Final results of phase II, randomized, double-blind study of sorafenib plus doxorubicin and placebo plus doxorubicin in patients with advanced hepatocellular carcinoma Abou-Alfa GK, Johnson P, Knox J, Davidenko I, Lacava J, Leung T, Mori A, Leberre M-A, Voliotis D, and Saltz LB Memorial Sloan-Kettering Cancer Center, New York, USA, The University of Birmingham, Birmingham, UK, Princess Margaret Hospital, Toronto, Canada, Krasnodar City Oncology Center, Krasnodar, Russia, Unidad Oncologica de Neuquen, Neuquen, Argentina, Hong Kong Sanatorium & Hospital, Hong Kong, Bayer Healthcare Pharma, Puteaux, France, Bayer HealthCare, France, Bayer HealthCare, West Haven, USA

HCC and Sorafenib  Hepatocellular carcinoma is the fifth most common cancer worldwide  Sorafenib is a VEGFR/PDGFR and raf kinase inhibitor  Sorafenib has shown prolonged overall survival and time to progression in patients with advanced HCC and Child-Pugh A 1. McGlynn, KA., at al. Int J Cancer Oct 15;94(2): Wilhelm S et al. Cancer Res. 2004;64: Llovet, J, et al. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S, 2007: LBA1

Phase I Sorafenib and Doxorubicin Pharmacokinetics  Concomitant administration of doxorubicin 60 mg/m2 and sorafenib revealed a 21% increase in AUC of doxorubicin  The toxicity profile was not markedly worse compared with that expected with either compound administered individually  All 4 patients accrued with HCC (out of 34), had stability of disease as best response and remained on therapy for more than one year Richly, H, et al. Ann Oncol May;17(5): Epub 2006 Feb 24.

Study Design *Doxorubicin total allowed 360 mg/m2 and in approved circumstances 450 mg/m2, after which sorafenib versus placebo can be continued as single agent Eligibility  Child-Pugh A  ECOG PS: 0, 1, 2 (1:1) Randomization (N~96) Period 1Period 2 Continue until withdrawal,PD, or death 6 cycles of: Doxorubicin 60 mg/m 2 IV* Day 1 in 21-day cycles Sorafenib 400 mg po bid 6 cycles of: Doxorubicin 60 mg/m 2 IV* Day 1 in 21-day cycles Placebo 2 tablets po bid Sorafenib 400 mg po bid

Study Objectives  Primary objective: TTP, defined as the time from randomization to radiological disease progression. TTP, defined as the time from randomization to radiological disease progression.  Secondary objectives: Overall survival (OS) Overall survival (OS) Progression Free Survival (PFS) Progression Free Survival (PFS) Overall response rate (RECIST criteria) Overall response rate (RECIST criteria) Exploratory evaluation of TTP, OS and PFS between the 2 study populations Exploratory evaluation of TTP, OS and PFS between the 2 study populations Safety Safety

Key Inclusion Criteria  ≥ 18 years of age  Histologically confirmed HCC  Measurable disease by RECIST  ECOG  Child-Pugh A  Adequate bone marrow, liver, and kidney functions  No prior cardiac history

Key Exclusion Criteria  Prior systemic therapy  Prior chemoembolization  EF < 45% or below normal limit  Significant GI bleed within 30 days  Major surgery within 4 weeks  History of organ allograft

 A reasonable sample size of 90 patients was selected given the exploratory nature of the study  Each study population was compared to historical control TTP of about 4 months  Each arm had 80% power to detect a difference of 100% in median TTP compared to historical controls at type I error rate of 0.1  All analyses were based on intent-to-treat  No interim analysis was planned Statistical Design Statistical Design

Demographics (n=96) DXR/sorafenib (n=47) DXR/placebo (n=49) Gender Gender n(%)Male 31 (66) 42 (86) Female 16 (34) 7 (14) Age (years) Mean6362 ECOG ECOG n(%) n(%)0 22 (47) 16 (33) 1 18 (38) 25 (51) 2/3 4 (9) 4 (8) Missing 3 (6) 4 (8) Child-Pugh Status Child-Pugh Status n(%)A 47 (100) 47 (96) B 0 (0) 2 (4) Extrahepatic disease Extrahepatic disease n(%)Yes24(51) 32 (65) No 23 (49) 17 (35) Macroscopic Vascular Invasion n(%) Yes 13 (28) 16 (33) No 33 (70) 32 (65) Missing 1 (2) DXR=Doxorubicin

Interim Analysis of DXR/Sorafenib Randomized Phase II Study  Considering the interim results of the Phase III SHARP trial 1, an Independent Data Monitoring Committee (DMC) performed an interim analysis in January 2007  In this preliminary analysis: “TTP and OS in the sorafenib/doxorubicin arm appear to be encouraging”  “The results for the Phase II trial, although immature, indicate that the patients randomized to receive doxorubicin may be at a considerable disadvantage.”  “DMC would advise the sponsor to consider discontinuation of this Phase II trial.” 1 Llovet, J, et al. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S, 2007: LBA1

ResultsDXR/sorafenib(n=47)DXR/placebo(n=49) TTP (months) OS (months) PFS (months) Response (CR+PR) n(%) 2 (4) 1 (2) Response (SD) 36 (77) 27 (55) Definitive analysis (data from March 2007 cutoff, independent assessment, TTP: 38 events, OS: 51 events, PFS: 70 events )

1.00 Exploratory Comparison Per Protocol : Time to Progression Based on Independent Tumor Assessment Proportion of Patients Months From Randomization months STRATA: Doxorubicin plus sorafenib Censored treatment: Doxorubicin + sorafenib Doxorubicin + placebo Censored treatment: Doxorubicin + placebo Median TTP: Doxorubicin + sorafenib: 8.6 (95% CI: ) Doxorubicin + placebo: 4.8 (95% CI: 2.2-8) Hazard Ratio: 0.6 p=0.076 Total # of events: 38

Exploratory Comparison Per Protocol: Overall Survival Survival Distribution Function Months From Randomization STRATA: Median OS: Doxorubicin + sorafenib: 13.8 (95% CI: 9.1-can not be estimated) Doxorubicin + placebo: 6.5 (95% CI: ) Hazard Ratio: 0.51 p= Total # of events: 51 Doxorubicin plus sorafenib Censored treatment: Doxorubicin + sorafenib Doxorubicin + placebo Censored treatment: Doxorubicin + placebo

Exploratory Comparison Per Protocol : Progression-Free Survival Based on Independent Tumor Assessment Proportion of Patients Months From Randomization months STRATA: Doxorubicin plus sorafenib Censored treatment: Doxorubicin + sorafenib Doxorubicin + placebo Censored treatment: Doxorubicin + placebo Median PFS: Doxorubicin + sorafenib 6.9 (95% CI: ) Doxorubicin + placebo 2.8 (95% CI: ) Hazard Ratio: 0.57 p=0.012 Total # of events: 70

March 2007 data cut-off Based on independent radiological assessment population: subjects valid for ITT Doxorubicin + placebo (n=49) Doxorubicin + sorafenib (n=47) Percent Change in Target Lesion From Baseline (Independent Assessment) Change in Target Lesion From Baseline (%) 62% 29%

Safety and Study Drug Administration DXR/sorafenib (n=48) DXR/placebo (n=49) All cause adverse events (AE) (%) Drug-related AE (%) 9288 Serious all cause AE (SAE) (%) 3842 Drug related SAE (%) 2115 AE leading to discontinuation (%) 3833 Death within 30 days (%) 1120 Median daily dose study drug (mg) Median total doxorubicin dose (mg/m 2 )

All Cause Toxicities With > 10% Grade 3-4 Reported Events DXR/sorafenib (n=48) DXR/placebo (n=49) n(%) All grades Grade 3-4 All grades Grade 3-4 Fatigue 35 (75) 7 (15) 31 (65) 7 (15) Abdominal pain 16 (34) 5 (10) 14 (29) 4 (8) Neutropenia 31 (66) 26 (55) 29 (60) 22 (46) Febrile Neutropenia 2 (4) 7 (15) Diarrhea 24 (51) 5 (11) 12 (25) 5 (10) Bilirubin 16 (34) 5 (11) 15 (31) 3 (6) Hand foot 14 (30) 4 (9) 2 (4) 0 (0) LV Dysfunction 9 (19) 1 (2) 0 (0) Hypertension 8(17) 8(17) 0 (0) NCI-CTC (version 3); NCI-CTC=National Cancer Institute–Common Toxicity Criteria

Conclusions  This randomized phase II study of doxorubicin plus sorafenib and doxorubicin plus placebo, showed encouraging TTP and OS outcome for the doxorubicin plus sorafenib  The increased incidence of mostly grade 1-2 left ventricular dysfunction (19%) with the combination requires careful further investigation  Any synergistic role between sorafenib plus doxorubicin in HCC needs to be further defined

Acknowledgments   All patients who participated in the study and their families   All principal investigators and healthcare teams at each center   Study teams at Bayer and Onyx