Sorafenib Plus TACE for the Treatment of Advanced Hepatocellular Carcinoma - Final Results of the Socrates Trial - A Erhardt, FT Kolligs, MM Dollinger, E Schott, H Wege IV, M Bitzer, C Gog, J Raedle, M Schuchmann, C Walter, D Blondin, C Ohmann, D Haeussinger

Study Rationale Rationale for combination of TACE (transarterial chemoembolization) and sorafenib (multikinase inhibitor with antiangiogenic activity) HCCs are hypervascular tumors Double targeting vascularization: embolization and inhibition of angiogenesis Local and systemic conventional chemotherapy (doxorubicin) Targeted therapy (intracellular signaling by sorafenib through Raf/VEGFR/PDGFR/c-kit) Synergistic action of doxorubicin and sorafenib HCC=hepatocellular carcinoma; PDGFR=platelet-derived growth factor receptor; VEGFR=vascular endothelial growth factor receptor. Adapted from Erhardt A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Study Design *With doxorubicin 50 mg plus lipiodol. MRI=magnetic resonance imaging; OS=overall survival; PFS=progression-free survival; TTP=time to progression. Adapted from Erhardt A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. Prospective, Nonrandomized Multicenter Phase II Trial Eligible patients TACE* Sorafenib (2 x 400 mg) Stopped 3 days before TACE Resumed 1 day after TACE Sorafenib (2 x 400 mg) Stopped 3 days before TACE Resumed 1 day after TACE Lead-in 14 days Cycle: 6 weeks Liver-specific MRI Endpoints: TTP (primary) OS PFS Safety

Inclusion Criteria Age ≥18 years Naive to treatment with respect to the HCC Histologically confirmed HCC not suitable for resection or treatment (3 lesions >3 cm or 1 lesion >5 cm); no extrahepatic spread Measurable lesion according to RECIST Child-Pugh ≤8 Total bilirubin ≤4.5 mg/dL ECOG PS 0-2 Life expectancy ≥12 weeks ECOG PS=Eastern Cooperative Oncology Group Performance Status; RECIST=Response Evaluation Criteria In Solid Tumors. Adapted from Erhardt A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Consort–Flow Diagram *1 patient withdrew consent; 1 patient moved away. Adapted from Erhardt A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. Assessed for eligibility (n=47) Patients with at least one sorafenib dose (n=43) Analysis Total patients (ITT n=43) Enrollment Allocation Registration (n=45) Excluded (n=2)* (no drug administered) Screening failure (n=2)

Patient Characteristics CharacteristicResults Gender, female/male14% (6) / 86% (37) Mean age69±9 years Etiology HCV HBV Other 30% 16% 64% Child-Pugh Score A B 81% 19% BCLC Stage Stage B Stage C 84% 16% Tumor size4.5 cm (1.5-26) AFP205±807 µg/L ALT54±30 U/L Platelets194±94×10 3 /µL AFP=alpha-fetoprotein; ALT=alanine aminotransferase; BCLC=Barcelona Clinic Liver Cancer; HBV=hepatitis B virus; HCV=hepatitis C virus. Adapted from Erhardt A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Response Evaluation* *Patients received a mean of 2.6±2.2 (range 0-10) TACE applications and a mean of 8.3±7.4 (range 0-28) cycles corresponding to 176 days/5.9 months). Patients were evaluated by central radiology. CR=complete response; EASL=European Association for the Study of the Liver; PD=progressive disease; PR=partial response; SD=stable disease. Adapted from Erhardt A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. MethodCRPRSDPD Only Baseline RECIST0 2 (4.7%) 32 (74.4%) 2 (4.7%) 7 (16.2%) EASL 3 (7.0%) 18 (41.9%) 11 (25.6%) 4 (9.3%) 7 (16.2%)

Time to Progression* *According to RECIST; data for 3 patients under investigation. Adapted from Erhardt A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. Survival Events: 12 patients progressed 5 patient deaths 2 patients with liver transplant 3 patients TACE not possible 7 patients only baseline 2 patients TACE not possible 2 patients did not tolerate sorafenib 2 patient deaths (diverticulitis, progression) 1 patient progressed from Child B to C Time in Days TTP: 18.9 months (568 days)

Overall Survival* *As of April 2011, 15 out of 43 patients were still alive. Adapted from Erhardt A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. Time in Days OS: 20.1 months (603 days) (95% CI: ) Survival 1200

Adverse Events SAEnGrade 1Grade 2Grade 3Grade 4 Hepatic encephalopathy Ascites40400 Renal insufficiency30021 Liver abscess20011 Diarrhea20110 Liver failure20002 Pneumonia20110 Bifascicular block / AF20011 AF=atrial fibrillation; SAEs=serious adverse events; SARs=serious adverse reactions. Adapted from Erhardt A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. 39 SAEs, 22 SARs were observed in the trial; events with ≥2 occurrences are shown.

Adverse Events (cont’d) Adverse EventnGrade 1Grade 2Grade 3Grade 4 Diarrhea Hand-foot syndrome Anorexia Asthenia Weight loss96300 ALT elevation72230 Hepatic encephalopathy71231 Thrombocytopenia62220 Ascites61410 Nausea64200 Hoarseness65100 Adapted from Erhardt A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. Adverse events with a frequency >10%

Discussion *According to RECIST; † According to EASL criteria. cTACE=conventional transarterial chemoembolization. Adapted from Erhardt A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. Studyn Drugs/ Intervention Prior Local Treatment (%) Child- Pugh B (%)CR+PR+SD (%) TTP (months) OS (months) Llovet et al, N Engl J Med Sorafenib vs control 495 vs (73)* vs (68)* 5.5 vs vs 7.9 Abou-Alfa et al, JAMA Doxorubicin + sorafenib vs doxorubicin 80 vs 4.1NA6.4 vs vs 6.5 Lammer et al, Cardiovasc Intervent Radiol DC beads vs cTACE 11 vs 1317 vs (63.4) † vs (51.8) † 7.2 vs 6.5NA Present study43Sorafenib plus TACE (74.5) † (79.1)*

Conclusion Combination of TACE plus sorafenib provides good tumor control Combination of TACE plus sorafenib results in promising TTP and OS Side effects are tolerable and in part related to the combination treatment compared to monotherapeutic approaches Present results have to be confirmed by the ongoing Phase III study (SPACE Trial)