Intermediate stage HCC treatment options: TACE + sorafenib 1 1

TACE: long-term survival outcomes are unsatisfactory 100 80 60 40 20 100 80 60 40 20 Chemoembolization Control Chemoembolization Control p < 0.0091 p = 0.0022 Probability of survival (%) Probability of survival (%) 0 12 24 36 48 60 0 6 12 18 24 30 36 42 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;359:1734-9. 2. Lo C-M, et al. Hepatology. 2002;35:1164-71.

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 0 100 200 300 400 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

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 138.26 ± 65.24 243.66 ± 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

Plasma VEGF levels significantly increase after TACE: clinical data NS 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

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 0 10 20 30 40 50 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

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

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

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;10:2878–82. 2. Wang B, et al. Acta Radiologica 2008;49:523–9. 3. Sergio A, et al. Am J Gastroenterol 2008;103:914–21. 4. Wilhelm SM, et al. Mol Cancer Ther 2008; 7:3129-3140. 9

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;10:2878-82. 2. Sergio et al. Am J Gastroenterol 2008;103:914-21. 3. Wilhelm et al. Mol Cancer Ther 2008;7:3129-40. 4. Llovet et al. New Engl J Med 2008;359:378-90. 5. Cheng et al. Lancet Oncol 2009;10:25-34. 6.Nexavar EU Summary of Product Characteristics.

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

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. NCT00990860. Chao et al. ILCA 2011: abstr O-026. 16. COTSUN. NCT00919009. Park et al. J Clin Oncol 29:2011 (Suppl 4); abstr 253. 17. Socrates. NCT00618384. Erhardt et al. J Hepatol 2011;54(Suppl.):S35: abstr. 79. 18. TACTICS. NCT01217034. 19. NCT01170104.

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. NCT00844883. Prof. J-F. Geschwind (personal communication). 21. ECOG. NCT01004978. 22. TACE-2. EudraCT: 2008-005073-36. UKCRN ID 5347. 23. SPACE. NCT00855218.

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 www.clinicaltrials.gov/ct2/show/NCT00478374. Dufour et al. Oncologist 2010;15:1198. 14 14 14 14

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

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

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. 1. Reyes et al. AASLD 2009; abstr LB9; 2. Reyes et al. ASCO-GI 2010, abstr. 254. 3. Reyes et al. CIRSE 2010, abstr. 254. www.ClinicalTrial.gov NCT00844883. 17

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. www.clinicaltrials.gov/ct2/show/NCT00990860. 18 18

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).

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).

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).

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).

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).

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).

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) www.clinicaltrials.gov/ct2/show/NCT00919009.

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).

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). www.clinicaltrials.gov/ct2/show/NCT00618384.

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).

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).

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).

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).

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).

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).

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. NCT00844883. Geschwind et al. J Clin Oncol 2011 [in press] 34 34 34 34

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 2011 [in press] 35 35 35

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

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

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

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

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 www.clinicaltrials.gov. NCT01217034. 40 40 40 40

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. www.ClinicalTrial.gov, NCT00855218 - EudraCT: 2008-005056-24 41

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) www.clinicaltrials.gov/ct2/show/NCT01004978.

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: 2008-005073-36 ; ISRCTN: 93375053; UKCRN ID 5347 43

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