sorafenib plus tace for the treatment of advanced hepatocellular carcinoma - final results of the...
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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
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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.
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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
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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.
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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)
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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.
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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%)
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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)
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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
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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.
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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%
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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
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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)