Phase III Trial of Sunitinib (Su) vs Sorafenib
(So) in Advanced Hepatocellular Carcinoma
(HCC)
A Cheng, Y Kang, D Lin, J Park, M Kudo,
S Qin, M Omata, SW Pitman Lowenthal,
S Lanzalone, L Yang, M Lechuga, E Raymond
SUN1170 Hepatocellular Carcinoma (HCC)
Study—Background and Rationale
Liver cancer is the third leading cause of cancer-related death worldwide1
 Approximately 80% of HCC cases are attributable to hepatitis B virus (HBV) or hepatitis
C virus (HCV) infection2
Sunitinib is an oral inhibitor of VEGFRs and other receptor tyrosine kinases
implicated in HCC angiogenesis, lymphangiogenesis, and disease
pathogenesis3-5
In 3 phase II studies, sunitinib had encouraging antitumor activity in patients with
advanced HCC6-8
 Clinical benefit rate: 38%-53%, TTP: 1.5-5.3 months, OS: 8.0-9.8 months
The open-label, Phase III SUN1170 trial compared the efficacy and safety of sunitinib
with that of sorafenib
 The SUN1170 trial was designed based on data from the sorafenib SHARP trial
(median OS 10.7 months)9
Clinical benefit rate=complete/partial response + stable disease; OS=overall survival; SHARP=Study of Heart and Renal
Protection; TTP=time to tumor progression; VEGFRs=vascular endothelial growth factor receptors.
1. Ferlay J et al. Int J Cancer. 2010;127:2093; 2. Perz JF et al. J Hepatol. 2006;45:529; 3. Yao DT et al. Hepatobiliary
Pancreat Dis Int. 2005;4:220; 4. Zhang ZL et al. World J Gastroenterol. 2006;12:4241; 5. Makinen. EMBO J. 2001;20:4752; 6.
Faivre S et al. Lancet Oncol. 2009;10:794; 7. Zhu AX et al. J Clin Oncol. 2009;27:3027; 8. Koeberle D et al. Oncologist.
2010;15:285; 9. Llovet JM et al. N Engl J Med. 2008;359:378.
Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
SUN1170 HCC—Study Design
Endpoints
Enrollment Criteria
• Advanced histologically
confirmed HCC
• No prior systemic chemotherapy
• ECOG PS 0-1
• Child-Pugh group A
Stratification
• Region (Asia vs Ex-Asia)
• Prior TACE (≤3 vs >3 courses)
• Tumor invasion (presence vs
absence of vascular invasions
and/or extrahepatic spread)
R
A
N
D
O
M
I
Z
AT
I
O
N
N=1200
• Primary: OS
• Secondary
Sunitinib
37.5 mg/day CDD
(n=600)
– PFS
– TTP
– Safety
Statistics
Sorafenib
400 mg BID
(n=600)
• Superiority/noninferiority
design
• Hypothesis: increase in
median OS from 10.7 to 13.3
months
• Noninferiority boundary of
median OS (9.5, 11.5 months)
• 1-sided log-rank test;
α=0.025, 90% power
CDD=continuous daily dosing; ECOG PS=Eastern Cooperative Oncology Group performance status; PFS=progression-free
survival; TACE=transarterial chemoembolization.
Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Study Outcome
The study was stopped after a planned safety review by an
independent data monitoring committee (events: 457
deaths)
 Higher incidence of serious adverse events (AEs) with sunitinib
resulted in an unfavorable risk-benefit relationship vs sorafenib
Enrollment was halted after 1074 patients had been
randomized from July 2008 to May 2010
Sunitinib discontinuation recommended and treatment
changed to standard of care
 If continued clinical benefit, further sunitinib treatment possible
based on investigator’s judgment
Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Baseline Patient Characteristics
(ITT Population)
Characteristic
Sunitinib
(n=530)
Sorafenib
(n=544)
Median age (range), y
59 (18-85)
59 (18-84)
Male gender (%)
82
84
Geographical region of Asia* (%)
76
75
Vascular invasion and/or extrahepatic
spread* (%)
79
76
≤3 courses
84
83
>3 courses
15
17
47†
47
55/21
53/22
0
9
13
1/2
58
57
≥3
29
28
13/87§
16/83
Prior TACE* (%)
ECOG PS of 1 (%)
HBV/HCV infection (%)
CLIP score (%)
BCLC Stage B/C (%)‡
* Stratification factor; †Includes 1 patient with ECOG performance status of 2; ‡Staging assigned retrospectively; §Percentage of 529 patients.
BCLC=Barcelona Clinic Liver Cancer; CLIP=Cancer of the Liver Italian Program; ITT=intent-to-treat.
Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Baseline Patient Characteristics
(ITT Population) (cont’d)
Sunitinib
(n=530)
Sorafenib
(n=544)
1
39
42
2
35
38
≥3
25
21
Liver
89
91
Lung
36
38
Lymph nodes
27
24
Other organs
35
27
Underlying cirrhosis
50
45
Partial or complete portal vein thrombosis
34
31
Esophageal varices
28
29
History of alcohol abuse
17
15
3
3
Characteristic
Number of involved disease sites per participant
Involved disease sites
Medical history relevant to primary diagnosis
Nonalcoholic steatohepatitis
Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Treatment Administration
(As-Treated Population)
Sunitinib
(n=526)
Sorafenib
(n=542)
Median relative dose intensity (%)
67
71
Median no. treatment cycles started
4
4
(1-27)
(1-31)
15
15
(0.4-107)
(0.3-124)
11
14
(0.4-217)
(0.3-122)
No. of patients with ≥1 year of treatment
26
55
Dose interruption, any cause (% of patients)
69
56
Dose reduction, any cause (% of patients)
48
69
(range)
Median no. weeks on study
(range)
Median no. weeks on treatment
(range)
Adapted from Cheng A et al. 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 Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Progression-Free Survival
(ITT Population)
Sunitinib
Median 3.6 months (95% CI: 2.8-4.1)
PFS probability (%)
1.00
Sorafenib
Median 3.0 months (95% CI: 2.8-4.0)
0.75
HR 1.13 (95% CI: 0.99-1.30)
P=.1215
0.50
0.25
0.00
0
5
10
15
20
25
30
Time (months)
Patients at risk
Sunitinib
530
117
21
4
1
0
0
Sorafenib
544
142
47
21
13
1
0
P-value based on stratified log-rank test.
Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Tumor Response
(ITT Population: Investigator Assessment)
Sunitinib
(n=530)
Sorafenib
(n=544)
Complete response
2 (<1)
1 (<1)
Partial response
33 (6)
32 (6)
Stable disease (≥12 weeks)
232 (44)
247 (45)
Clinical benefit rate*
267 (51)
280 (51)
Best Objective
Response1
n, (%)
* Odds ratio for clinical benefit rate (95% CI): 1.03 (0.81-1.31); P=.816.
1. Therasse P et al. J Natl Cancer Inst. 2000;92(3):205-216.
Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Subgroup Analysis of Efficacy Results
(ITT Population—Asian vs Ex-Asian Region)
Sunitinib
(n=530)
Sorafenib
(n=544)
Hazard ratio
(95% CI)
P-value*
7.9
10.2
1.30 (1.13-1.50)
.0010
Asian regions†
7.7
8.8
1.21 (1.03-1.42)
.0171
Ex-Asian regions‡
9.3
15.1
1.64 (1.20-2.26)
.0036
3.6
3.0
1.13 (0.99-1.30)
.1215
Asian regions
2.9
2.8
1.03 (0.88-1.20)
.3930
Ex-Asian regions
4.2
5.6
1.46 (1.07-2.00)
.0182
TTP (months), ITT
4.1
3.8
1.13 (0.98-1.31)
.1688
Asian regions
4.0
2.8
1.03 (0.88-1.21)
.3850
Ex-Asian regions
5.0
6.1
1.41 (1.00-1.99)
.0495
Median OS (months), ITT
Median PFS (months), ITT
Ex-Asian regions=regions excluding Asia; ITT population (sunitinib=529; sorafenib=544).
* P-value based on stratified log-rank test; †Asian population: sunitinib=402, sorafenib=410; ‡Ex-Asian
population: sunitinib=127, sorafenib=134.
Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
OS in Patients With HBV Infection
OS probability (%)
(Exploratory Analysis)
1,00
ITT Population
0,75
Sunitinib (n=290)
Median 7.6 months (95% CI:
6.7-8.6)
Sorafenib (n=288)
Median 8.0 months (95% CI:
6.8-9.1)
0,50
HR 1.10 (95% CI: 0.92-1.33)
P=.1714
0,25
0,00
0
5
10
15
20
25
30
35
40
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
7.6
8.0
7.6
7.9
7.9
15.3
1.10 (0.92-1.33)
1.10 (0.91-1.33)
1.08 (0.49-2.36)
.1714
.1844
.3749
P-values based on stratified log-rank test.
Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
OS in Patients With HBV Infection
(Exploratory Analysis)
1,00
Ex-Asian regions
Sunitinib (n=21)
Median 7.9 months (95% CI: 5.5-not reached)
OS probability (%)
0,75
Sorafenib (n=25)
Median 15.3 months (95% CI: 4.0-21.3)
HR 1.08 (95% CI: 0.49-2.36)
P=.3749
0,50
0,25
0,00
0
5
10
15
20
25
30
35
40
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
7.6
8.0
7.6
7.9
7.9
15.3
1.10 (0.92-1.33)
1.10 (0.91-1.33)
1.08 (0.49-2.36)
.1714
.1844
.3749
P-values based on stratified log-rank test.
Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
OS in Patients With HCV Infection
OS probability (%)
(Exploratory Analysis)
1,00
ITT Population
0,75
Sunitinib (n=113)
Median 9.2 months (95% CI:
7.0-12.0)
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 Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Most Common Treatment-Emergent AEs
(Grade* 3 or 4 in >5% of Patients; As-Treated Population)
Sunitinib (%; n=526)
Sorafenib (%; n=541)
Hematologic AEs
Grade 3
Grade 4
Grade 3
Grade 4
Thrombocytopenia
24
6
4
1
Neutropenia
23
2
2
<1
Leukopenia
12
1
<1
0
Anemia
6
3
3
1
Hand-foot syndrome
13
0
21
<1
Increased AST
8
<1
9
<1
Diarrhea
7
<1
9
0
Fatigue
6
<1
4
<1
Asthenia
6
<1
4
0
Decreased appetite
6
0
4
0
Nonhematologic AEs
* National Cancer Institute—Common Terminology Criteria for AEs (NCI-CTCAE) v3.0.
AST=aspartate aminotransferase.
Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Bleeding AEs
(All Causes; As-Treated Population)
Grade* (%)
Sunitinib
(n=526)
Sorafenib
(n=542)
All
G3/4
G5
All
G3/4
G5
37
10
2
20
4
1
Gastrointestinal
18
7
1
12
4
<1
Hepatic tumor
1
<1
<1
<1
<1
0
Any bleeding
Selected bleeding sites
* NCI-CTCAE v3.0.
G=grade.
Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Deaths on Study*
(All Causes; As-Treated Population)
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 Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Conclusions
Sunitinib did not demonstrate superiority or noninferiority
in OS, compared with sorafenib in patients with
advanced HCC
PFS, TTP, and ORR were comparable between treatment
arms
Frequency and severity of AEs were higher with sunitinib
than sorafenib
In patients with HBV infection, OS was similar between
arms. In patients with HCV infection, OS was shorter
with sunitinib
ORR=overall response rate.
Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Acknowledgements
Thanks to all of the participating patients and their
families, as well as the global network of investigators,
research nurses, study coordinators, and operations staff
This study was supported by funding from Pfizer Inc.
Medical writing support was provided by Molly Heitz at ACUMED®
(Tytherington, UK) and was funded by Pfizer Inc.
Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.