Prof Dr Markus Peck-Radosavljevic

1
Sorafenib for Advanced HCC Current Status and
Future Prospects

• Prof Dr Markus Peck-Radosavljevic
• Allgemeines Krankenhaus Medizinische
  Universität Wien
• Vienna, Austria

2
Liver Cancer IncidenceSixth Most Common Cancer
Worldwide1
Lung
1,549,121
Breast
1,301,867
Colon/Rectal
1,167,020
Stomach
1,066,543
Prostate
782,647
Liver
711,128
Cervix Uteri
559,094
Esophagus
529,283
330,963
Leukemia
Bladder
314,256
Ovary
230,555
226,787
Corpus Uteri
Oral Cavity
200,774
Non-Hodgkin's Lymphoma
196,298
0
200,000
400,000
600,000
800,000
1,000,000
1,200,000
1,400,000
1,600,000
1,800,000

• HCC is the most common primary liver malignancy
  in adults2

1. Garcia M, et al. American Cancer Society,
2007. www.cancer.org. Accessed March 20, 2008.
2. Perz JF, et al. J Hepatol. 200645529-538.
3
BCLC Staging System
HCC
End Stage
Advanced Stage
Intermediate Stage
Early Stage
Surgical Treatment Local Ablation
Sorafenib
TACE
(30) Potentially Curative Treatments 5-y
Survival 40-70
(50-60) Randomized Trials Median Survival If
Untreated 6-16 mo
(10) BSC Survival lt3 mo
TACE transarterial chemoembolization BSC
best supportive care. Llovet JM, et al. J Natl
Cancer Inst. 2008100698-711.
4
Targeted agents in development for HCC
Agent Phase ofdevelopment Anti-angiogenic targets Anti-angiogenic targets Anti-angiogenic targets Anti-proliferative targets Anti-proliferative targets Anti-proliferative targets
Agent Phase ofdevelopment VEGF VEGFR PDGFR EGFR Raf mTOR
Sorafenib III complete
Thalidomide III recruiting
Cetuximab II complete
Erlotinib II complete
Gefitinib II complete
Bevacizumab II ongoing
Sunitinib II ongoing
Brivanib II recruiting
Cediranib II recruiting
Lapatinib II ongoing
RAD001 I/II recruiting
TSU-68 I/II recruiting
Status as of September 2008
http//clinicaltrials.gov/. Accessed September,
2008 Llovet JM, Bruix J. J Hepatol
200848S20S37.
5
Sorafenib Targets Tumor Cell Proliferation and
Angiogenesis
Endothelial Cell or Pericyte
Tumor Cell
Paracrine stimulation
HGF
PDGF-b
VEGF
Autocrineloop
VEGFR-2
PDGFR-b
Apoptosis
RAS
RAF
Mcl-1
RAF
Sorafenib
Mitochondria
Sorafenib
MEK
Angiogenesis
Mitochondria
Differentiation
HIF
ERK
HGF
Proliferation
Apoptosis
PDGF
Migration
VEGF
Tubule formation
Nucleus
Nucleus
Proliferation
Survival
HGF hepatocyte growth factor. Avila MA, et al.
Oncogene. 2006253866-3884 Liu L, et al. Cancer
Res. 20066611851-11858 Semela D, et al. J
Hepatol. 200441864-880 Wilhelm SM, et al.
Cancer Res. 2004647099-7109.
6
Phase III SHARP and Asia-Pacific studies
SHARP1
Asia-Pacific2

• Eligibility
• Advanced HCC, ECOG PS 02, Child-Pugh A, no prior
  systemic therapy
• Stratification
• MVS and/or EHS, ECOG PS (0 vs. 12), geographic
  region

RANDOMIZE11
RANDOMIZE21
n299
n303
n150
n76
Sorafenib 400 mg bid
Placebo
Sorafenib 400 mg bid
Placebo
1º endpoints OS, TTSP 2º endpoints TTP, DCR,
safety
Endpoints OS, TTSP, TTP, DCR, safety (no 1º
endpoint defined)
1Llovet JM, et al. N Engl J Med
2008359378390 2Cheng A, et al. Lancet
Oncol. 2009 10 25-34.
7
SHARP Sorafenib increases overall survival
compared with placebo
1.00
Sorafenib (n299) Median OS 10.7 mo.(95 CI
9.413.3)
0.75
Placebo (n303) Median OS 7.9 mo.(95 CI
6.89.1)
Survival probability
0.50
HR 0.69(95 CI 0.550.87)plt0.001
0.25
OBrien-Fleming threshold for statistical
significance was p0.0077
0.00
0
4
6
8
10
12
14
16
2
1
3
5
7
9
11
13
15
17
Months
Patients at risk
290
270
249
234
213
200
172
140
111
89
68
48
37
24
7
1
0
Sorafenib
299
295
272
243
217
189
174
143
108
83
69
47
31
23
14
6
3
0
Placebo
303
OS overall survival HR hazard ratio.
Llovet JM, et al. N Engl J Med 2008359378390.
8
SHARP sorafenib delays progression compared with
placebo
1.00
HR 0.5895 CI 0.450.74plt0.001
0.75
Probability of progression
0.50
Sorafenib (n299) Median TTP 5.5 mo.(95 CI
4.16.9)
0.25
Placebo (n303) Median TTP 2.8 mo.(95 CI
2.73.9)
0.00
0
4
6
8
10
2
1
3
5
7
9
11
12
Months
Patients at risk
299
0
2
4
10
18
23
37
65
91
101
155
267
Sorafenib
303
0
1
1
3
10
11
21
41
62
78
142
275
Placebo
TTP time to tumor progression HR hazard
ratio.
Llovet JM, et al. N Engl J Med 2008359378390.
9
SHARP low incidence of grade 34 events
Sorafenib (n299) Sorafenib (n299) Placebo(n302) Placebo(n302)
Treatment-emergent SAEs, 52 52 54 54
Drug-related SAEs, 13 13 9 9
Grade Grade Grade Grade
Drug-related AEs, Any 3 / 4 Any 3 / 4
Diarrhea 39 8 / 0 11 2 / 0
HFSR 21 8 / 0 3 lt1 / 0
Anorexia 14 lt1 / 0 3 1 / 0
Alopecia 14 0 / 0 2 0 / 0
Nausea 11 lt1 / 0 8 1 / 0
Weight loss 9 2 / 0 1 0 / 0
Pain (abdomen) 8 2 / 0 3 1 / 0
Bleeding 7 1 / 0 4 1 / lt1
Vomiting 5 1 / 0 3 1 / 0
Liver dysfunction lt1 lt1 / 0 0 0 / 0
AEs adverse events SAEs serious adverse
events HFSR hand-foot skin reaction.
Llovet JM, et al. N Engl J Med 2008359378390.
10
Phase III Asia-Pacific studyoverall survival
1.00
Sorafenib (n150) Median OS 6.5 mo.95 CI
5.67.6
HR 0.68(95 CI 0.500.93)p0.014
0.75
Placebo (n76) Median OS 4.2 mo.95 CI 3.75.5
Survival probability
0.50
0.25
0.00
0
4
8
12
22
2
6
10
14
16
18
20
Months
Patients at risk
134
103
78
53
Sorafenib
150
32
21
15
13
4
1
0
62
41
26
23
Placebo
76
15
9
5
4
1
0
0
Cheng A, et al. Lancet Oncol. 2009 10 25-34.
11
Asia-Pacific PIII Study Time to Progression
1.00
Sorafenib Median 2.8 mo (95 CI 2.6-3.6)
0.75
Placebo Median 1.4 mo (95 CI 1.3-1.5)
0.50
Progression-free probability
HR (S/P) 0.57 (95 CI 0.42-0.79)Plt0.001
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
Placebo
76
19
10
8
3
0
0
0
0
1
0
0
Cheng A, et al. Lancet Oncol. 2009 10 25-34.
12
Asia-Pacific Trial1 vs SHARP2Baseline Patient
Characteristics
Asia-Pacific(N226) SHARP1(N602)
Median age (range), years 51 (23-86) 67 (21-89)
Sex (male), 85 87
ECOG PS (0/1/2), 26/69/5 54/38/8
MVI, 35 38
EHS, 69 51
BCLC stage (B/C), 4/96 17/82
Hepatitis virus status (HBV/HCV), 73/8 18/28
No. of tumor sites,
1 11 44
2 35 31
3 20 12
4 35 13
Sites of disease,
Lung 50 21
Lymph node 32 26
1. Cheng A, et al. Lancet Oncol 2009 10
25-34. 2. Llovet JM, et al. N Engl J Med. 2008
Jul 24359(4)378-90.
13
SHARP and Asia Pacific Phase III Summary

• OS, TTP, and PFS hazard ratios were similar in
  the SHARP and the Asia-Pacific studies, despite
  more advanced disease in the Asia-Pacific liver
  cancer study patients
• Sorafenib is safe and efficacious in
  patientswith HCC across geographic regions and
  across different etiologies

14
Nexavar in Patients with HCC and ChildPugh B
Liver Dysfunction
15
Efficacy of Sorafenib in HCCPinter,
Peck-Radosavljevic, et al., The Oncologist, in
press


plt0.0001 log rank
16
Phase II Trial Maximum Percentage Change in
Tumor Size From Baseline
200
50
46
100
Reduction from baseline ()
0
CP A (n98)
CP B (n38)
-100
CP Child-Pugh CP A CP Class A CP B CP
Class B. Reported for each patient. Data on
file, Bayer HealthCare.
17
Nexavar in Combination With Doxorubicin in HCC
18
Phase II Trial of Doxorubicin Sorafenib in HCC
Study Design
Period 2
Period 1

• Eligibility
• Advanced HCC
• ECOG PS 0-2
• CP A
• No prior systemic therapy
• No prior chemoembolization
• No history of organ allograft

R A N D O M I Z E
Doxorubicin60 mg/m2 sorafenib400 mg bid q3w
Sorafenib400 mg bid
n47
Doxorubicin60 mg/m2 placebo q3w
Placebo
n49
11

• Primary objective
• TTP (independent assessment)
• Secondary objectives
• ORR, PFS, OS, safety

Sorafenib or placebo continued until withdrawal,
PD, or death in Period 2. q3w once every 3
weeks. Abou-Alfa GK, et al. Eur J Cancer Suppl.
20075(4)259. Updated from Abstract 128. Poster
and oral presentation at ASCO-GI Orlando, FL
January 2008.
19
Phase II Trial of Doxorubicin Sorafenib in HCC
Baseline Patient Characteristics
Patients () Patients ()
Doxorubicin Sorafenib (n47) Doxorubicin Placebo(n49)
Male 66 86
Mean age, years 63 62
ECOG PS
0 47 33
1 38 51
2/3 9 8
Missing 9 8
CP class
A 100 96
B 0 4
Extrahepatic disease 51 65
MVI 28 33
Data for macroscopic vascular invasion not
available for 1 patient (2) in each
group. Abou-Alfa GK, et al. Eur J Cancer Suppl.
20075(4)259. Updated from abstract 128. Poster
and oral presentation at ASCO-GI Orlando, FL
January 2008.
20
Phase II Trial of Doxorubicin Sorafenibin HCC
OS
Doxorubicin sorafenibMedian 13.7 months(95
CI 10.4-N/E)
Doxorubicin placeboMedian 6.5 months(95 CI
4.9-9.5)
Censored treatment
Probability of Survival
HR0.45 P0.0049
0
20.0
5.0
7.5
10.0
12.5
15.0
17.5
2.5
Months
Abou-Alfa GK, et al. Eur J Cancer Suppl.
20075(4)259. Updated from abstract 128. Poster
and oral presentation at ASCO-GI Orlando, FL
January 2008.
21
Phase II Trial of Doxorubicin Sorafenib in HCC
AEs With 10 Grade 3/4 Incidence
All-Cause AEs Patients () Patients () Patients () Patients () Patients ()
All-Cause AEs Doxorubicin Sorafenib(n47) Doxorubicin Sorafenib(n47) Doxorubicin Placebo(n49) Doxorubicin Placebo(n49)
All-Cause AEs Any Grade Grades 3/4 Any Grade Grades 3/4
Fatigue 75 15 65 15
Neutropenia 66 55 60 46
Diarrhea 51 11 25 10
Elevated bilirubin 34 11 31 6
Abdominal pain 34 10 29 8
HFSR 30 9 4 0
Left ventricular dysfunction 19 2 2 0
Hypertension 17 0 0 0
Febrile neutropenia 4 4 15 15
Abou-Alfa GK, et al. Eur J Cancer Suppl.
20075(4)259. Updated from abstract 128. Poster
and oral presentation at ASCO-GI Orlando, FL
January 2008.
22
Sorafenib Future Directions
23
Sorafenib in the Management of Patients With HCC
Ph III Adjuvant
Adjuvant
Ph II Post-TACE
Ph II TACE
Intermediate
Ph III SHARP
Ph III Asia-Pacific
Ph II Doxorubicincombination
Advanced/ metastatic
Ph II and Ph III Targeted agentcombinations
Bayer HealthCare, data on file.
24
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 57
• Intermediate/high risk of recurrence

• Randomization
• n1,100
• Stratification
• Prior curative treatment
• Geographical region

• Endpoints
• RFS
• OS
• Biomarkers
• Other

Sorafenib400 mg bid
Placebo
RFA radiofrequency ablation PEI
percutaneous ethanol injection RFS
recurrence-free survival.
25
Sorafenib in patients with advanced HCC after
TACE

• Phase III, randomized, double-blind,
  placebo-controlled study of sorafenib as
  treatment of HCC after TACE
• Japan

• Prior treatment
• TACE
• Eligibility criteria
• Age gt18
• Advanced HCC
• Exclusion criteria
• Prior systemic chemotherapy
• Vital organ failure

Sorafenib400 mg bid

• Endpoints
• Primary
• TTP
• Secondary
• OS

• Randomization
• n390

Placebo
TACE transarterial chemoembolization TTP
time to progression OS overall survival.
http//clinicaltrials.gov/. Accessed September,
2008.
26
Sorafenib in patients with advanced HCC
undergoing TACE - SPACE

• Phase II, randomized, double-blind,
  placebo-controlled study of sorafenib as
  treatment of HCC starting before TACE
• International, 90 centers
• Scheduled TACE (cycles) 1, 3, 7, 13, q6cycles
  there after
• Optional TACE (cycles) 10, 15

TACE transarterial chemoembolization TTP
time to progression OS overall survival.
27
Investigator-sponsored studies of sorafenib in
HCC
Advanced stage
Early stage
Surgery/ablation
Transplant
TACE/TAE
HAI
Systemic agents
Radio- therapy
BSC
Sorafenib
Other agents
After surgery/ablation
After transplant
With TACE/TAE
With HAI

• Dose escalation
• Sub-population
• - CP-B
• Long-term use
• Others

2ndline
Targeted agent

• Cyto-toxic
• Other

1
9
2
4
4
8

1
6
1
1
2
3
Status as of July 2008
28
BCLC-Classifikation AlgorithmLlovet et al., J
Natl Cancer Inst 2008 100 698
29
(No Transcript)
30
SHARP comparable patient characteristics in
sorafenib and placebo groups
Sorafenib(n299) Placebo(n303)
Median age, years 65 66
Male, 87 87
Etiology,
HBV 19 18
HCV 29 27
Alcohol 26 26
Other 26 28
Prior therapies,
Surgical resection 19 20
Loco-regional therapies 48 45
HBV hepatitis B virus HCV hepatitis C virus.
Llovet JM, et al. N Engl J Med 2008359378390.
31
SHARP stratification by region and disease
status
Sorafenib(n299) Placebo(n303)
Region,
Europe 88 87
North America 9 10
Other 3 4
ECOG PS,
0 54 54
1 38 39
2 8 7
Vascular invasion/extrahepatic spread, Vascular invasion/extrahepatic spread, Vascular invasion/extrahepatic spread,
Present 70 70
Absent 30 30
HBV hepatitis B virus HCV hepatitis C virus.
Llovet JM, et al. N Engl J Med 2008359378390.
32
SHARP response assessment
Sorafenib (n299) Placebo(n303)
Overall response
CR, n 0 0
PR, n () 7 (2.3) 2 (0.7)
SD, n () 211 (71) 204 (67)
PD, n () 54 (18) 73 (24)
DCR, 43 32
Median duration of treatment, mo. 5.3 4.3
TTSP (as assessed by FHSI-8), mo. 4.1 4.9
Independent review by Response Evaluation
Criteria in Solid Tumors (RECIST). DCR
disease control rate (CRPRSD 28 days). CR
complete response PR partial response SD
stable disease PD progressive disease TTSP
time to symptomatic progression FHSI-8
Functional Assessment of Cancer
Therapy-Hepatobiliary Symptom Index-8.
Llovet JM, et al. N Engl J Med 2008359378390.
33
Asia-Pacific PIII Study Baseline Patient
Characteristics
Sorafenib(n150) Placebo(n76)
Median age (range), years 51 (23-86) 52 (25-79)
Male, 85 87
ECOG PS,
0 25 28
1 69 67
2 5 5
MVI,
No 64 66
Yes 36 34
EHS,
No 31 32
Yes 69 68
BCLC stage C, 95 96
BCLC Barcelona Clinic Liver Cancer. Cheng A, et
al. Lancet Oncol. 2009 10 25-34.
34
Asia-Pacific Study RECIST Response

Sorafenib(n150) Placebo(n76)
ORR (CRPR), 3 1
CR 0 0
PR 3 1
SD, 54 28
PD, 31 54
DCR, 35 16
DCR CR PR maintained for ?4 weeks SD
documented at least 12 weeks from baseline. Cheng
A, et al. J Clin Oncol. 200826. Abstract 4509.
Updated from oral presentation at ASCO Chicago,
IL June 2008.
35
Phase II Trial of Doxorubicin Sorafenibin HCC
TTP (Independent Assessment)
Doxorubicin sorafenibMedian 8.6 mo(95 CI
4.8-12.6)
Doxorubicin placeboMedian 4.8 mo (95 CI
2.2-8.0)
Censored treatment
Progression-free probability ()
HR0.60 P0.076
0
15.5
5.0
7.5
10.0
12.5
2.5
Months
Assessed by an independent review
committee. Abou-Alfa GK, et al. Eur J Cancer
Suppl. 20075(4)259. Updated from abstract 128.
Poster and oral presentation at ASCO-GI Orlando,
FL January 2008.