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

Eligiblepatients TACE* TACE*

Sorafenib(2 x 400 mg)

Stopped 3 days before TACEResumed 1 day after TACE

Sorafenib(2 x 400 mg)

Stopped 3 days before TACEResumed 1 day after TACE

Lead-in14 days

Cycle: 6 weeks Liver-specific MRI

Endpoints:TTP (primary)

OSPFS

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 weeksECOG 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 onesorafenib 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

Characteristic ResultsGender, female/male 14% (6) / 86% (37)

Mean age 69±9 yearsEtiology

HCVHBVOther

30%16%64%

Child-Pugh ScoreAB

81%19%

BCLC StageStage BStage C

84%16%

Tumor size 4.5 cm (1.5-26)AFP 205±807 µg/L

ALT 54±30 U/L Platelets 194±94×103/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.

Method CR PR SD PDOnly

Baseline

RECIST 0 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.

Su

rviv

al

Events:12 patients progressed5 patient deaths2 patients with liver transplant3 patients TACE not possible7 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

0 100 200 300 400 5000

0.2

0.4

0.6

0.8

1.0

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: 527-741)

0 200 400 600 800 1000

0

0.2

0.4

0.6

0.8

1.0

Su

rviv

al

1200

Adverse Events

SAE n Grade 1 Grade 2 Grade 3 Grade 4

Hepatic encephalopathy

7 1 2 3 1

Ascites 4 0 4 0 0

Renal insufficiency 3 0 0 2 1

Liver abscess 2 0 0 1 1

Diarrhea 2 0 1 1 0

Liver failure 2 0 0 0 2

Pneumonia 2 0 1 1 0

Bifascicular block / AF 2 0 0 1 1

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 Event n Grade 1 Grade 2 Grade 3 Grade 4

Diarrhea 25 13 8 3 1

Hand-foot syndrome 20 8 9 3 0

Anorexia 14 9 5 0 0

Asthenia 12 10 2 0 0

Weight loss 9 6 3 0 0

ALT elevation 7 2 2 3 0

Hepatic encephalopathy 7 1 2 3 1

Thrombocytopenia 6 2 2 2 0

Ascites 6 1 4 1 0

Nausea 6 4 2 0 0

Hoarseness 6 5 1 0 0

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.

Study nDrugs/

Intervention

Prior Local

Treatment (%)

Child-Pugh B

(%) CR+PR+SD (%)TTP

(months)OS

(months)

Llovet et al,N Engl J Med 2008

602 Sorafenib vs control

49 5 vs 2 0+2+71 (73)* vs 0+1+67 (68)*

5.5 vs 2.8 10.7 vs 7.9

Abou-Alfa et al, JAMA 2010

96 Doxorubicin + sorafenib

vs doxorubicin

8 0 vs 4.1 NA 6.4 vs 2.8 13.7 vs 6.5

Lammer et al, Cardiovasc Intervent Radiol 2010

212 DC beads vs cTACE

11 vs 13 17 vs 17.5

24.9+24.7+11.8 (63.4)† vs

22.2+21.3+8.3 (51.8)†

7.2 vs 6.5 NA

Present study 43 Sorafenib plus TACE

0 19 7+41.9+25.6 (74.5)†

0+4.7+74.4 (79.1)*

18.9 20.1

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)