GIDEON (Global Investigation of therapeutic
DEcisions in hepatocellular carcinoma [HCC] and
Of its treatment with sorafeNib) second interim
analysis in >1500 patients: clinical findings in
patients with liver dysfunction
Jorge A. Marrero, M.D., M.S.
Comprehensive Cancer Center,
University of Michigan, Ann Arbor, MI, United States
R. Lencioni, M. Kudo, S. L. Ye,
K. Nakajima, F. Cihon, A. Venook
Introduction
Sorafenib is the only systemic therapy indicated
to treat HCC1
 In two Phase III studies (SHARP and Asia-Pacific), sorafenib significantly
improved OS in patients with uHCC2-3
Pivotal studies generally included patients with preserved liver
function
 Investigation of sorafenib in wider patient groups is needed4
GIDEON is the largest prospective study in uHCC ever conducted
 In total, 3322 patients have been enrolled from 39 countries
uHCC, unresectable hepatocellular carcinoma; OS, overall survival;
1.NCCN Guidelines™: Hepatobiliary Cancers. Available at: http://www.nccn.org/ Accessed: June 7, 2011. 2. Llovet JM, et al. N
Engl J Med. 2008;359(4):378-390. 3. Cheng AL, et al. Lancet Oncol. 2009;10(1):25-34. 4. Lencioni R, et al. Int J Clin Prac.
2010;64(8):1034-1041.
The GIDEON study design and objectives
GIDEON is a non-interventional study
 Primary objective: to evaluate safety of sorafenib in patients with uHCC
who are candidates for systemic therapy and for whom the decision to
treat with sorafenib was made in clinical practice
 Secondary objectives: efficacy, duration of therapy; methods of patient
evaluation, diagnosis and follow-up; co-morbidities and practice patterns
GIDEON will also provide information in patient subgroups
where data are currently limited
 Including patients with Child-Pugh B status who were generally excluded
from sorafenib Phase III trials in uHCC
uHCC, unresectable hepatocellular carcinoma;
Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting .
The GIDEON study:
second interim analysis
Per protocol the second interim analysis was planned when ~1500 treated
patients were followed for ≥4 months
1571 patients in the safety population
 Includes patients who received ≥1 dose of sorafenib and had ≥1 follow-up
assessment after start of treatment
1612 patients in the ITT population
 ITT population used for analysis of OS and TTP
 Includes patients who received ≥1 dose of sorafenib >2 days before study entry;
excludes patients previously treated with sorafenib
All statistical analyses performed were descriptive in nature
ITT, intent to treat; OS, overall survival; TTP, time-to-progression
Lencioni R, et al. Int J Clin Prac. 2010;64(8):1034-1041.
Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting .
Selected patient baseline characteristics
by Child-Pugh status at start of therapy
Totala
(n=1571)
Child-Pugh A
(<7)
(n=957)
Child-Pugh B
(7-9)
(n=367)
Child-Pugh C
(>9)
(n=35)
100
61
23
2
Male / female,
% of n
82 / 18
83 / 17
81 / 19
83 / 17
Median age,
years (range)
62 (18-98)
64 (18-94)
61 (23-86)
58 (39-82)
0
40
50
26
14
1
43
39
47
54
2
9
6
17
14
3
2
1
3
14
4
<1
<1
0
0
Patients, % of n
ECOG PS, % of n
aChild-Pugh
status unknown for 5 patients; 207 patients are not evaluable and not tabulated
ECOG PS, Eastern Cooperative Oncology Group performance status
Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting .
Selected patient baseline characteristics
by Child-Pugh status at start of therapy
Totala
(n=1571)
Child-Pugh A
(<7)
(n=957)
Child-Pugh B
(7-9)
(n=367)
Child-Pugh C
(>9)
(n=35)
I
7
7
7
11
II
11
13
9
9
III
34
34
39
34
IV
36
37
31
34
A
7
8
5
3
B
19
20
21
0
C
54
58
54
11
D
6
4
4
77
% of n
TNM stage
BCLC stage
aChild-Pugh
status unknown for 5 patients; 207 patients are not evaluable and not tabulated
BCLC, Barcelona Clinic Liver Cancer; TNM, tumor node metastases
Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting .
Initial sorafenib dose by Child-Pugh status and
Child-Pugh B status
Totala
(n=1571)
Child-Pugh A
(<7)
(n=957)
Child-Pugh B
(7-9)
(n=367)
Child-Pugh C
(>9)
(n=35)
800 mg
74
77
71
69
600 mg
1
1
1
0
400 mg
22
20
23
26
200 mg
3
2
3
6
100 mg
<1
<1
0
0
% of n
aInitial
dosing data missing for 8 patients; Child-Pugh status unknown for 5 patients
Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting .
Sorafenib dosing and average daily dosing by ChildPugh statusa
Totalb
(n=1571)
Child-Pugh A
(<7)
(n=957)
Child-Pugh B
(7-9)
(n=367)
Child-Pugh C
(>9)
(n=35)
Mean daily dose, mgc
630
631
633
619
Median daily dose, mgc
693
680
721
680
Dose increase, % of n
16
18
13
3
Dose increase to
800 mg from lower
initial doses, % of n
6
6
5
0
12
13
10
3
2
3
4
2
0
3
1
1
1
0
4
0.2
0.1
0
0
Number of dose
increases
1
aData
at study entry; bDosing data missing for 8 patients; Child-Pugh status unknown for 5 patients; cAssessed in the 79% of patients for whom dosing
data were available
Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting .
Sorafenib dose interruptions and modifications by ChildPugh statusa
Totalb
(n=1571)
Child-Pugh A
(<7)
(n=957)
Child-Pugh B
(7-9)
(n=367)
Child-Pugh C
(>9)
(n=35)
Dose
interruption
24
24
22
20
Dose
modification
42
45
37
34
Dose increase
16
18
13
3
Dose reduction
33
37
27
29
% of n
aData
at study entry
data missing for 8 patients; Child-Pugh status unknown for 5 patients
bDosing
Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting .
Duration of sorafenib therapy
by Child-Pugh statusa
Total
(n=1571)
Child-Pugh A
(<7)
(n=957)
Child-Pugh B
(7-9)
(n=367)
Child-Pugh C
(>9)
(n=35)
≤4 weeks, %
17
13
23
46
>4-8 weeks, %
18
17
23
23
>8-20 weeks, %
35
38
28
23
>20-28 weeks, %
12
13
9
0
>28 weeks, %
16
18
14
6
Median treatment
duration, weeks
12
14
9
4
aData
at study entry
Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting .
Overview of treatment-emergent safety data
by Child-Pugh statusa
Totalb
(n=1571)
Child-Pugh A
(<7)
(n=957)
Child-Pugh B
(7-9)
(n=367)
Child-Pugh C
(>9)
(n=35)
AEs (all grades)
83
82
89
86
Drug-related AEs (all grades)
64
67
63
46
AEs (grade 3/4)
30
29
31
34
Drug-related AEs (grade 3/4)
23
24
22
23
SAEsb
37
29
56
63
9
8
15
6
AEs resulting in permanent
discontinuation of sorafenibd
28
24
38
51
Deathse
22
16
34
37
% of n
Drug-related SAEsc
aData
at study entry; bChild-Pugh status missing or not evaluable for 56 patients; cAn SAE is defined as any 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; dAny AE; eTreatment-emergent deaths occurring up to 30 days after last sorafenib dose
AEs, adverse events; SAEs, serious adverse events
Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting .
Overview of treatment-emergent safety data
by Child-Pugh B statusa
Child-Pugh B
(7-9)
(n=367)
Child-Pugh B
(7)
(n=196)b
Child-Pugh B
(8)
(n=96)b
Child-Pugh B
(9)
(n=69)b
AEs (all grades)
89
88
90
94
Drug-related AEs (all grades)
63
67
60
59
AEs (grade 3/4)
31
29
33
36
Drug-related AEs (grade 3/4)
22
21
24
23
SAEsc
56
45
65
77
Drug-related SAEsc
15
14
15
19
AEs resulting in permanent
discontinuation of sorafenibd
38
36
39
48
Deathse
34
30
39
39
% of n
aData
at study entry; bPatients with Child-Pugh status available; cAn SAE is defined as any 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; dAny AE; eTreatment-emergent deaths occurring up to 30 days after last sorafenib dose
AEs, adverse events; SAEs, serious adverse events
Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting .
Treatment-emergent drug-related AEs
by Child-Pugh statusa,b
Total
Any grade
(n=1571)
Total
G3/G4
(n=1571)
Child-Pugh A
(<7)
(n=957)
Child-Pugh B
(7-9)
(n=367)
Child-Pugh C
(>9)
(n=35)
Diarrhea
25
3/0
26
23
9
HFSR
24
5/0
29
15
3
Fatigue
14
3 / <1
15
11
17
Rash /
desquamation
12
2 / <1
13
10
6
Anorexia
9
1/0
10
8
3
Hypertension
7
2/0
9
3
0
Alopecia
6
0/0
8
3
3
Nausea
6
<1 / 0
5
5
6
Weight loss
5
<1 / 0
5
4
3
Pain, abdomen,
NOS
3
<1 / 0
3
4
6
% of n
aIncidence
≥5% in any group and any grade; bAt start of therapy
HFSR, hand-foot skin reaction; NOS, not otherwise specified
Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting .
Cause of deatha,b while on sorafenib therapy or within 30
days of discontinuing therapyc
Totald
(n=343)
Child-Pugh Ae
(<7)
(n=154)
Child-Pugh Be
(7-9)
(n=125)
Child-Pugh C
(>9)
(n=13)
138 (40)
61 (40)
50 (40)
4 (31)
38 (11)
15 (10)
15 (12)
3 (23)
9 (3)
4 (3)
2 (2)
1 (8)
Liver-related
49 (14)
22 (14)
18 (14)
2 (15)
HCC-related and
MOF
15 (4)
8 (5)
4 (3)
0
MOF
22 (6)
10 (6)
8 (6)
1 (8)
n (%) deaths
HCC-related
HCC- and liverrelated
HCC- and liverrelated, and MOF
aIncidence
>2% in total group; bPatients may be included in more than one cause of death category; bBy Child-Pugh status at study entry; dChild-Pugh
status missing for 1 patient; eData missing for 7 Child-Pugh A and 7 Child-Pugh B patients
HCC, hepatocellular carcinoma; MOF, multi-organ system failure
Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting .
Preliminary overall survival by Child-Pugh
statusa at study entry
Child Pugh A (<7)
(n=984), median
(95% CI) 312 (284,
341) days
10.3 months
1.0
Survival distribution function
0.9
Child Pugh B (7-9)
(n=376), median
(95% CI) 147 (126,
189) days
4.8 months
Child Pugh C (>9)
(n=36), median
(95% CI) 62 (46, 94)
days
2.0 months
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
a207
patients not evaluable
CI, confidence interval
100
200
300
400
500
600
Time since start of treatment (days)
Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting .
Preliminary time-to-progressiona by
Child-Pugh statusb at study entry
Child Pugh A (<7)
(n=984), median
(95% CI) 129 (119,
146) days
4.2 months
1.0
TTP distribution function
0.9
0.8
Child Pugh B (7-9)
(n=376), median
(95% CI) 109 (93,
140) days
3.6 months
Child Pugh C (>9)
(n=36), median
(95% CI) 64 (28,
110) days
2.1 months
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
100
200
300
400
500
Time since start of treatment (days)
aTTP
was documented radiological disease progression; RECIST v 1.0 used for tumor evaluation; b207 patients not evaluable
TTP, time-to-progression; RECIST, Response Evaluation Criteria In Solid Tumors
Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting .
Conclusions (1)
Based on the second interim analysis, there is no evidence
suggesting that treating physicians use a different dosing
strategy for Child-Pugh B patients compared with ChildPugh A patients
Duration of sorafenib therapy was shorter in Child-Pugh B
patients than in Child-Pugh A patients
Compared with Child-Pugh A patients, Child-Pugh B patients
did not have a higher incidence of drug-related AEs, but had
a higher incidence of liver-associated AEs
In patients with moderate liver dysfunction, no unexpected
AEs were observed
Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting .
Conclusions (2)
The vast majority of deaths were due to HCC or underlying
liver disorders
The differences in patient outcomes across Child-Pugh groups
likely reflect differences in prognosis
Consistent with previously reported studies, these preliminary
data indicate that Child-Pugh status appears to be a useful
prognostic factor for overall survival
The GIDEON study is ongoing, and the safety, tolerability, and
efficacy of sorafenib in HCC patients will continue
to be evaluated
Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting .