (22)
• Grade 34 toxicities included thrombocytopenia
  (43), neutropenia (24), CNS symptoms (24),
  asthenia (22) and haemorrhage (14)
• four patients experienced grade 5 toxicity
  (bleeding, drowsiness, hepatic encephalopathy and
  renal failure)

RECIST Response Evaluation Criteria In Solid
Tumors CNS central nervous system
Faivre SJ, et al. ASCO 2007, Chicago, IL, USA
13
Molecular targeted therapies anti-VEGF

• Rationale
• VEGF overexpression in HCC
• VEGF known mitogen for hepatocytes
• VEGFR expression variable

Poon R, Br J Surg, 2004
14
Treatment of advanced HCC
Phase II sorafenib as a primary treatment of
HCC (n137)

• Characteristics of the study
• Sorafenib 400mg bid in 28-day cycles in 137
  patients with advanced HCC.
• Characteristics 48 HCV, TNM Stage III/IV
  (31/66), Child A72
• Response WHO PR 3 (2.2), MR 8 (5.8),
  stable disease gt4m 33.6

Overall survival 9.2 mo
Time-to-progression (TTP) 5.5 mo
Abou-Alfa G et al, JCO 2006
15
Sorafenib improves survival in hepatocellular
carcinomaPhase III randomized,
placebo-controlled trial (SHARP)
PIs JM Llovet and J Bruix, S Ricci, V
Mazzaferro, P Hilgard, J-L Raoul, S Zeuzem, A
Santoro, MS Shan, M Moscovici, Dimitris Voliotis,
A Forner, M Schwartz for the SHARP Investigators
Study Group
Child-Pugh A to avoid liver deaths of
Child-Pugh B patients obscuring outcome
to capture the impact on HCC
progression (competing risk)

• Stratification
• Macroscopic vascular
• invasion (portal vein)
• and/or extrahepatic spread
• ECOG PS
• Geographical region

Sorafenib (n299) 400mg po bid continuous dosing
Placebo (n303) 2 tablets po bid continuous
dosing
Llovet et al, NEJM 2008
16
Phase III SHARP trial
Overall survival (intention-to-treat)
SorafenibMedian 10.7 mo (95 CI 9.4, 13.3)
PlaceboMedian 7.9 mo(95 CI 6.8, 9.1)
Survival probability
Hazard ratio (S/P) 0.69 (95 CI 0.55, 0.87).
Plt0.001
Weeks
0
80
8
16
24
32
40
48
56
64
72
OBrien-Fleming threshold for statistical
significance was P0.0077.
Llovet et al, NEJM 2008
17
Phase III SHARP trial
Time to progression (independent central review)
SorafenibMedian 5.5 mo(95 CI 4.1, 6.9)
Probability of progression
PlaceboMedian 2.8 mo(95 CI2.7, 3.9)
Weeks
Patients at risk Sorafenib
299
Placebo
303
Llovet et al, NEJM 2008
18
Phase III SHARP trial
Exploratory subgroup survival analysis
Sorafenib benefit
Placebo benefit
ECOG PS 0
ECOG PS 1 2
No extrahepatic spread
Extrahepatic spread
No macroscopic vascular invasion
Macroscopic vascular invasion
No macroscopic VI/extrahepatic spread
Macroscopic VI and/or extrahepatic spread
Hazard Ratio (95CI)
Llovet et al, NEJM 2008
19
Usual comments about SHARP

• SHARP is just informative for HCV European HCC
• There is no attempt for biomarker assessment
• 3 months survival improvement is marginal
• Unknown efficacy in Child-Pugh B

20
Asian-Pacific sorafenib study

• Eligibility
• Advanced HCC
• ECOG 0-2
• Child-Pugh A
• No prior systemic therapy
• Stratification
• Macroscopic vascular invasion (portal vein)
  and/or extrahepatic spread
• ECOG PS
• Geographic area

R A N D O M I Z E
n150
Sorafenib 400 mg bid
n76
Placebo
21

• End points
• Overall survival, time to symptomatic progression
  (FSHI8-TSP),time to progression, response
  (RECIST), and safety
• No primary end point defined

Cheng, et al. ASCO 2008
21
Overall survival
Asian-Pacific sorafenib study
1.00
SorafenibMedian 6.5 months (95 CI 5.6, 7.6)
0.75
PlaceboMedian 4.2 months (95 CI 3.7, 5.5)
Survival probability
0.50
0.25
HR (S/P) 0.68 95 CI 0.50, 0.93 P0.014
0
2
4
8
10
12
14
16
20
22
6
18
0
Months
Patients at Risk
150
134
103
78
53
32
21
15
13
4
1
0
Sorafenib
76
62
41
26
23
15
9
5
4
1
0
0
Placebo
Cheng, et al. ASCO 2008
22
Time to progression
Asian-Pacific sorafenib study
1.00
SorafenibMedian 2.8 months(95 CI 2.6, 3.6)
0.75
PlaceboMedian 1.4 months (95 CI 1.3, 1.5)
Progression-free probability
0.50
HR (S/P) 0.57 95 CI 0.42, 0.79Plt0.001
0.25
0
2
4
8
10
12
14
16
20
22
6
18
0
Months
Patients at risk
Sorafenib
150
80
38
19
11
8
5
2
1
0
0
0
76
19
10
8
3
0
0
0
0
0
0
0
Placebo
Adapted from Cheng, et al. ASCO 2008
23
BCLC Staging and Treatment Strategy
HCC
Stage D
Stage A - C
Stage 0
PST gt2, Child-Pugh C
PST 0-2, Child-Pugh A-B
PST 0, Child-Pugh A
Very early stage (0) Singlelt 2cm.
Terminal stage (D)
Early stage ( A) Single or 3 nodules lt 3cm, PS 0
Intermediate stage ( B) Multinodular, PS 0
Advanced stage (C) Portal invasion, N1,M1, PS
1-2
Single
3 nodules lt3cm
Portal pressure/ bilirubin
Portal invasion, N1,M1
Associated diseases
Increased
No
Yes
No
Yes
Liver Transplantation (CLT / LDLT)
PEI/RF
Chemoembolization
Resection
Sorafenib
Sharp
10.7 months
6.5 months
Asia
24
Usual comments about SHARP

• SHARP is just informative for HCV European HCC
• There is no attempt for biomarker assessment
• 3 months survival improvement is marginal
• Unknown efficacy in Child-Pugh B

25
Predictors of Survival
All patients (univariate analysis)
c-Kit
VEGF
HGF
Low HGF Median OS 10.8 months (n366)
Low c-Kit Median OS 8.8 months (n245)
Low VEGF Median OS 10.6 months (n368)
High HGF Median OS 6.0 months (n122)
High c-Kit Median OS 10.4 months (n244)
High VEGF Median OS 6.2 months (n122)
HR 0.775 (95 CI 0.620,0.970) P0.026
HR 1.780 (95 CI 1.390,2.280) Plt0.001
HR 1.530 (95 CI 1.191,1.965) Plt0.001
4
6
8
10
12
14
16
18
20
22
4
6
8
10
12
14
16
18
20
22
4
6
8
10
12
14
16
18
20
22
Time (Months)
Time (Months)
Time (Months)

• High c-KIT levels and low HGF and VEGF levels
  correlated with longer OS in the univariate
  analysis.

Llovet et al AASLD 2008
26
Baseline plasma c-KIT and Sorafenib
Prediction of survival

• Patients with high c-KIT showed a trend of better
  survival benefit from sorafenib (interaction
  P-value0.081).

Llovet et al AASLD 2008
27
Baseline plasma c-KIT and Sorafenib
Prediction of time to progression
Patients with Low Baseline c-KIT
1.00
HR 0.80 (95 CI 0.55, 1.17) (n245)
Progression Probability
0.75
0.50
Sorafenib Median TTP 4.1 mo Placebo Median TTP
3.9 mo
0.25
0.00
0 2 4 6 8 10 12
Time (Months)

• Patients with high c-KIT showed a better time to
  progression with sorafenib (interaction
  P-value0.05).

Llovet et al AASLD 2008
28
Baseline plasma HGF and Sorafenib Effect
Patients with Low Baseline HGF
Patients with High Baseline HGF
1.00
1.00
0.75
0.75
Survival Probability
Survival Probability
0.50
0.50
0.25
0.25
HR 1.10 (95 CI 0.72, 1.67) (n122)
HR 0.69 (95 CI 0.53, 0.90) (n366)
0
0
Time (Months)
Time (Months)

• Patients with low HGF showed a trend of better
  survival benefit from sorafenib (interaction
  P-value0.073), but not with TTP (p0.3)

Llovet et al AASLD 2008
29
Usual comments about SHARP

• SHARP is just informative for HCV European HCC
• There is no attempt for biomarker assessment
• 3 months survival improvement is marginal
• Unknown efficacy in Child-Pugh B

30
Impact of molecular agents in cancer outcomes
Endpoint, absolute gain HR (95 CI)
Hepatocellular carcinoma (advanced) Survival
(3 m) Sorafenib (n299) vs placebo
(n303)1 0.69 (0.550.87) Colorectal
(metastatic) Survival (4.7 m) IFL
bevacizumab (n402) vs IFL (n411) 2 0.66
(NA) Cetuximab (n287) vs BSCare (n285)
3 Survival (1.5 m) 0.77
(0.640.92) Lung cancer Paclitax. carbo vs
bevacizumab (n434 vs n444) 4 Survival (2
m) 0.79 (0.690.93) Erlotinib (n488)
vs placebo (n243) 5 Survival (2
m) 0.79 (0.580.85) Breast cancer
(Advanced (HER2) Chemotherapy vs
trastuzumab (n235 vs n234) 6 TTP 0.51
(0.390.59) Paclitaxel vs bevacizumab
(n347 vs n326) 7 PFS 0.60 (0.510.70)
1. Llovet et al NEJM 2008, 2. Hurwitz et al NEJM
2004, 3. Jonkers et al NEJM 2007, 4. Sandler
et al NEJM 2006, 5. Shepherd et al NEJM 2005,
6. Slamon et al NEJM 200 7. Miller et al. NEJM
2007
Llovet and Bruix, Hepatology 2008
31
Usual comments about SHARP

• SHARP is just informative for HCV European HCC
• There is no attempt for biomarker assessment
• 3 months survival improvement is marginal
• Unknown efficacy in Child-Pugh B

32
Sorafenib in HCC. Phase I PK Non-HCC vs HCC,
Non-Japanese vs Japanese and CPA vs CPB
Non-Japanese with advanced solid tumors
Japanese with advanced solid tumors
Non-Japanese with HCC (CPA)
Japanese with HCC (CPA)
Non-Japanese with HCC (CPB)
Japanese with HCC (CPB)
Advanced Solid Tumor Patients
HCC Patients (CPA)
HCC Patients (CPB)

• PK equivalent irrespective of ethnicity or
  Child-Pugh status

ss steady state

• Data on file. Bayer HealthCare

33
Sorafenib for HCC and Child-Pugh B patients

• Child-Pugh B includes a wide range of profile and
  outcome
• Impact on tumor biology is not modulated by liver
  function
• PK, Safety and AEs in Child-Pugh B are the same
• Child-Pugh B 7 can be safely treated.
• RCT vs placebo unlikely

34
BCLC Staging and Treatment Strategy
HCC
Stage D
Stage A - C
Stage 0
PST gt2, Child-Pugh C
PST 0-2, Child-Pugh A-B
PST 0, Child-Pugh A
Very early stage (0) Singlelt 2cm.
Terminal stage (D)
Early stage ( A) Single or 3 nodules lt 3cm, PS 0
Intermediate stage ( B) Multinodular, PS 0
Advanced stage (C) Portal invasion, N1,M1, PS
1-2
Single
3 nodules lt3cm
Portal pressure/ bilirubin
Portal invasion, N1,M1
Associated diseases
Increased
No
Yes
No
Yes
Liver Transplantation (CLT / LDLT)
PEI/RF
Chemoembolization
Resection
Sorafenib
Sympt. Treat. (20)
Curative Treatments (30) 50 - 75 at 5
years
Non-curative treatments (50) 3 year survival
10-40
Sem Liv Dis 1999 to JNCI 2008
35
Future prospects for Sorafenib
36
Impact of sorafenib results

• Effective first-line option for advanced HCC
  available
• should be standard first line therapy
• Proves the hope of molecular targeted therapy in
  HCC
• new agents to be investigated in second
  line/failures
• Opens the path to multipathway blockade
• Evaluation in the adjuvant setting (surgery,
  ablation, TACE)

37
Critical issues in combination therapy

• Selection of best partner for sorafenib
• Optimal dosage for efficacy and safety
• Underlying cirrhosis variceal bleeding,
  renal failure, ascites, encephaloptahy, HBV/HCV
  flares
• How to define efficacy RR by RECIST (No
  meaning), TTP?
• Transition from phase 1 into phase 2. RCT phase
  2.
• Target population

Llovet et al, JNCI 2008
38
Impact of sorafenib results

• Effective first-line option for advanced HCC
  available
• Proves the hope of molecular targeted therapy in
  HCC
• Opens the path to multipathway blockade
• Evaluation in the adjuvant setting (surgery,
  ablation, TACE)

39
Design double-blind RCT
RFS TTR OSBiomarkers
Sorafenib 400mg bid
8 weeks randomise Stratify- prior curative
tx- geographical region - CP status
Resection RFA PEI
11
Placebo

• Significant OS benefit in phase III gives
  rationale to go into adjuvant setting
• Prospective, randomized, double-blind,
  placebo-controlled, company sponsored phase III
  study
• Primary endpoint recurrence-free survival
• Patients n1100 (randomised)
• Global trial, significant number of patients from
  China
• FPFV August 2008

Clinicaltrials.gov
40
TACE for HCC Sorafenib as coadjuvant
Trial in the pipeline SPACE (2009) Target
population Child-Pugh A Technique DCBeads
End-point TTP, Survival
41
BCLC Staging and Treatment Strategy
HCC
Stage D
Stage A - C
Stage 0
PST gt2, Child-Pugh C
PST 0-2, Child-Pugh A-B
PST 0, Child-Pugh A
Very early stage (0) Singlelt 2cm.
Terminal stage (D)
Early stage ( A) Single or 3 nodules lt 3cm, PS 0
Intermediate stage ( B) Multinodular, PS 0
Advanced stage (C) Portal invasion, N1,M1, PS
1-2
Single
3 nodules lt3cm
Portal pressure/ bilirubin
Portal invasion, N1,M1
Associated diseases
Increased
No
Yes
No
Yes
Liver Transplantation (CLT / LDLT)
PEI/RF
Chemoembolization
Resection
Sorafenib
Combination trial
SPACE Adjuvant trial
STORM Adjuvant trial
42
Barcelona-Clínic Liver Cancer (BCLC) Group
Liver Unit J. Bruix, JM. Llovet, A. Forner,
M. Reig,, C Rodriguez Radiology C. Brú, R.
Vilana, Ll. Bianchi, C. Ayuso, J. Rimola,, X.
Montañá, I. Real, M. Burrel Surgery J.
Fuster Pathology M. Solé Oncology
J. Maurel Nurse A. Godoy
Laboratory L. Boix A. Villanueva V. Tovar
C. Alsinet L. Cabellos JM. Lopez J.
Peix H. Cornellà
Ad .support N. Perez D. Segarra
Oct. 2008