1. Intermediate stage HCC treatment options: TACE + sorafenib1 1

2. TACE: long-term survival outcomes are unsatisfactory
100 80 60 40 20
100 80 60 40 20
Chemoembolization
Control
Chemoembolization
Control
p <
p =
Probability of survival (%)
Probability of survival (%)
Time since randomization (months)
Time since randomization (months)
3-year overall survival (OS): 26%2–29%1 Sustained objective response rate (ORR) (3–6 months): 35%1–39%2 No difference in survival of intention-to-treat (ITT) population between non-responders and control group1
1. Llovet JM, et al. Lancet. 2002;359:
2. Lo C-M, et al. Hepatology. 2002;35:

3. Distance of tumour cell from blood vessels (μm)
Hypoxia in the post-TACE tumour micro-environment leads to angiogenesis
Tumour cells become more acidic and more hypoxic further they are from blood vessels O2
>100μm
7.4
7.2
7.0
6.8
6.6 14 12 10 8 6 4 2
Acidosis Oxygen
Acidosis (pH)
Hypoxia
Angiogenesis
Distance of tumour cell from blood vessels (μm)
HIF-1a
HIF-1b
HRE
Gene
Glycolysis
Survival/ apoptosis
VEGF Ang2, NOS
PDGF-β
HIF-1 responds to hypoxia in tumour
VEGF is a key mediator of tumour neovascularisation (growth and permeability)
HIF = hypoxia inducible factor; HRE = hypoxia response element Ang-2 = angiopoietin-2; NOS = nitric oxide synthase PDGF-β = platelet-derived growth factor-β
Carmeliet P, Jain RK. Nature 2000; 407: 249–57 3 3

4. VEGF levels in the liver significantly increase after TACE: clinical data
After TACE for HCC, VEGF levels in the tumour increase
Control
TACE
51.69 ± 18.17
58.57 ± 15.75
Microvessel density (not significant)
Microvessels visible in the pericapsular area
± 65.24
± 88.88
VEGF expression:
number of VEGF+ cells per 500 tumour cells (p<0.01)
VEGF+ cells indicated by brown staining
Wang B, et al. Acta Radiol 2008; 49: 523–9 4 4

5. Plasma VEGF levels significantly increase after TACE: clinical dataNS NS
p=0.018
103 84 76
Plasma VEGF (ng/L) 64
(n=45)
(n=30)
(n=44)
(n=18)
pre-TACE 1 3 7
Days post-TACE
NS = not significant
Li X, et al. W J Gastroenterol 2004; 10: 2878–82 5 5

6. Survival probability (%) Time since TACE (months)
High VEGF plasma levels significantly correlate with poor outcomes after TACE
130
120
110
100 90 80 70 60 50
100 75 50 25
Responders
Total
Non-responders
VEGF (pg/mL)
Survival probability (%)
VEGF levels below median
VEGF levels above median median = 43.65pg/dL
Pre-TACE 3 28
Days post-TACE
Time since TACE (months)
Plasma VEGF concentration increased following TACE
the increase is greatest in patients who did not respond to TACE
Patients with lower plasma VEGF levels had longer survival than those with higher levels (p=0.008)
Sergio A, et al. Am J Gastroenterol 2008; 103: 914–21 6 6

7. Vessel counts per surface area
Combining TAE with an anti-angiogenic agent improves outcomes: preclinical data
1,200
900
600
300 35 30 25 20 15 10 5 * *
Tumour volume (mm3)
Vessel counts per surface area
AAV-
angiostatin
TAE
TAE + AAV- angiostatin
AAV-
angiostatin
TAE
TAE + AAV- angiostatin
Combining embolisation and an anti-angiogenic agent significantly reduced tumour volume and tumour vessel density versus embolisation alone
*Significant difference from HCC tumours treated with TAE alone in a rat model (p<0.01); AAV = adeno-associated virus
Jiang H et al. Int J Cancer 2007; 121: 416–24 7 7

8. Transarterial chemoembolisation leads to central necrosis with a rim of peripheral hypoxia
(A) The surviving tissue exposed to hypoxia releases growth factors such as VEGF which stimulate the growth of the residual tumor lesions. (B) When TACE is performed in combination with a systemic targeted therapy, the growth factor response is blunted preventing the growth of the residual lesions.
Dufour J-F and Jonson P. J Hepatology 2009

9. The rationale for combining TACE with sorafenib
Rationale for adjuvant or combination use of sorafenib to prevent recurrence after TACE
Angiogenesis may play an important role in tumour progression after TACE:
Temporary increases in plasma VEGF levels observed after TACE in patients with HCC1
Liver VEGF levels increase after TACE2
VEGF production correlates with both tumour response and survival after TACE3
Anti-angiogenic activity of sorafenib4 may delay tumour progression after TACE
TACE, transarterial chemoembolization; VEGF, vascular endothelial growth factor . 1. Li X, et al. W J Gastroenterol 2004;10:2878– Wang B, et al. Acta Radiologica 2008;49:523–9. 3. Sergio A, et al. Am J Gastroenterol 2008;103:914– Wilhelm SM, et al. Mol Cancer Ther 2008; 7: 9

10. Rationale for combining TACE with antiangiogenic therapy for intermediate-stage HCC
Although TACE is effective for the treatment of intermediate-stage HCC, progression is frequent
Angiogenesis may play an important role in tumor survival after TACE1
VEGF reduction correlates with both tumor response and survival after TACE2
There is a rationale for investigating the concomitant use of TACE with antiangiogenic therapy
sorafenib has antiangiogenic and antiproliferative activity3
sorafenib improved overall survival in patients with advanced HCC and is the only agent approved for the treatment of HCC and was well tolerated4,5,6
1. Li et al. W J Gastro(everolienterol 2004;10: Sergio et al. Am J Gastroenterol 2008;103: Wilhelm et al. Mol Cancer Ther 2008;7:
4. Llovet et al. New Engl J Med 2008;359: Cheng et al. Lancet Oncol 2009;10: Nexavar EU Summary of Product Characteristics.

11. Sorafenib and TACE combination: different approaches
Sequential schedule
 standard
TACE, transarterial chemoembolization. 1. Strebel BM, Dufour J-F. Expert Rev Anticancer Ther 2008;8:1743–9.
Interrupted
schedule
Continuous
TACE
Sorafenib
Time
Sequential schedule
 efficacy-based*
*Repeat TACE based on efficacy of initial treatment 11

12. Systemic therapy with anti-angiogenic properties concomitantly with TACE for the treatment of HCC (1)
Agent
Trial phase
Region
Trial schema
Primary endpoint
Efficacy data
Safety data
Sorafenib15 II
Asia
TACE + sorafenib
Safety
n = 147
CR: 41 patients
PR/SD: 93 patients
PD: 13 patients
Most frequent G3/4 toxicities:
Skin reaction
Hand–foot skin reaction
Increased liver enzymes
Sorafenib16
TACE + sorafenib (n = 50)
TTP, safety
n = 50
TTP 5.1 mo
Hand–foot skin reaction 40%
Thrombocytopenia 28%
Sorafenib17
Europe
TACE + sorafenib (n = 72)
TTP
n = 44
RECIST criteria: CR 0%, PR 2%, SD 26%, PD 3%
EASL criteria: CR 2%, PR 15%, SD 11%, PD 3%
45 SAEs
Four Grade 5 AEs (progressive disease with liver and multi-organ failure)
Sorafenib18
TACE vs. TACE + sorafenib (n = 228)
TTUP NA
Sorafenib19
TACE + sorafenib (n = 63)
15. START. NCT Chao et al. ILCA 2011: abstr O COTSUN. NCT Park et al. J Clin Oncol 29:2011 (Suppl 4); abstr Socrates. NCT Erhardt et al. J Hepatol 2011;54(Suppl.):S35: abstr TACTICS. NCT NCT

13. Systemic therapy with anti-angiogenic properties concomitantly with TACE for the treatment of HCC (2)
Agent
Trial phase
Region
Trial schema
Primary endpoint
Efficacy data
Safety data
Sorafenib20 II
USA
DC Bead™ TACE + sorafenib (n = 50)
Safety
n = 36
EASL criteria: PR 54%, SD 46%
RECIST criteria: SD 96%, PD 4%
Most frequent Grade 3/4 toxicities:
Fatigue
RUQ pain
Increased liver enzymes
Sorafenib21
III
TACE or DC Bead™ TACE + placebo vs. TACE or DC Bead™ TACE + sorafenib (n = 400)
PFS NA
Sorafenib22
Europe
DC Bead™ TACE + placebo vs. DC Bead™ TACE + sorafenib (n = 412)
Efficacy
Sorafenib23
Europe, Asia,
DC Bead™ TACE + placebo vs. DC Bead™ TACE + sorafenib (n = 300)
TTP
20. Johns Hopkins Study. NCT Prof. J-F. Geschwind (personal communication) ECOG. NCT TACE-2. EudraCT: UKCRN ID SPACE. NCT

14. Phase I trial: TACE + sorafenib (continuous) in patients with HCC
Primary endpoint
Safety
Secondary endpoints
VEGF levels in blood prior to and after treatment
Eligibility criteria
ECOG PS 0–1
Child–Pugh A/B (<10)
No prior systemic treatment
BCLC Ba
Sorafenib
(dose escalation from 200 mg BID
to 400 mg BID)
Initiated 1 week before first TACE,
without a pause for TACE treatment +
TACE
with doxorubicin (50 mg)
(n = 21)
Key exclusion criteria:
- Treatment with any anti-cancer therapy for HCC (previous hepatic surgical resection allowed)
Any other active primary tumor
Advanced liver disease (Child-Pugh C, active gastrointestinal bleeding within 30 days, encephalopathy, or marked ascites)
- Ejection fraction < 50%
- Portal vein occlusion
- Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an additional experimental drug
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to treatment
- Transplant candidates (unless they have progressed past MILAN criteria)
aIn July 2008, the protocol was amended by restricting inclusion to patients with BCLC stage B disease to ensure a more homogenous patient population
Dufour et al. Oncologist 2010;15:1198. 14 14 14 14

15. Continuous administration of TACE in combination with sorafenib in patients with HCC: results
Results from May 2007 to January 2009
21 patients screened for inclusion:
14 patients received sorafenib with TACE
Median age: 63.5 years
78% male
93% ECOG PS 0
93% Child–Pugh A
No dose-limiting toxicities in first three patients receiving sorafenib 200 mg BID
Subsequent patients received sorafenib 400 mg BID
27 TACE procedures performed (median of two per patient; range 1–4)
Two SAEs after first TACE: one cholecystitis, one hospitalization with thigh pain
Median duration sorafenib therapy: 246 days (range 14–547 days)
Sorafenib-related AEs Grade ≥3: hand–foot skin reaction (n = 3), weight loss (n = 2), diarrhea (n = 1), abdominal pain (n = 1), thrombocytopenia (n = 3)
VEGF levels significantly decreased after sorafenib + TACE treatment (from 93 to 67 ng/L)
Dufour et al. Oncologist 2010;15:1198. 15 15 15

16. Continuous administration of sorafenib in combination with TACE in patients with HCC: results
Author conclusions Continuous administration of sorafenib 400 mg BID + TACE was tolerable The AE profile was similar to that of sorafenib monotherapy, except for thrombocytopenia, which may be more frequent with this combination There were no increases in circulating VEGF levels after TACE
Dufour et al. Oncologist 2010;15:1198. 16 16 16

17. DEB-TACE up to 4 times/year
Phase II trial of sorafenib + doxorubicin eluting bead-transarterial chemoembolization (DEB-TACE) for patients with HCC
DEB-TACE up to 4 times/year
Selected entry criteria:
Unresectable HCC
ECOG 0–1
Child-Pugh A–B7
50 Patients
Single arm
Continuous sorafenib for as long as is beneficial
Sorafenib held 3d pre and post DEB-TACE in the first 8 pts, then continuous schedule
Interim results:1, 2, 3
4% decrease at 3 weeks in tumor size (p=0.79)
49% decrease at 3 weeks in tumor enhancement (p<0.0001)
25% increase at 3 weeks in apparent diffusion coefficient (p=0.01)
RECIST: partial response 1/24 (4%), stable disease 23/24 (96%)
EASL: partial response 14/24 (58%), stable disease 10/24 (42%)
Findings: Combination did not result in greater toxicities than that reported for either therapy alone
EASL, European Association for the Study of the Liver; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; RECIST, Response Evaluation Criteria in Solid Tumours TACE, transarterial chemoembolization Reyes et al. AASLD 2009; abstr LB9; 2. Reyes et al. ASCO-GI 2010, abstr Reyes et al. CIRSE 2010, abstr NCT 17

18. Repeated every 6 to 8 weeks
Phase II trial of study in Asia of the combination of TACE with sorafenib in patients with hepatocellular carcinoma (START)
A prospective trial investigating the combination of TACE and sorafenib in patients with unresectable HCC
HCC patients
BCLC B
ECOG PS 0,1
Child–Pugh score ≤ 7
Size of largest tumor ≤ 10 cm
TACE naive
Abdominal CT scan and AFP assessed 4 weeks after TACE to determine need for further TACE
TACE
(Lipiodol and 30–60 mg doxorubicin) +
Sorafenib
(400 mg b.i.d)
Primary end-point
Child–Pugh safety (NCI–CTCAE v. 3.0)
Secondary end-point
Efficacy
Repeated every 6 to 8 weeks
Sorafenib 400 mg twice daily will be initiated on Day 4 (up to Day 7) after 1st TACE (Day 1).
Sorafenib will be interrupted after the evening dose 4 days before next TACE cycle and restarted on Day 4 (up to Day 7) of the new TACE cycle. 18 18

19. Phase II START 3rd interim analysis: baseline patient characteristics
An interim safety analysis was performed at the end of 2010 when a total of 166 patients had received one or more doses of sorafenib
Patient characteristics (n = 166)
Patients, n
166
Median age, years (range)
56.4 (48–64)
BCLC Staging system A/B/C, %
17.3/80.9/1.9
Child–Pugh A/B, %
91.6/7.7
HBV related, % 82
Previous treatment (n =146)
Surgical resection for primary HCC No/Yes, %
89.7/10.3
Loco-regional treatment for HCC No/Yes, %
89.0/11.0
Adapted from Chao Y et al. Oral presentation, ILCA Hong Kong, 2011 (abstr O-026).

20. Phase II START 3rd interim analysis: efficacy (n = 147)
Patients (%)
27.9
24.5
38.8
8.8
TACE + sorafenib was associated with good response rates:
Complete response in 41 patients
Partial response or stable disease in 93 patients
ORR was 52.4%
Median PFS: 270 days; TTP: 280 days; OS probability of >90% after 2 years follow up
Adapted from Chao Y et al. Oral presentation, ILCA Hong Kong, 2011 (abstr O-026).

21. Phase II START 3rd interim analysis: safety (n = 166)
Skin and gastrointestinal adverse events were most common drug-related adverse events
Number of patients with drug-related adverse events (%)
All Grades
Grades 3/4
Skin/subcutaneous tissue disorders
62.6
10.2
Gastrointestinal disorders
23.8
3.4
General/administration site events
8.8
0.7
Abnormal lab investigations
7.5
Respiratory/thoracic/ mediastinal disorders
Nervous system disorders
Vascular disorders
Adapted from Chao Y et al. Oral presentation, ILCA Hong Kong, 2011 (abstr O-026).

22. Number of patients with drug-related adverse events (%)
Phase II START 3rd interim analysis: top Grade 3/4 AEs (non-laboratory) (n = 166)
Top 5 Grade 3/4 drug-related AEs (non-laboratory) were skin reaction, hand-foot skin reaction, diarrhea/vomiting, and blister
Number of patients with drug-related adverse events (%)
Grade 3
Grade 4
Grades 3/4
Skin reaction
4.1
Hand-foot skin reaction
2.7
Diarrhoea
1.4
Vomiting
Blister
Chao et al. Oral presentation, ILCA Hong Kong, 2011 (abstr O-026).

23. Number of patients with drug-related adverse events (%)
Phase II START 3rd interim analysis: top Grade 3/4 AEs (laboratory) (n = 166)
Top 5 Grade 3/4 drug-related AEs (laboratory) were elevated liver transferases (ALT / AST) and decreased neutrophil / platelet / white blood cell counts
Number of patients with drug-related adverse events (%)
Grade 3
Grade 4
Grades 3/4
Alanine aminotransferase increased
6.8
Aspartate aminotransferase increased
4.1
1.4
5.5
Neutrophil count decreased
Platelet count decreased
3.4
White blood cell count decreased
Chao Y et al. Oral presentation, ILCA Hong Kong, 2011 (abstr O-026).

24. Phase II START 3rd interim analysis
Author conclusions
TACE and sorafenib combination therapy was effective:
52.4% of patients had CR/PR through RECIST assessment
Clinical progression of disease in 8.8% of patients after the first cycle of TACE+ sorafenib treatment
This combination therapy achieved a median PFS of 270 days, TTP of 280 days and an OS probability of >90% after 2 years follow up
No un-expected or new safety signals from this study
Adapted from Chao Y et al. Oral presentation, ILCA Hong Kong, 2011 (abstr O-026).

25. Phase II COTSUN Korea trial: TACE + sorafenib (continuous)
Sorafenib on day 3 after first TACE
Sorafenib continuous up to 24 weeks
TACE every 4–6 weeks on demand
Primary endpoints
TTP
Safety and tolerability
Secondary endpoints
PFS
ORR
N = 50
Sorafenib 400 mg BID +
TACE
Lipiodol + doxorubicin
30–60 mg → Gelfoam
Eligibility criteria
≥1 bi-dimensional lesion (CT or MRI)
Child–Pugh A or B ≤7
ECOG PS ≤1
interim analysis (n = 50) Patient characteristics:
Mean age: 61.5 years
82% BCLC B
18% BCLC C
56% HBV
16% HCV
Median follow-up: 5.3 months (range 1.0–13.1 months)
Median number of TACE sessions: 1 (range 1–4 sessions)

26. Phase II COTSUN Korea trial: interim analysis (n = 50)
Results
AEs more severe than NCI–CTCAE Grade 3:
Hand–foot skin reaction (40%)
Thrombocytopenia (28%)
ALT/AST increase (38/34%)
Dose reduction of sorafenib in 50% of patients, mostly due to hand–foot skin reaction
Median TTP was 5.1 months (range 3.8–6.3 months)
Author conclusions
Interim analysis showed that a combination of TACE and sorafenib was well tolerated and the trial could be continued
Preliminary evidence of anti-tumor activity was observed
Park J-W et al. Poster presented at ASCO GI 2011, San Francisco USA (abstr. 253).

27. Phase II SOCRATES study: TACE + sorafenib (interrupted)
Sorafenib 400 mg BID
n = 72
Eligibility criteria
Unresectable HCC
Measurable disease (RECIST)
ECOG PS 0–2
Child–Pugh <B8
Primary endpoint
TTP
Secondary endpoint
Safety
Sorafenib administered for ≥14 days
TACE repeated
every 6 weeks*
TACE
TACE
Sorafenib withheld 3 days pre- TACE
Sorafenib withheld 3 days post- TACE
*One cycle = 6 weeks
Adapted from Erhardt A et al. Poster presented at ASCO 2011, Chicago, IL, USA (abstr. 4107).

28. Phase II SOCRATES study: baseline patient characteristics
Sorafenib + TACE (n = 43)
Female/male, % (n)
14 (6) /86 (37)
Mean age, years (SD)
69 (9)
Etiology HCV/HBV/other, %
30/16/64
Child–Pugh A/B, %
81/19
Tumor size
4.5 cm (1.526)
BCLC B/C, %
84/16
AFP µg/L, mean (SD)
205 (807)
ALT U/L, mean (SD)
54 (30)
Platelets x103 µl
194 (94)
Erhardt A et al. Poster presented at ASCO 2011, Chicago, IL, USA (abstr. 4107).

29. Phase II SOCRATES study: final response data (ITT: n = 43)
Patients, n (%) CR PR SD PD
Only baseline
RECIST
EASL
3 (7.0)
2 (4.7)
18 (41.9)
32 (74.4)
11 (25.6)
4 (9.3)
7 (16.2)
Patients were evaluated by central radiology
Patients received:
a mean of 2.6±2.2 [range 0–10] TACE applications
a mean of 8.3±7.4 [range 0–28] cycles
Erhardt A et al. Poster presented at ASCO 2011, Chicago, IL, USA (abstr. 4107).

30. Phase II SOCRATES study: final TTP data (ITT: n = 43)*
RECIST criteria
Discontinuation before a radiological progression was censored
Events:
12 × progression
5 × death
2 × LTX
3 × TACE not possible
7 × only baseline
2 × TACE not possible
2 × sorafenib not tolerated
2 × death (diverticulitis, progression)
1× progression (Child B to C)
TTP: 18.9 mo (568 days)
(95% CI: 515)
*According to RECIST; data for 3 patients under investigation
Erhardt A et al. Oral presentation at EASL 2011, Berlin, Germany (abstr. 79).

31. Phase II SOCRATES study: final overall survival data (ITT: n = 43)*
OS: 20.1 months
(603 d)
(95% CI: 527, 741)
*As by April 2011: 15 out of 43 patients still alive
Erhardt A et al. Poster presented at ASCO 2011, Chicago, IL, USA (abstr. 4107).

32. Phase II SOCRATES study final analysis: safety
Frequent Adverse events (>10%)
TACE + sorafenib (n = 43) n
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Diarrhea 25 13 8 3 1
Hand–foot skin reaction 20 9
Anorexia 14 5
Asthenia 12 10 2
Weight loss 6
ALT elevation 7
Hepatic encephalopathy
Thrombocytopenia
Ascites 4
Nausea
Hoarseness
Erhardt A et al. Poster presented at ASCO 2011, Chicago, IL, USA (abstr. 4107).

33. Phase II SOCRATES study final analysis: conclusions
Combination of TACE plus Sorafenib allowed an acceptable tumor control Combination of TACE plus Sorafenib resulted in an increased TTP and OS Side effects were tolerable and in part related to the combination treatment compared to the monotherapeutic approaches Present results have to be confirmed by the ongoing phase III study (SPACE Trial)
Erhardt A et al. Poster presented at ASCO 2011, Chicago, IL, USA (abstr. 4107).

34. Sorafenib 400 mg b.i.d. initiated 1 week before first TACE
Johns Hopkins University phase II trial of doxorubicin-eluting LC Bead® TACE plus sorafenib in patients with unresectable HCC
Primary end-point: safety
Secondary end-point: tumor response (EASL, RECIST), TTP, OS
Eligibility criteria
Unresectable HCC (beyond Milan)
> 18 years old
ECOG PS 0/1
Child–Pugh A/B (< 8)
Adequate end organ function*
(n = 50)
Sorafenib 400 mg b.i.d. initiated 1 week before first TACE
Continue until tumor progression or toxicity +
Up to 4 treatments/6 months: TACE with doxorubicin-LC Bead® 100 mg doxorubicin
Key exclusion criteria:
- Treatment with any anti-cancer therapy for HCC (previous hepatic surgical resection allowed)
Any other active primary tumor
Advanced liver disease (Child-Pugh C, active gastrointestinal bleeding within 30 days, encephalopathy, or marked ascites)
- Ejection fraction < 50%
- Portal vein occlusion
- Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an additional experimental drug
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to treatment
- Transplant candidates (unless they have progressed past MILAN criteria)
*Absolute neutrophil count > 1,500 /mm3, platelets > 50,000 /mm3, normal creatinine, total bilirubin ≤ 3, AST and ALT < 5 x upper limit of normal.
NCT
Geschwind et al. J Clin Oncol 2011 [in press] 34 34 34 34

35. Patient characteristics: Phase II Trial of DEB-TACE plus Sorafenib
Variable
Value
Patients enrolled 35
Mean age, years (range)
64 (31–88)
Male/female
26/9
Child–Pugh status A/B
31/4
ECOG Performance Status 0/1
16/19
HBV/HCV/other etiology
2/13/20
Portal vein Thrombosis (yes/no)
11/24
BCLC B/C
12/23
Mean index tumor size, cm (SD)
7.7 ±4.2
Diane updated 3/20/2011
Geschwind et al. J Clin Oncol [in press] 35 35 35

36. Tumor Response: Phase II Trial of DEB-TACE plus Sorafenib
36 patients treated to date, 35 patients completed Cycle 1 (n = 26 evaluated for efficacy)
Tumor response by MR imaging
Features
Pre- DEB-TACE
Post- DEB-TACE
Change at 3 weeks (%)
p value
Tumor Size ± SD (cm)
7.9 ± 4.3
7.6 ± 4.5
– 4
0.79
Tumor Enhancement (%) 85
43.5
– 49
< 0.01
*ADC (x 10–3 mm2/sec)
1.2
1.54
+ 25%
0.01
Diane updated # patients treated, 2/23/2011
35 patients completed cycle 1, but 2/35 were not able to tolerate sorafenib and exited the study after 1 week of sorafenib
EASL
Partial response:14/26 (54%)
Stable disease: 12/26 (46%)
RECIST
Stable disease: 25/26 (96%)
Progressive disease: 1/26 (4%)
*ADC = apparent diffusion coefficient measured by functional diffusion weighted MR.
Geschwind et al. J Clin Oncol 2011 [in press] 36 36 36

37. Tumor Response: Phase II Trial of DEB-TACE plus Sorafenib
68-year-old male, right lobe lesion 2 cycles of DEB-TACE and sorafenib Bridged to surgical resection 3 months after end of second cycle
Baseline
21 Days Post-treatment
10.3 cm, 90% enhancement
10.2 cm, 30% enhancement
TACE #1
TACE #2
Geschwind J-F et al. Presented at 2nd Asia–Pacific Primary Liver Cancer Expert Meeting, 1–3 July 2011, Osaka, Japan. 37 37 37

38. Tumor Response: Phase II Trial of DEB-TACE plus Sorafenib
73-year-old male, right lobe lesion
1 cycle of DEB-TACE and sorafenib
Stable for 20 months JH
T1 contrast-enhanced images
Baseline:
8.1 cm, 90% enhancement
3 weeks post DEB-TACE:
6.3 cm, 10% enhancement
20 months post DEB-TACE:
5.7 cm, <10 % enhancement
Geschwind J-F et al. Presented at 2nd Asia–Pacific Primary Liver Cancer Expert Meeting, 1–3 July 2011, Osaka, Japan. 38

39. All Grade 3/4 toxicities (any cause)
Incidence of Grade 3/4 Toxicities: Phase II Trial of DEB-TACE plus Sorafenib
All Grade 3/4 toxicities (any cause) 60 50 40 30 20 10
Cycle 1 (n = 27)
Cycle 2 (n = 19)
Cycle 3 (n = 12)
Percentage
Cycle 1: 1 patient exited, unable to tolerate sorafenib; 2 patients currently in Cycle 1, so n=21
Not able to add in the n=1, 6% for a flutter
HFSR
DOE
Fatigue
Pain-abd-RUQ
Lymphopenia
Pain (other)
Hypertension
Pain in chest
Increased lipase
Rash /mucositis
Encephalopathy
Hyperbilirubinemia
PE / >coagulopathy
Increased liver enzyme
All remaining toxicities were Grade 1/2 (no unexpected events)
Pain-abd-RUQ = abdominal pain, right upper quadrant
DOE = Dyspnea on exertion; PE = pulmonary embolism
Geschwind J-F et al. Presented at 2nd Asia–Pacific Primary Liver Cancer Expert Meeting, 1–3 July 2011, Osaka, Japan. 39 39

40. Phase II TACTICS randomized trial: TACE vs
Phase II TACTICS randomized trial: TACE vs. TACE + sorafenib in patients with HCC
Status: recruiting
Sorafeniba +
TACE
TACE repeated when tumor increases
Primary endpoint
TTUP
Secondary endpoints
TTP
Overall survival
ORR
Tumor markers
Safety
Eligibility criteria
ECOG PS 0–1
Child–Pugh A
No prior systemic treatment
(n = 228)
TACE
TACE repeated when tumor increases
Key exclusion criteria:
- Treatment with any anti-cancer therapy for HCC (previous hepatic surgical resection allowed)
Any other active primary tumor
Advanced liver disease (Child-Pugh C, active gastrointestinal bleeding within 30 days, encephalopathy, or marked ascites)
- Ejection fraction < 50%
- Portal vein occlusion
- Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an additional experimental drug
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to treatment
- Transplant candidates (unless they have progressed past MILAN criteria)
a400 mg OD stopped 2 days before first TACE; resumption of sorafenib 3–21 days after TACE
When tolerability is confirmed at 1 week after resumption, sorafenib is increased to 400mg BID
NCT 40 40 40 40

41. SPACE: Sorafenib or Placebo in combination with TACE for intermediate stage HCC
Phase II, randomized, double-blind, placebo-controlled study of sorafenib in intermediate-stage HCC in combination with DEB-TACE using beads loaded with doxorubicin
Study start date: March 2009
Estimated completion date: Dic 2011
Endpoints
Primary
TTP
Secondary OS
TTUP
Time to vascular invasion
Time to EHS
Eligibility criteria
Unresectable HCC
Multinodular HCC
Child–Pugh A
ECOG PS 0
Exclusion criteria
EHS/MVI
Contraindication to TACE
DEB-TACE +
sorafenib 400 mg bid
Randomization
(n=307)
1:1
DEB-TACE + placebo
DEB, drug-eluting bead; ECOG, Eastern Cooperative Oncology Group; EHS, extrahepatic spread; HCC, hepatocellular carcinoma; MVI, macrovascular invasion; OS, overall survival; TACE, transarterial chemoembolization; TTP, time to progression; TTUP, time to untreatable progression. NCT EudraCT: 41

42. ECOG: phase III study investigating the combination of sorafenib with TACE
A phase III randomized, double-blind trial of TACE with or without sorafenib in patients with unresectable HCC
status: recruiting
contact information: ECOG Group Chair’s Office (Robert L. Comis)
Eligibility criteria
Unresectable HCC
Child–Pugh A -B7
ECOG PS 0-1
Exclusion criteria
EHS
Main portal vein invasion
Ascites
Sorafenib 400 mg b.i.d.
and TACE (doxorubicin,
mitomycin C and cisplatin)
Primary end-point
PFS
Secondary end-points OS
Toxicity
Randomization
1:1
(n = 400)
Placebo and TACE
(doxorubicin,
mitomycin C and cisplatin)

43. TACE-2: Phase III study investigating the combination of sorafenib with TACE
Investigator-sponsored, randomized, placebo-controlled, double-blinded, Phase III trial evaluating sorafenib in combination with TACE in unresectable HCC
Study start date: August 2010
Estimated completion date: 07 January 2013
Target recruitment: 412 patients (UK, Ireland, France and Italy)
Status: recruitment opened November 2010
Eligibility criteria
Unresectable HCC
At least 1 unidimensional CT/MRI- measurable lesion
Child–Pugh A ≤6
ECOG PS ≤1
Exclusion criteria
EHS
Contraindication to TACE
Child–Pugh B ≥7 or C
Prior embolization, systemic or radiation tx
1º endpoint
PFS 2º endpoints OS
Toxicity
QoL
Number of TACE performed
Health economics
Sorafenib 400 mg BID continuous
DEB-TACE with doxorubicin (150 mg)
2-5 weeks initiate TACE
1:1 Randomization (n = 412)
Placebo PO BID continuous
QoL = quality of life. EudraCT: ; ISRCTN: ; UKCRN ID 5347 43

44. Adjuvant Sorafenib after TACE to prevent Recurrence of Hepatocellular CarcinOma (ASTRO)
Italy, phase II, double-blind, randomised, placebo-controlled adjuvant trial after TACE-based treatments
Primary endpoint
Time to recurrence
Secondary endpoints
RFS OS
Other
Prior treatment
TACE ± RFA/PEI
Eligibility criteria
Child–Pugh score 5–7
Radiological CR
Randomisation 1:1 (n=216)
Stratification
Unifocal vs. Multifocal
Sorafenib 400 mg b.i.d.
Placebo 44