Sorafenib and HCC:
Is It All About VEGF?
Bert H O'Neil
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, NC
Sorafenib Phase II: Child-Pugh B Cirrhosis
Therapy
Length of therapy (weeks)
Dose reduction
Child-Pugh A
n=98
25
31%
Child-Pugh B
n=38
13
21%
Outcomes
SD (≥4 months)
TTP (median)
OS
Child-Pugh A
n=98
49%
21 weeks
Child-Pugh B
n=38
26%
13 weeks
41 weeks
14 weeks
OS=overall survival; SD=stable disease; TTP=time to tumor progression.
Abou-Alfa GK et al. J Clin Oncol. 2008;26(15S):Abstract 4518.
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Adverse Events (Note Half Exposure for CP B
Patients)
Child-Pugh A
n=98
97
52
Child-Pugh B
n=38
97
68
Fatigue
41
37
Diarrhea
59
47
Hand-foot syndrome
30
13
Increased bilirubin
18
40
Encephalopathy
2
11
Worsening ascites
11
18
Events (%)
All adverse events
Serious adverse events
C-P=Child-Pugh.
Abou-Alfa GK et al. J Clin Oncol. 2008;26(15S):Abstract 4518.
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
GIDEON and C-P B
GIDEON is a registry that tracks the ‘real-world’ use of
sorafenib in about 3200 patients in 32 countries without
a prespecified hypothesis
 The SHARP study was comprised almost exclusively of patients
with well-compensated C-P A) cirrhosis
 GIDEON can provide us with important information on safety and
single-arm efficacy in the C-P B population
GIDEON=Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment
with sorafeNib; SHARP=Study of Heart and Renal Protection.
Llovet J et al. N Engl J Med. 2008;359:378-390.
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
GIDEON and C-P B (cont’d)
Similar numbers started with standard dose sorafenib
Mean and median dose was similar
Surprisingly, dose interruptions and modifications were
similar
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Overview of Treatment-Emergent Safety Data by
Child-Pugh Status*
(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
SAEs‡
37
29
56
63
Drug-related SAEs‡
9
8
15
6
AEs resulting in permanent
discontinuation of sorafenib§
28
24
38
51
Deaths║
22
16
34
37
Total†
% of n
* Data at study entry; †Child-Pugh status missing or not evaluable for 56 patients; ‡An 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; §Any AE; ║Treatment-emergent deaths occurring
up to 30 days after last sorafenib dose.
AEs=adverse events; SAEs=serious adverse events.
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Duration of Sorafenib Therapy by ChildPugh
Status*
≤4 weeks, %
Total
(n=1571)
Child-Pugh A
(<7)
(n=957)
Child-Pugh B
(7-9)
(n=367)
Child-Pugh C
(>9)
(n=35)
17
13
23
46
30%
23
46%
>4-8 weeks, %
18
17
>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
* Data at study entry.
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
23
Preliminary Time-to-Progression*
by Child-Pugh Status† at Study Entry
Child-Pugh A (<7)
(n=984), median (95% CI)
129 (119, 146) days
4.2 months
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
1.0
TTP distribution function
0.9
0.8
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)
* TTP was documented radiological disease progression; RECIST v. 1.0 used for tumor evaluation; † 207 patients not evaluable.
RECIST=Response Evaluation Criteria in Solid Tumors.
Adapted from O’Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Preliminary Overall Survival
by Child-Pugh Status* at Study Entry
Child-Pugh A (<7)
(n=984), median (95% CI)
312 (284, 341) days
10.3 months
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
Survival distribution function
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
100
200
300
400
Time since start of treatment (days)
* 207 patients not evaluable.
CI=confidence interval.
Adapted from O’Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
500
600
What Does GIDEON Add?
GIDEON suggests that safety is similar between CP A and
C-P B patients
However, duration of therapy for the C-P B population was
exceedingly short—8.5 weeks
This suggests that equivalent numbers of adverse events
occur in a shorter period of time
The low number of dose reductions in the CP B population
is also interesting, but is also affected by the short
treatment duration
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
What Does GIDEON Add? (cont’d)
Does GIDEON suggest we should be starting sorafenib at
full dose in future studies in the CP B population?
 YES
Do GIDEON’s results support the routine use of sorafenib
in the CP B population?
 NO—this use should be considered investigational and standard of
care remains best supportive care
 Authors’ conclusions appropriately conservative in this regard
 Reminds us that testing drugs in CP A population is best
Adapted from O'Neil BH et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Sunitinib vs Sorafenib
Sunitinib has good efficacy in RCC compared to sorafenib
and produced Phase II results in HCC comparable to
those seen with sorafenib
Different kinase inhibition profiles might suggest
differential activity between these agents in HCC
 However, no strong a priori hypothesis regarding non–VEGFrelated targets
HCC=hepatocellular carcinoma; RCC=renal cell carcinoma; VEGF=vascular endothelial growth factor.
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Cross-Trial Characteristics
SHARP
n=299
Asian Study
n=150
Sun vs Sor
N=544
65 yrs
52 yrs
59 yrs
87%
85%
84%
Viral hepatitis B/C
19/29%
71/11%
53/22%
Child-Pugh (A/B)
95/5%
97/3%
100/0
ECOG performance status 0/1
54/38%
25/70%
53/47
Vascular invasion/
Extrahepatic spread
36/53%
36/69%
31/76%
19%
48%
NR
100%?
Median age
Male
Surgical resection
Loco-regional therapy
ECOG=Eastern Cooperative Oncology Group; NR=no response.
Llovet J et al. N Engl J Med. 2008;359:378-390; Cheng AL et al. Lancet Oncology. 2009;10:25-34.
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
OS—Primary Endpoint
(ITT Population)
Sunitinib
Median 7.9 months (95% CI: 7.4-9.2)
OS probability (%)
1.00
Sorafenib
Median 10.2 months (95% CI: 8.9-11.4)
0.75
HR 1.30 (95% CI: 1.13-1.50)
P=.0010
0.50
0.25
0.0
0
5
10
15
20
25
30
35
40
Time (months)
Patients at risk
Sunitinib
530
354
208
112
41
8
0
0
0
Sorafenib
544
388
245
139
61
12
1
0
0
P-value based on stratified log-rank test.
CI=confidence interval; HR=hazard ratio.
Adapted from O’Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
What Can We Learn From This Negative Trial
(Other Than the Obvious)?
Was toxicity the main difference-maker?
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Overview of Treatment-Emergent AEs
(All Causes; As-Treated Population)
Sunitinib
(n=526)
100%
45%
Sorafenib
(n=542)
100%
37%
Grade* 3 or 4 AEs
82%
74%
Grade* 5 AEs
19%
17%
Discontinued due to AEs
13%
13%
Temporarily discontinued due to AEs
77%
59%
Dose reduced due to AEs
30%
35%
Any AE
Serious AEs
* National Cancer Institute—Common Terminology Criteria for AEs (NCI-CTCAE) v3.0.
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Deaths on Study*
Event
Sunitinib
(n=526)
Sorafenib
(n=542)
Deaths (all causes; n, %)
92 (17%)
83 (15%)
Disease progression
76%
86%
Toxicity
18%
2%
Dehydration ± organ failure
3%
0
CNS hemorrhage
3%
0
Esophageal varices/GI hemorrhage†
3%
1%
7%
13%
Pneumonia
2%
1%
Septic shock/sepsis
1%
2%
0
2%
Cause (% of total deaths: SU n=92; SO n=83)†
Other/unknown cause
Unknown reason
* Deaths during the study or within 28 days after the last dose of study medication. Participants may have more
than one cause of death; †Includes deaths attributed to tumor hemorrhage.
CNS=central nervous system; GI=gastrointestinal; SU=sunitinib; SO=sorafenib.
Adapted from O’Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
What Can We Learn From This Negative Trial
(Other Than the Obvious)?
Are there potential biologic explanations for differential
results?
 VEGFRs?
 RAFs
 Other?
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Kinase Profiles
Sunitinib
PDGFRB
Sorafenib
0.075
MLCK
23
KIT
0.1
KIT
0.37
TNIK
25
DDRI
1.5
FLT3
0.47
MERTK
26
XAK
6.3
PDGFRA
0.79
CLK4
29
DDR 2
6.6
RIOK1
35
FLT 3
13
DRAK 1
1
VEGFR2
1.5
LKB1
38
PET
13
VEGFR1 (FLT-1)
1.8
PIP5K2B
39
CFS 1R
28
BIKE
5.5
MAP4K5
41
VEGFR1 (FLT-1)
31
PHKG 1
5.5
ARK 5
48
B
37
PHKG 2
5.9
JAK 1
49
FLK 8
46
9
MYLK2
49
VEGFR2
59
AAK 1
11
TYRO3
49
PDGFRA
62
RET
12
FLT4
50
TIE 1
68
CSNK 1E
13
MST 2
56
FLT 4
95
ITK
13
SLK
56
CSNK 1D
15
MST 3
63
SgK 085
15
TTK
63
MAP4K1
16
BLK
65
PAK 3
16
CAMK2A
80
STK 33
17
CSNK 2A1
81
AMPK 1
19
PTK 2B
82
LOK
19
AMPK 2
MST 1
19
PLK
100
CLK 2
20
TRKA
100
GAK
20
CLK 1
22
DAPK3
22
AXL
BRAF V600E
260
RAF1 (c-RAF)
230
89
Karaman MW et al. Nat Biotechnol. 2008;26(1):127-132.
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Inhibited by Sunitinib
Inhibited by both
Inhibited by Sorafenib
No Activity With MEK Inhibitor Selumetinib
(AZ6244) in HCC
pERK1/2
ERK1/2
Zero radiographic responses
TTP ≈8 weeks
O’Neil B et al. J Clin Oncol. 2011; in press.
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Sorafenib and HCV-Related HCC
Subgroup analysis of HCV-infected patients in SHARP
 Placebo 7.9 mo
 Sorafenib group 14 mo
HCV=hepatitis C virus.
Bolondi L et al. ASCO GI Annual Meeting; January 25-27, 2008; Orlando, FL.
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
OS in Patients With HCV Infection
(Exploratory Analysis)
1,00
ITT Population
Sunitinib (n=113)
Median 9.2 months (95% CI: 7.0-12.0)
OS probability (%)
0,75
Sorafenib (n=119)
Median 17.6 months (95% CI: 11.4-)
HR 1.52 (95% CI: 1.09-2.13)
P=.0165
0,50
0,25
0,00
0
5
10
15
20
25
30
Time (months)
Median OS, months
HR (95% CI)
P-value (1-sided)
Sunitinib
ITT
Sorafenib
ITT
Sunitinib
Asia
Sorafenib
Asia
Sunitinib
Ex-Asia
Sorafenib
ex-Asia
9.2
17.6
9.7
12.6
8.6
18.3
1.52 (1.09-2.13)
1.40 (0.92-2.14)
1.76 (0.99-3.10)
.0165
.0721
.0544
P-values based on stratified log-rank test.
Adapted from O’Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
HCV NS5A and HCC
Nonstructural HCV protein that interacts with a large
number of cellular proteins, including oncogenes
Recent evidence suggests c-RAF is part of the HCV
replication complex
 Sorafenib produced c-RAF dependent decrease in HCV replication
 This effect was not replicated with 2 different MEK inhibitors!
Himmelsbach K et al. Gut. 2009;58:1644-1653.
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Activity
HCV replication inhibition
90,000
80,000
70,000
60,000
50,000
40,000
30,000
20,000
10,000
0
6-cont
5 M
7.5 M
10 M
15 M
20 M
sorafenib sorafenib sorafenib sorafenib sorafenib
sorafenib
Before therapy
During therapy
1.00E-07
actin
Genomes/mL
HCV
1.00E-06
1.00E-05
1.00E-04
1.00E-03
1.00E-02
Patient 1
Himmelsbach K et al. Gut. 2009;58:1644-1653.
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Patient 2
Patient 3
Do HCV-Associated miRNAs Sensitize Cells to
Sorafenib?
140
Hep-SWX cells
Hep-394 cells
120
Control pre-miR
Pre-miR-193b
120
Cell viability (%)
Cell viability (%)
100
100
80
60
40
80
60
40
20
20
0
0
0.001
0.001
0.1
Sorafenib (M)
0.1
10
10
Cells transfected with HCV genome
Sorafenib (M)
Cells transfected with miRNA
induced by HCV
miRNA=micro RNA.
Braconi C et al. Clin Cancer Res. 2010;16(3)957-966.
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
1000
Summary
Sorafenib can be used with relative safety in the CP B HCC
population
 But OS appears to be short
Sorafenib was superior to sunitinib for HCC
 The superiority of sorafenib over sunitinib in HCV-infected patients
raises interesting questions about non–VEGFR-related activities of
sorafenib
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Do We Need More VEGF Inhibitors
for HCC?
Experience in RCC might suggest yes
A better-tolerated VEGFR agent would be welcome
 Sunitinib does not fill this role
 Others may, including bevacizumab
 Studies of brivanib and linifanib vs sorafenib should report in the
near future
Caution that Phase II data for all of these agents have
looked similar, risk of Phase III trial failure may be high
Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.