Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON) study

1
Global Investigation of therapeutic DEcisions
inhepatocellular carcinoma and Of its treatment
with sorafeNib (GIDEON) study
2
Introduction

• Sorafenib is the only systemic therapy
  indicatedto treat HCC1-4
• In two Phase III studies (SHARP and
  Asia-Pacific), sorafenib significantly improved
  OS in patients with uHCC5-6
• GIDEON allows evaluation of several clinically
  relevant patient subgroups, including those with
  more advanced liver dysfunction in whom data were
  previously limited
• GIDEON was the largest prospective study in uHCC
  ever conducted7
• Over 3000 patients have been enrolled from 39
  countries8

uHCC, unresectable hepatocellular carcinoma OS,
overall survival
1.NCCN Guidelines Hepatobiliary Cancers.
Available at http//www.nccn.org/ Accessed May
29,2014. 2. EASLEORTC Clinical Practice
Guidelines Management of hepatocellular
carcinoma Journal of Hepatology 2012 vol. 56 j
908943 Available on http//www.easl.eu/assets/ap
plication/files/d38c7689f123edf_file.pdf . 3.
Position paper AISF DLD 2013 45(2013) 712-723. 4.
AIOM Guidelines. Available at http//www.aiom.it/
5. Llovet JM, et al. N Engl J Med.
2008359(4)378-390. 6. Cheng AL, et al. Lancet
Oncol. 200910(1)25-34. 7. Lencioni R, et al.
Int J Clin Prac. 201064(8)1034-1041. 8. Marrero
JA et al. Abstract presented at AASLD 2011 Annual
Meeting
3
The GIDEON study design and objectives

• The GIDEON study is a large, global, prospective,
  non-interventional study of patients with
  unresectable HCC who are eligible for systemic
  therapy and for whom the decision has been taken
  to treat with sorafenib under real-life practice
  conditions.
• Primary objective The primary objective of
  GIDEON is to evaluate the safety of sorafenib in
  uHCC patients under real-life clinical practice
  conditions and to gather more comprehensive data
  on the use of sorafenib in patients with
  Child-Pugh B liver function, who were excluded
  from the randomised clinical trials.
• Secondary objectives evaluate the efficacy OS,
  progression-free survival (PFS), time to
  progression (TTP), response rate and stable
  disease rate of sorafenib determine the
  duration of therapy according to various patient
  characteristics evaluate methods of patient
  evaluation, diagnosis and follow-up assess
  comorbidities and their influence on treatment
  and outcome in real-life practice rather than a
  controlled clinical trial setting and evaluate
  the practice patterns of the physicians involved
  in the care of these patients.

Lencioni R, et al. Int J Clin Prac.
201064(8)1034-1041.
4
The GIDEON study design and objectives

• Planned subgroup analyses conducted globally,
  regionally and by country will include
• the impact of baseline characteristics on safety,
  particularly Child-Pugh B
• the relationship between baseline characteristics
  and efficacy
• the duration of sorafenib therapy and reasons for
  discontinuation
• the effect of other treatments for HCC on outcome
  and the impact of different practice patterns on
  outcome.

Lencioni R, et al. Int J Clin Prac.
201064(8)1034-1041.
5
The GIDEON study Patient eligibility

• Eligibility criteria include
• Patients with histologically or cytologically
  documented or radiographically diagnosed
  unresectable HCC who are candidates for systemic
  therapy, and for whom a decision has been made to
  treat with sorafenib
• life expectancy of gt 8 weeks
• Have provided signed informed consent.

Lencioni R et al. Int J Clin Pract 20106410344
6
The GIDEON study safety, efficacy, treatment and
baseline patient assessments and end-points
Safety Adverse events Relation Seriousness NCI-CTC grade Action taken Outcome Child-Pugh score ECOG PS Efficacy OS TTS PFS RR SD Treatment for HCC Sorafenib therapy Duration of treatment Reason for discontinuation Other therapies Prior Concurrent Following Sorafenib Baseline characteristics History of HCC Duration from initial diagnosis Disease extent Stage (BCLC, TNM, CLIP) Tumor burden, presence of metastasis Previous treatment Aetiology Liver disorders Child-Pugh, cirrhosis ECOG PS Age, gender, race Co-morbidities
BCLC, Barcellona Clinic Liver Cancer CLIP,
Cancer of the Liver Italian Program ECOG,
Eastern Cooperative Oncology Group performance
status HCC, hepatocellular carcinoma NCI-CTC,
National Cancer Institute-Common Toxicity
Criteria OS, overall survival PFS,
progressio-free survival RR, rensponse rate SD,
stable disease TNM, tumor node metastases TTP,
time to progression
Lencioni R et al. Int J Clin Pract 201064103441
7
The GIDEON study timeline and planned analyses
2008-2009
2013-2015
2011-2012
2010
Phase I Objectives Phase II Objectives Phase III Objectives Phase IV and V Objectives
Site initiation Study initiation Safety assessment in Child-Pugh B First interim analysis (500 patients) Second interim analysis (1500 patients) Safety assessment in Child-Pugh B Efficacy assessment of sorafenib in a board population of patients with HCC 3000th patient Last patients last visit 31 December 2013 Analysis of final data - Safety - Efficacy Provide data to regolatory organizations
Lencioni R et al. Int J Clin Pract 201064103441
8
GIDEON study regional distribution of patients

• A total of 3371 patients were enrolled from 39
  countries, across 5 different regions

Marrero J, et al. J Clin Oncol 31, 2013 (suppl
abstr 4126)
9
GIDEON final analysispatients population

• 3202 patients in the safety population
• Safety population used for analysis of AEs and
  serious AEs
• 3213 patients in the ITT population
• ITT population used for analysis of OS and TTP

• ITT, intent to treat OS, overall survival TTP,
  time-to-progression
• Marrero J, et al. J Clin Oncol 31, 2013 (suppl
  abstr 4126)

10
GIDEON final analysisbaseline patients
characteristics by CP status
of n Child-Pugh A (n1968) Child-Pugh B (n666) Child-Pugh C (n74) total (n3202)
Number of patients 615 208 23 100
Male/female 82/18 81/19 82/18 82/18
Median age, years 64 61 58 62
ECOG PS
0 or 1 88 72 59 83
gt2 7 21 34 12
TNM stage
I 5 4 7 5
II 15 9 14 12
III 36 43 34 35
IV 36 33 30 35
BCLC stage
A 8 6 0 7
B 22 20 0 20
C 57 56 1 52
D 3 5 89 5
includes 493 non-evaluable patients BCLC,
Barcelona Clinic Liver Cancer ECOG PS, Eastern
Cooperative Oncology Group performance status
TNM, tumor node metastasis Marrero J, et al. J
Clin Oncol 31, 2013 (suppl abstr 4126)
11
GIDEON final analysis overall
treatment-emergent safety data by CP status
of n Child-Pugh A (n1968) Child-Pugh B (n666) Child-Pugh C (n74) total (n3202)a
AEs (all grades) 84 88.6 91.9 85.3
Drug-related AEs (all grades) 68.5 64.4 39.2 66.0
Serious AEsb (all grades) 36.0 60.4 70.3 43.3
Drug-related serious AEs (all grades) 8.8 14.1 2.7 9.3
All grade 3 or 4 32.5 31.6 17.6 31.8
Drug-related grade 3 or 4 25.5 22.0 10.8 23.6
AEs resulting in permanent discontinuation of sorafenib 28.9 40.1 43.2 31.4
Deathsc 17.7 35.9 51.4 23.7
Patients who received gt1 dose of sorafenib and
had gt1 follow-up assessment were included in the
safety analysis. aIncludes 493 non-evaluable
patients bAny AE occurring at any dose that
results in any of the following outcomes death
life-threatening hospitalization or prolongation
of existing hospitalization persistent or
significant disability/incapacity congenital
anomaly/birth defect medically important event
cTreatment-emergent deaths occurring up to 30
days after last sorafenib dose Marrero J, et al.
J Clin Oncol 31, 2013 (suppl abstr 4126)
12
GIDEON final analysis rate of drug-related AEsa
by CP status
Rate, event per patient-yeara Child-Pugh A (n1968) Child-Pugh B (n666) Child-Pugh C (n74) Total (n3202)b
Any AE 1.17 25.5 1.41 1.24
Diarrhea 0.48 25.5 0.39 0.51
HFSR 0.54 17.0 0.19 0.50
Fatigue 0.27 14.3 0.49 0.29
Rash / desquamation 0.21 8.6 0.15 0.21
Anorexia 0.18 7.4 0.24 0.18
Nausea 0.09 6.2 0.34 0.12
Pain, abdomen, NOS 0.05 3.6 0.19 0.06
Liver dysfunction 0.03 3.6 0 0.03
aRate calculation based on treatment-emergent AEs
with gt10 incidence and 365.25 days per year
bIncludes 493 non-evaluable patients
Marrero J, et al. J Clin Oncol 31, 2013 (suppl
abstr 4126)
13
GIDEON final analysis onset time of AEs gt
grade 3 by CP status
Time to AE onset (days)
Child-Pugh A
Child-Pugh B

• The onset time of AEs was comparable between
  Child-Pugh A and Child-Pugh B patients, with the
  majority of AEs occurring within the first 30
  days of treatment in both groups

Marrero J, et al. J Clin Oncol 31, 2013 (suppl
abstr 4126)
14
GIDEON final analysis sorafenib dosing and
treatment duration by CP status
Child-Pugh A (n1968) Child-Pugh B (n666) Child-Pugh C (n74) total (n3202)a
Initial dose of 800 mg, of 84 88.6 91.9 85.3
Initial dose of 400 mg, of n 68.5 64.4 39.2 66.0
Median daily dose, mg 36.0 60.4 70.3 43.3
Median treatment duration, weeks 8.8 14.1 2.7 9.3

• Overall and across Child-Pugh subgroups, the
  majority of patients received the recommended
  initial dose of 800 mg
• The median daily dose was similar across
  Child-Pugh subgroups
• Duration of treatment was longer in Child-Pugh A
  patients than in Child-Pugh B patients

aIncludes 493 non-evaluable patients Marrero J,
et al. J Clin Oncol 31, 2013 (suppl abstr 4126)
15
GIDEON final analysis duration of sorafenib
treatment by CP status
Duration of sorafenib treatment
Child-Pugh A
Child-Pugh B

• Overall, the majority of patients received
  sorafenib for either ,8 weeks (29.5) or gt24
  weeks (35.9), and 31.2 of patients received
  sorafenib for gt28 weeks
• In Child-Pugh B patients treated with sorafenib,
  25.7 were treated for 24 weeks

Marrero J, et al. J Clin Oncol 31, 2013 (suppl
abstr 4126)
16
GIDEON final analysis OS by CP status
Overall survival

• Median overall survival (OS months) was longer
  in Child-Pugh A patients than in Child-Pugh B and
  C patients (13.6 vs 5.2 and 2.6, respectively)

CI, confidence interval Marrero J, et al. J Clin
Oncol 31, 2013 (suppl abstr 4126)
17
GIDEON final analysis TTP by CP status
Time to progression

• Time to progression (TTP) was comparable between
  Child-Pugh A and B patients

The imaging examination interval was at the
investigators discretion
Marrero J, et al. J Clin Oncol 31, 2013 (suppl
abstr 4126)
18
GIDEON final analysis OS by BCLC stage
Overall survival

• Patients with BCLC stage A had a median OS 3
  times that of patients with BCLC stage C

Bronovicki J-P, et al. Presented at ECC 2013. P
2594
19
GIDEON final analysis TTP by BCLC stage
Time to progression
Bronovicki J-P, et al. Presented at ECC 2013. P
2594
20
GIDEON final analysis OS by TNM stage
Overall survival

• Median OS (months) was similar across TNM stages
  IIIA, IIIB, IIIC, and IV (9.5 vs 9.2 vs 10.8 vs
  9.1)

TNM, tumor node metastasis
Bronovicki J-P, et al. Presented at ECC 2013. P
2594
21
GIDEON final analysis TTP by TNM stage
Time to progression
TNM, tumor node metastasis
Bronovicki J-P, et al. Presented at ECC 2013. P
2594
22
GIDEON final analysis OS by ECOG performance
status
Overall survival

• Median OS was greater in patients with an ECOG PS
  of 0 or 1 than in patients with an ECOG PS of 2
  or 3

Bronovicki J-P, et al. Presented at ECC 2013. P
2594
23
GIDEON final analysis TTP by ECOG performance
status
Time to progression
Bronovicki J-P, et al. Presented at ECC 2013. P
2594
24
Conclusions

• The safety profile of sorafenib in uHCC patients
  appears consistent, irrespective of liver
  function
• AEs observed across Child-Pugh subgroups were in
  keeping with the known AE profile of sorafenib
• Child-Pugh status does not appear to influence
  the approach to sorafenib dosing, although
  duration of treatment is shorter in Child-Pugh B
  patients than in Child-Pugh A patients
• Discontinuation of sorafenib due to AEs is higher
  in Child-Pugh B patients
• Consistent with previous reports, Child-Pugh
  status is a strong prognostic factor for OS in
  uHCC patients, regardless of treatment with
  sorafenib
• TTP was similar in Child-Pugh A and Child-Pugh B
  patients, while OS was longer in Child-Pugh A
  patients

Marrero J, et al. J Clin Oncol 31, 2013 (suppl
abstr 4126)
25
GIDEON final analysis the European subset

• A total of 1113 patients in 22 European countries
  were evaluable for safety
• At study initiation the majority of European
  patients (82.4) started sorafenib therapy at the
  full prescribing dose of 800 mg/day 15.4
  received 400 mg/day of sorafenib and 2.2
  received an alternative dose

Alternative doses included 200 and 600 mg/day
Daniele B, et al. Presented at ECC 2013. P 2581
26
GIDEON final analysis - the European subset
baseline patients characteristics by initial dose
of n 400 mg/day (n171) 800 mg/day (n917) Overall (n1113)
Male 84.8 83.6 83.3
Median age, years (range) 69.0 (1590) 66.0 (1994) 66.0 (1594)
Etiology of underlying liver disease, a
Hepatitis B 18.7 18.2 18.1
Hepatitis C 36.3 34.8 35.6
Alcohol use 30.4 35.1 34.3
NASH 2.9 3.4 3.2
Unknown 17.0 17.6 17.2
ECOG PS,
0 31.6 47.4 45.4
1 45.0 38.4 39.2
2 12.9 9.6 10.1
3 5.3 1.1 1.7
4 0 0.1 lt0.1
Unknown 5.3 3.4 3.6
aBaseline data collected at study entry, patients
may have multiple responses
Daniele B, et al. Presented at ECC 2013. P 2581
27
GIDEON final analysis - the European subset
baseline patients characteristics by initial dose
of n 400 mg/day (n171) 800 mg/day (n917) Overall (n1113)
Child-Pugh status, b
A 58.5 66.0 64.8
B 25.7 18.8 19.9
C 1.8 1.0 1.1
Not evaluablec 14.0 14.3 14.3
BCLC stage, b
A 10.5 7.5 8.5
B 23.4 24.3 24.3
C 40.9 55.9 52.9
Not evaluable/unknownd 18.7 8.3 10.0
Missinge 0.6 0.2 0.3
bAt study entry cNecessary data for scoring were
not collected in investigators routine practice
dNo record is available, eg transfer from other
hospitals, data to assess BCLC are not available
eNo data entry on case report form for missing
patients
Daniele B, et al. Presented at ECC 2013. P 2581
28
GIDEON final analysis - the European subset
baseline patients characteristics by initial dose
of n 400 mg/day (n171) 800 mg/day (n917) Overall (n1113)
TNM stage, b
I 6.4 4.7 5.6
II 13.5 10.8 11.1
IIIa 34.5 30.4 31.1
IIIb 1.8 2.4 2.3
IIIc 8.2 11.6 10.9
IV 20.5 28.7 27.2
Not evaluablec 14.6 11.3 11.7
Time from initial diagnosis to start of sorafenib therapy
Number of patients with available data 140 (81.8) 782 (85.3) 941 (84.6)
Median, months 2.84 3.83 3.72
bAt study entry cNecessary data for scoring were
not collected in investigators routine practice
Daniele B, et al. Presented at ECC 2013. P 2581
29
GIDEON final analysis - the European subset
history of of prior treatment by prior TACE and
ctTACE
of n Prior TACE n368 No prior TACE n745 Concomitant TACE n52 No concomitant TACE n1061 Overall n1113
Surgery 15.5 15.4 7.7 15.8 15.5
Locoregional therapy 100 15.6 78.8 41.8 43.5
TACE 100 0 73.1 34.1 33.1
RFA 26.4 9.3 17.3 14.8 14.9
HAI 1.6 0.7 0 1.0 1.0
PEI 8.2 3.9 3.8 5.4 5.3
Other LRTs 1.4 1.1 1.9 1.1 1.2
Systemic therapy a 3.5 3.9 1.9 1.1 3.8
Other non-systemic therapy b 1.1 1.1 1.9 3.9 1.2
Patients in the concomitant TACE groups may also
be part of the prior TACE group aChemotherapy,
immunotherapy, or others bRadiotherapy and other
locoregional therapy ct, concomitant HAI,
hepatic arterial infusion LRT, locoregional
therapy PEI, percutaneous ethanol injection
RFA, radiofrequency ablation
P. I. Stal, et al. Presented at UEGW. P 1196
30
GIDEON final analysis - the European subset
duration of sorafenib treatment by initial dose
Duration of sorafenib treatment

• The duration of treatment was greater for the 800
  mg/day patient group compared with the 400 mg/day
  patient group (18.0 vs 13.0 weeks)

Time in weeks from initial visit to last visit
date (for ongoing patients) or last dosing date 1
Daniele B, et al. Presented at ECC 2013. P 2581
31
GIDEON final analysis - the European subset OS
by initial dose
Overall survival

• Patients who received an initial dose of
  sorafenib of 800 mg/day had greater median OS
  (12.1 months 95 CI 10.513.8) than those
  patients who started on 400 mg/day (9.4 months
  95 CI 6.312.6)

Daniele B, et al. Presented at ECC 2013. P 2581
32
GIDEON final analysis - the European subset OS
by TACE and ct-TACE treatment
Overall survival

• Median OS was greater in patients with prior TACE
  (464 days, 15.3 months) compared with those who
  did not receive prior TACE (309 days, 10.2
  months)
• The same result was seen in patients who received
  ctTACE (494 days, 16.3 months) compared with no
  ctTACE (336 days, 11.1 months)

P. I. Stal, et al. Presented at UEGW. P 1196
33
GIDEON final analysis OS by underlying liver
disease aetiology
Overall survival according to hepatitis B as
aetiology
Overall survival according to hepatitis C as
aetiology
14.2 months (432 days)
11.7 months (358 days)
Overall survival according to alcohol use
While a small advantage in OS was reported for
patients with hepatitis C, TTP was comparable
for each of the underlying aetiologies
12.9 months (394 days)
Ratziu V, et al. Presented at EASL 2014. P957
34
GIDEON final analysis TTP by underlying liver
disease aetiology
HCC aetiology Median TTP, months (days)
Hepatitis B 6.5 (197)
Hepatitis C 6.0 (184)
Alcohol use 6.1 (187)

• Median time to progression (TTP) in the
  intent-to-treat (ITT) population (n1113) was
  comparable for patients with known underlying
  aetiologies

Ratziu V, et al. Presented at EASL 2014. P957
35
GIDEON final analysis - the European subset
rate of treatment-emergent AEs and SAEs by
initial dose
400 mg/day (n171) 800 mg/day (n917) Overall (n1113)
AEs (all grades) 95.9 87.8 88.3
Drug-related AEs (all grades) 73.7 68.8 68.8
Serious Aes a (all grades) 57.3 44.5 46.2
Drug-related serious AEs (all grades) 11.1 11.1 10.9
AEs resulting in permanent discontinuation of study drug 43.9 33.7 35.1

• There was an increase in AEs (all grades) in the
  group receiving an initial dose of 400 mg/day vs
  800 mg/day (95.9 vs 87.8), and an increase in
  drug-related AEs (73.7 vs 68.8) and serious Aes
  (57.3 vs 44.5)
• All other AE categories were comparable between
  the two groups

Includes 25 patients who received an alternative
dose of sorafenib aAny AE occurring at any dose
that results in any of the following outcomes
death life-threatening hospitalization or
prolongation of existing hospitalization
persistent or significant disability /
incapacity congenital anomaly / birth defect
medically important event
Daniele B, et al. Presented at ECC 2013. P 2581
36
GIDEON final analysis - the European subset
rate of treatment-emergent AEs and SAEs by prior
TACE and ctTACE
Prior TACE n368 No prior TACE n745 Ct-TACE n52 No ct-TACE n1061 Overall n1113
AEs (all grades) 89.4 87.8 94.2 88.0 88.3
Drug-related AEs (all grades) 76.4 65.1 86.5 68.0 68.8
Serious AEs (all grades) 40.8 48.9 36.5 46.7 46.2
Drug-related serious AEs (all grades) 11.7 10.5 7.7 11.0 10.9
AEs resulting in permanent discontinuation of study drug 39.4 33.0 30.8 35.3 35.1

• Overall, AEs and serious AEs (SAEs) were similar
  in the prior TACE and no prior TACE populations.
  The same observation was seen in the ctTACE and
  no ctTACE populations
• The incidence of drug-related AEs was greater in
  patients who received prior TACE (76.4) than
  those who received no prior TACE (65.1)
• The same pattern was seen for patients who had
  received prior ctTACE (86.5) compared with
  patients who had received no ctTACE (68.0)

Patients in the concomitant TACE groups may also
be part of the prior TACE group aAny AE
occurring at any dose that results in any of the
following outcomes death life-threatening
hospitalization or prolongation of existing
hospitalization persistent or significant
disability /incapacity congenital anomaly /
birth defect medically important event P. I.
Stal, et al. Presented at UEGW. P 1196
37
GIDEON final analysis - the European subset
rate of drug-related AEs by liver disease
aetiology
Overview of treatment-emergent AEs according to
aetiology of patients underlying liver disease
Hepatitis B n201 Hepatitis C n396 Alcohol use n507 NASH n36 Overall n1113
AEs (all grades) 90.0 85.4 89.2 82.2 83.3
Drug-related AEs (all grades) 67.2 67.9 69.6 63.9 68.8
Serious AEs (all grades) 42.8 42.2 50.9 40.3 46.2
Drug-related serious AEs (all grades) 12.1 7.0 10.8 8.9 10.9
AEs resulting in permanent discontinuation of study drug 29.4 32.8 37.3 36.1 35.1
Treatment-emergent deaths 28.4 22.2 27.4 22.5 25.7

• The incidence of AEs (all grades), drug-related
  Aes (all grades), serious AEs (all grades), and
  AEs resulting in permanent discontinuation of
  study drug were comparable in patients with all
  known underlying aetiologies

Baseline data collected at study entry, patients
may have multiple responses aDeaths while on
treatment or within 30 days of last sorafenib
dose NASH, non-alcoholic steatohepatitis
Ratziu V, et al. Presented at EASL 2014. P957
38
Conclusions

• In this real-life clinical practice setting, the
  majority of patients (82.4) received the
  recommended initial sorafenib dose of 800 mg/day
• Patients on 800 mg/day tended to continue on
  treatment for longer, have less discontinuations
  and have a greater median overall survival
  compared with those patients receiving the lower
  400 mg/day dose
• Patients treated with ctTACE lived longer than
  those with no ctTACE. However, it is not clear
  that this finding is a result of treatment effect
  or the patients selection for ctTACE, due to the
  limitation and potential bias of an observational
  study
• The incidences of AEs for the 800 mg/day and 400
  mg/day sorafenib doses were similar
• Adverse event profiles of sorafenib are
  comparable regardless of history of prior TACE or
  ctTACE treatment

Daniele B, et al. Presented at ECC 2013. P 2581
P. I. Stal, et al. Presented at UEGW. P 1196
39
GIDEON final analysis the Italian subset

• Overall, 278 patients have been enrolled in Italy
  between June 09 and April 11

Salvatore DA, et al. Presented at EASL 2014. P
237
40
GIDEON final analysis - the Italian
subset baseline patients characteristics
Baseline Factor n 274
Age median (range) 70 (44-90)
Sex n ()
Male 227 (82.8)
Female 47 (17.2)
ECOG PS,
0 168 (61,3)
1 84 (30,7)
2 20 (7,3)
Missing 2 (0,7)
TNM stage
I 24 (8,8)
II 43 (15,7)
IIIa 98 (35,8)
IIIb 3 (1,1)
IIIc 34 (12,4)
IV 52 (19)
N/A 20 (7,3)
BCLC
A 33 (12)
B 87 (32)
C 142 (52)
D 5 (1,5)
N/E 7 (2,5)
Salvatore DA, et al. Presented at EASL 2014. P
237
41
GIDEON final analysis - the Italian subset
history of of prior treatment by prior TACE and
ctTACE
of n Prior TACE n100 No prior TACE n174 Concomitant TACE n11 No concomitant TACE n263 Overall n274
Surgery 16 14.4 9.1 15.2 15
Locoregional therapy 100 27.5 72.7 52.3 53.6
TACE 100 0 72.7 35 36.5
RFA 39 18.7 27.3 25.9 25.9
HAI 2 0.6 0 1.1 1.1
PEI 17 11.7 9.1 13.7 13.5
Other LRTs 0.06 1 0 0.8 0.7
Systemic therapy a 1 0.6 0.8 0 0.7
Other non-systemic therapy b 2 0.6 9.1 0.8 1.1
Patients in the concomitant TACE groups may also
be part of the prior TACE group aChemotherapy,
immunotherapy, or others bRadiotherapy and other
locoregional therapy. HAI, hepatic arterial
infusion LRT, locoregional therapy PEI,
percutaneous ethanol injection RFA,
radiofrequency ablation TACE, transarterial
chemoembolization
Vito L, et al. Presented at EASL 2014. P 447
42
GIDEON final analysis - the Italian subset OS
by BCLC
Overall survival

• Patients with BCLC stage B had longer OS than
  BCLC stage C median OS was not reached for
  patients with BCLC stage A

Salvatore DA, et al. Presented at EASL 2014. P
237
43
GIDEON final analysis - the Italian subset OS
by ECOG-PS
Overall survival

• The majority of patients had an ECOG PS of 0 or
  1. Median OS was greater in patients with an ECOG
  PS of 0 or 1 than in patients with an ECOG PS of 2

Salvatore DA, et al. Presented at EASL 2014. P
237
44
GIDEON final analysis - the Italian subset OS
by TACE
Overall survival

• Median OS was greater in patients with prior TACE
  (697 days, 22.9 months) compared with those who
  did not receive prior TACE (341 days, 11.2
  months)

Vito L, et al. Presented at EASL 2014. P 447
45
GIDEON final analysis - the Italian subset OS
by ctTACE
Overall survival

• For the small cohort of patients who underwent
  ctTACE mOS was not reached whilst for those no
  ctTACE mOS was 383 days

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46
GIDEON final analysis - the Italian subset
rate of treatment-emergent AEs and SAEs by prior
TACE and ctTACE
Prior TACE n100 No prior TACE n174 Concomitant TACE n11 No concomitant TACE n263 Overall n274
AEs (all grades) 84 78.9 90.9 84.0 80.8
Drug-related AEs (all grades) 79 59.6 90.9 65.8 66.8
Serious Aes a (all grades) 28 32.2 27.3 30.8 30.6
Drug-related serious AEs (all grades) 9 7.6 0 8.5 8.1
AEs resulting in permanent discontinuation of study drug 37 30.4 18.2 33.5 32.8

• The overall incidence of AEs and serious AEs
  (SAEs) was similar in the prior TACE and no prior
  TACE populations. The same observation was seen
  in the ctTACE and no ctTACE populations

Patients in the concomitant TACE groups may also
be part of the prior TACE group aAny AE
occurring at any dose that results in any of the
following outcomes death life-threatening
hospitalization or prolongation of existing
hospitalization persistent or significant
disability / incapacity congenital anomaly /
birth defect medically important event
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47
Conclusions

• The results of the Italian cohort from the GIDEON
  study are consistent with the global results of
  the study
• Patients treated with prior TACE lived longer
  than those with no prior TACE possibly because of
  the earlier stage of disease at initial diagnosis
  among the first group
• Patients treated with ctTACE lived longer than
  those with no ctTACE. However, due to the small
  number of patients treated with ctTACE and to the
  limitation and potential bias of an observational
  study it is not possible to attribute this
  difference to a different treatment effect
• Adverse event profiles of sorafenib are
  comparable among the patients with or without
  prior TACE and ct TACE. Potential differences
  among those receiving or not ctTACE might be
  caused by the small number of patients in the
  ctTACE group

Salvatore DA, et al. Presented at EASL 2014. P
237
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