GI ASCO 2012Non-colon update
Dr. Delilah Lisa Topic, MD, FRCPCClinical Fellow – St. Michael’s Hospital
Supervisor: Dr. Brezden-Masley
GI ASCO 2012 – Jan 19-21st, 2012 San Francisco, CA
GI ASCO 2012
Non-colon › Esophagogastric› Pancreatic› Hepatobiliary
ESOPHAGOGASTRIC
Esophagogastric
Phase III trial of everolimus in previously treated patients with advanced gastric cancer (AGC): GRANITE-1
Survival analysis according to disease subtype in AVAGAST: First-line capecitabine and cisplatin, plus bevacizumab or placebo, in patients with AGC
Phase III trial of everolimus (EVE) in previously treated patients with
advanced Gastric Cancer: GRANITE-1Eric Van Cutsem, MD, PhD
University Hospital Leuven/Belgium
Background
Gastric cancer is aggressive and difficult to treat
5 year survival for advanced/metastatic is <5%
Limited options upon failure of first-line chemotherapy
PI3
K/A
KT/M
TO
R PA
TH
WAY
Key regulator of cell proliferation, growth, survival, metabolism, and angiogenesis Disregulated in 50-60% of gastric cancersEverolimus -Oral mTor inhibitor, efficacy in preclinical models of gastric cancer -Promising efficacy and tolerability in small phase II study (n=53) OS 10.1 mos, PFS 2.7mos
Phase 3 GRANITE-1 Study Design
9
• Confirmed advanced gastric cancer• Progression after 1 or 2 lines of previous systemic
chemotherapy
Everolimus 10 mg PO daily
+ BSC*(n = 439)
Placebo PO daily+
BSC(n = 217)
SC
RE
EN
Treatment until
disease progression
or intolerable
toxicity
• Stratification by region: Asia vs rest of world• Stratification by number of lines of previous
systemic chemotherapy (1 vs 2)
Safety follow-up: EOT + 28
d
Survival follow-up: every 3
mo
RA
ND
OM
IZE
2:1
(N =
656
)
BSC, best supportive care; EOT, end of treatment; PO, orally.
ClinicalTrials.gov identifier: NCT00879333.
Van Cutsem E et al. GI Cancer Symposium 2012 (Abstr LBA3).
Eligibility criteria
Inclusion criteria› Age >18yrs› Confirmed gastric adenocarcinoma› Documented progression after 1-2 lines of chemo› ECOG ≤2› Adequate bone marrow, renal, and hepatic function
Exclusion criteria› >2 lines of systemic treatment for advanced disease› Anticancer treatment within 3 wks or major surgery
within 2 weeks of study randomization› Chronic treatment with steriods or immunosuppressive
agents› Enteral feeding› CNS metastases› Any severe/uncontrolled medical condition
Study Endpoints Primary:
› OS Secondary:
› PFS› ORR› AEs› Time to definitive deterioration of ECOG › Time to 5% deterioration in global health/QOL
Exploratory:› Correlation between biomarkers and clinical
endpoints
Participating Countries North America
› Canada› United States
Central and South America› Argentina› Colombia› Mexico› Peru
East Asia› China› Hong Kong› Japan› Korea› Taiwan
Other Asia and Pacific Region› Australia› New Zealand› Thailand
Europe and Middle East› Belgium› France› Germany› Israel› Italy› Netherlands › Russia› Spain› United Kingdom
Baseline Patient Characteristics
Everolimus + BSC (n=439)
Placebo + BSC (n=217)
Age, median (range) 62.0 (20.0-86.0) 62.0 (26.0-88.0)
Age <65 yrs, n (%) 260 (59.2) 129 (59.4)
Male, n (%) 322 (73.3) 161 (74.2)
Race, n (%)
Caucasian 166 (37.8) 75 (34.6)
Age, yrs (median) 251 (57.2) 126 (58.1)
Other 22 (5.0) 16 (7.4)
Region, n (%)
Asia 243 (55.4) 120 (55.3)
Rest of world 196 (44.6) 97 (44.7)
ECOG, n (%)
0 144 (32.8) 70 (32.3)
1 269 (61.3) 120 (55.3)
2 25 (5.7) 27 (12.4)
Baseline Disease CharacteristicsEverolimus + BSC (n=439)
Placebo + BSC (n=217)
Anatomical site, n (%)
Proximal 162 (36.9) 94 (43.3)
Distal 276 (62.9) 123 (56.7)
GEJ involvement, n (%)
118 (26.9) 69 (31.8)
Lauren classification,n (%)
AdenoCa, diffuse AdenoCa, intest’l AdenoCa, mixed AdenoCa, NOS Other
93 (21.2)82 (18.7)29 (6.6)105 (23.9)129 (29.4)
37 (17.1)50 (23.0)18 (8.3)45 (20.7)67 (30.9)
Gastrectomy, n(%) Partial Total
126 (28.7)97 (22.1)
60 (27.6)46 (21.2)
Previous lines chemo,n(%) 1 2
210 (47.8)229 (52.2)
103 (47.5)114 (52.5)
Overall Survival
15
Pro
bab
ility
of
over
all s
urvi
val (
%)
100
80
60
40
20
00 2 4 6 8 10 12
Time (months)14
Censoring TimesEverolimus + BSC (n/N = 352/439)Placebo + BSC (n/N = 180/217)
Kaplan-Meier medians Everolimus + BSC: 5.39 months Placebo + BSC: 4.34 months
Hazard ratio: 0.90 (95% CI, 0.75-1.08)Log-rank P value = 0.1244
No. of patients still at riskTime (months)EverolimusPlacebo
16 18 20 22 24
0 2 4 6 8 10 12 14 16 18 20 22 24
217 172 117 82 60 35 28 16 12 8 4 1 0439 355 253 195 139 87 52 30 13 6 3 1 0
CI, confidence interval.
Van Cutsem E et al. GI Cancer Symposium 2012 (Abstr LBA3).
Overall Survival by Stratification Factors
16
ROW, rest of world.
Van Cutsem E et al. GI Cancer Symposium 2012 (Abstr LBA3).
Priorchemotherapy
Region
Cross-class.of strata
Hazard Ratio(95% CI)
0.80.6Everolimus
10 mg/dPlacebo
In favor of
1.0 1.2 1.4
All (N = 656) 0.90 (0.75-1.08)
2 (n = 343) 0.90 (0.70-1.15)
Asia (n = 363) 0.96 (0.75-1.23)
ROW (n = 293) 0.85 (0.65-1.10)
1 prior chemo & ROW (n = 167) 0.91 (0.64-1.31)
2 prior chemo & ROW (n = 126) 0.74 (0.50-1.09)
1 (n = 313) 0.94 (0.73-1.23)
0.98 (0.71-1.35)2 prior chemo & Asia (n = 217)
0.94 (0.63-1.39)1 prior chemo & Asia (n = 146)
Progression-Free Survival
17
Pro
bab
ility
of
prog
ress
ion-
free
sur
viva
l (%
)
100
80
60
40
20
00 2 4 6 7 9 10
Time (months)12
Censoring TimesEverolimus + BSC (n/N = 386/439)Placebo + BSC (n/N = 206/217)
Kaplan-Meier medians Everolimus + BSC: 1.68 months Placebo + BSC: 1.41 months
Hazard ratio: 0.66 (95% CI, 0.56-0.78)Log-rank P value < 0.0001
No. of patients still at riskTime (months)EverolimusPlacebo
14 15 17 21
0 2 4 5 7 9 11 12 14 16 17 20 21
217 55 23 17 7 3 2 2 2 2 2 1 0439 179
1
168367 92
3
28117 60
6
844 37 20
8
627 10
10
213 6 3 2
15
23
13
25 1
19
20
18
21 0 0
18 2019161311851 3
Van Cutsem E et al. GI Cancer Symposium 2012 (Abstr LBA3).
Tumour Response
Everolimus + BSC (n=379)
Placebo + BSC (n=191)
Best overall response, n (%)
CR 1 (0.3) 0
PR 16 (4.1) 4 (2.1)
SD 147 (38.8) 38 (19.9)
PD 157 (41.4) 119 (62.3)
unknown 58 (15.3) 30 (15.7)
ORR (CR+PR), n (%) 17 (4.5) 4 (2.1)
DCR (CR+PR+SD),n (%) 164 (43.3) 42 (22.0)
Best Percentage Change From Baseline in Tumor Size
19
Best
% c
hange f
rom
base
line
(measu
rab
le lesi
ons)
160%
140%
120%
100%
80%
60%
40%
20%
0%
–20%
–40%
–60%
–80%
–100%
160%
140%
120%
100%
80%
60%
40%
20%
0%
–20%
–40%
–60%
–80%
–100%
Everolimus 10 mg/day (n = 304) Placebo (n = 154)
Van Cutsem E et al. GI Cancer Symposium 2012 (Abstr LBA3).
Adverse Events
Everolimus + BSC (n=437)
Placebo + BSC (n=215)
Any AE, n(%) 433 (99.1) 208 (96.7)
Any grade 3/4 AE, n(%) 310 (70.9) 115 (53.5)
Any serious AE, n(%) 207 (47.4) 89 (41.4)
AE leading to discontinuation,n(%)
94 (21.5) 34 (15.8)
AE requiring dose interruption/reduction, n(%)
242 (55.4) 46 (21.4)
AE requiring additional therapy,n %)
395 (90.4) 174 (80.9)
All deaths, n(%) 352 (80.5) 179 (83.3)
On-treatment deaths, n(%) 88 (20.1) 49 (22.8)
Most Common AEsEverolimus + BSC (n=437) Placebo + BSC(n=215)
Adverse Event, n(%)
All grades Grades 3/4 All grades Grades 3/4
Nonheme Decreased Appetite
208 (47.6) 48 (11.0) 78 (36.3) 12 (5.6)
Stomatitis 174 (39.8) 20 (4.6) 23 (10.7) 0 Fatigue 150 (34.3) 34 (7.8) 65 (30.2) 11 (5.1) Nausea 132 (30.2) 16 (3.7) 69 (32.1) 8 (3.7) Diarrhea 115 (26.3) 15 (3.4) 33 (15.3) 2 (0.9)
Heme Anemia 114 (26.1) 70 (16.0) 42 (19.5) 27 (12.6)
Thrombocytopenia
80 (18.3) 22 (5.0) 5 (2.3) 3 (1.4)
Neutropenia 47 (10.8) 17 (3.9) 6 (2.8) 1 (0.5)
Abn biochem Hypokalemia 52 (11.9) 26 (5.9) 9 (4.2) 2 (0.9) Increased ALP 34 (7.8) 20 (3.6) 6 (3.8) 3 (1.4) Increased AST 34 (7.8) 14 (3.2) 8 (3.7) 2 (0.9)
GRANITE-1Conclusions Everolimus monotherapy did not
significantly improve OS in patients with AGC as second/third line therapy
Everolimus did reduce the risk of progression, compared with BSC› Median PFS 1.411.68, HR 0.66, p<0.001
Disease control 22%43%
GRANITE-1 Conclusions
Safety profile was similar to that observed with everolimus in other malignancies
Disease control signal worth further study?› Biomarkers to identify those who benefit
Survival analysis according to disease subtype in AVAGAST: First-
line capecitabine and cisplatin plus bevacizumab or placebo in
pts with advanced gastric cancer
Manish Shah, MD
Gastric cancer: not one disease!
Clinical/epidemiological data suggest there are three subtypes:› Type 1: proximal, non-diffuse› Type 2: diffuse› Type 3: distal, non-diffuse
Each subtype has different gene expression profile
Gastric cancer: 3 subtypesSUBTYPE PREVALENT RISK FACTORS
Proximal(Type 1)
Environmental
Clinical
Genetic
Tobacco useAlcoholObesityGERDNone specifically identified
Diffuse(Type 2)
EnvironmentalClinicalGenetic
None specifically identifiedH. Pylori infectionCDH-1 mutationFamily history (non CDH-1 mutant)
Distal(Type 3)
Environmental
Clinical
Genetic
High dietary saltEating fruits/vegetables*TobaccoAge (peak at 50-70)H. Pylori infectionUse of NSAIDs/ASA*Immune regulatory SNPs
AVAGAST
Global, randomized, phase III study Bevacizumab + chemo vs. placebo + chemo
(first-line treatment for AGC) Primary endpoint: OS
› Was not met (12 mos vs 10 mos, p=0.1002) Regional efficacy differences were noted
› Patients from Europe/Americas did better
Regional differences
Several analyses have been performed to better understand regional differences
Analysis has revealed:› It is the ‘high risk’ pts from Europe/Americas
that derive more benefit from bevacizumab
Objectives
To examine the OS data according to gastric cancer subtype and region
To identify if disease subtype was:› Prognostic› Predictive of bevacizumab benefit
(Europe/Americas) To examine the distribution of angiogenic
biomarkers across subtypes› Do gastric cancer subtypes have different
biomarker expression profiles?
AVAGAST: trial design
Placebo + capecitabine + cisplatin (n=387)
Bevacizumab + capecitabine+ cisplatin (n=387)
Locally advanced or metastatic gastric cancer
(n=774)R
Endpoints
Primary: Overall survival
Secondary: Progression-free survival
Exploratory: Changes in candidate biomarkers: pVEGFA, NRP-1, VEGFA, VEGFR1, VEGFR2
5-FU allowed if capecitabine contraindicated
Maximum of 6 cycles of cisplatin
Capecitabine and bevacizumab / placebo until PD
Stratification factors:
1. Geographic region
2. Fluoropyrimidine backbone
3. Disease status
Disease subtype: distribution by region
All patients(n=733)
Asia-Pacific(n=355)
Europe/Americas(n=378)
Bevacizumab plus chemotherapy
Placebo plus chemotherapy
Pat
ien
ts (
%)
Biomarker distribution
There appears to be differences in biomarker distribution amongst gastric cancer subtypes
Subtype pVEGF-A (median)
NRP-1(median)
VEGF-A(median)
VEGFR1(median)
VEGFR2(median)
Total 111 90 90 130 100
Proximal 104.2 100 100 110 100
Diffuse 102.8 80 78.5 140 100
Distal 134.5 100 100 120 100
Disease subtype: prognostic effect (overall survival in non-Asian
patients)
309172
287262
224747
182835
142221
71312
354
110
000
No. at riskType 1Type 2Type 3
Proximal
Diffuse
Distal
Study month
100
90
80
70
60
50
40
30
20
10
00 3 6 9 12 15 18 21 24
Survival rate (%)
Overall survival by disease subtype
Disease subtype
Region Pts/arm (placebo/bev
Median OS, mo (placebo/bev)
OS Hazard ratio(95% CI)
Proximal AllAsia-PacificEur/Americas
35/355/930/26
11.3/10.411.3/NR12.8/10.4
1.05(0.59,1.89)0.39(0.10,1.58)1.50(0.77,2.93)
Diffuse AllAsia-PacificEur/Americas
206/176115/10091/76
9.3/11.911.0/13.56.5/9.9
0.83(0.65,1.06)0.96(0.69,0.34)0.68(0.48,0.97)
Distal AllAsia-PacificEur/Americas
126/15554/7272/83
11.1/13.315.5/13.99.0/11.7
0.87(0.64,1.16)1.10(0.70,1.73)0.72(0.48,1.07)
Does disease subtype predict response to Bevacizumab? (Europe/Americas only)
Subtype Region Pts/arm(Pla/Bev)
Median OS, mo(Pla/Bev)
Hazard ratio(95% CI)
Proximal AllEurope/Americas
35/3530/26
11.3/10.412.8/10.4
1.051.50
Diffuse AllEurope/Americas
206/17691/76
9.3/11.96.5/9.9
0.830.68
Distal AllEurope/Americas
126/15572/83
11.1/13.39.0/11.7
0.870.72
Diffuse/distal
Europe/Americas 163/159 7.3/11.4 0.67
Overall survival in pts with diffuse/distal disease (Europe/Americas only)Population: Europe/Americas with type 2/3 disease
Hazard ratio 0.67 (95% CI 0.52–0.88)
Study month
100
90
80
70
60
50
40
30
20
10
00
163159
134144
94119
6394
4363
2528
910
13
00
No. at riskPla + chemoBev + chemo
0 3 6 9 12 15 18 21 24
Pla + chemoBev + chemo
Survival rate (%)
Predictive biomarkers with bevacizumab
Biomarker Subgroup N Hazard ratio for OS (95% CI)
P value
pVEGF-A LowHigh
357355
1.01 (0.77-1.31)0.72 (0.57-0.93)
0.07
NRP-1 LowHigh
350329
0.75 (0.58-0.97)1.07 (0.81-1.40)
0.06
Biomarker distribution according
to subtypesSubtype NRP-1
(n=679), medianpVEGF-A(n=712), median
Total 90 111
Proximal 100 104.2
Diffuse 80 102.8
Distal 100 134.5
Biomarker distribution (summary)
Proximal (type 1) gastric cancer appears to have the ‘worst’ profile for bevacizumab› High NRP-1, low pVEGF-A
Diffuse (type 2) and distal (type 3) appear to have at least one biomarker that may support benefit to an antioangiogenic strategy› Diffuse (type 2) low NRP-1› Distal (type 3) high pVEGF-A
AVAGAST Conclusions
Gastric cancer is more than one disease! Gastric cancer subtypes have different
prognoses› In all regions, diffuse (type 2) did worse
The addition of bev to chemo appears to improve outcomes in pts from Europe/Americas with diffuse and distal disease
Biomarkers NRP-1 and plasma pVEGF-A provide a rationale for subtype-specific outcomes with bevacizumab› Additional evaluation warranted
Pancreatic
Malignant progression in intraductal papillary mucinous neoplasms (IPMN) of the pancreas: Results of 157
patients selected for radiographic surveillance
Jennifer Lafemina, MDMemorial Sloan-Kettering
“Its just a cyst – don’t worry!”
Intraductal papillary mucinous neoplasms (IPMN) – not “just a
cyst” Represents a field defect of ductal
instability Main and branch duct IPMN carry a risk of
malignancy in target cyst itself› 57-95% for MD-IPMN› 6-46% for BD-IPMN
Risk of developing malignancy in region other than target cyst is poorly defined
Objectives
Identify patients with IPMN who underwent resection
Define:› Pathologic characteristics of target cyst› Risk of developing a PDAC in a region separate
from the target cyst
Methods
Retrospective review Pts evaluated at MSKCC from Feb ‘89-Aug
‘10:› Radiologic confirmation of target cyst› Pathologic confirmation of IPMN and/or cyst
fluid CEA level ≥200ng/mL› Time from IPMN diagnosis to resection ≥6 mos
Patient demographicsVariable
Number (%) 97 (100%)
Gender, N (%) Female 54 (55)
Resection type, N (%) Pancreaticoduodenectomy Distal pancreatectomy Enucleation Total pancreatectomy Central pancreatectomy
53(55)32(33)6(6)4(4)2(2)
Time, diagnosis to resection, median mos 15.5
Time, first MSKCC visit to resection, median mos
2.1
Age at diagnosis, yrs, median 69
Objectives
Identify patients with IPMN who underwent resection › Define pathologic characteristics of
target cyst› Define the risk of developing a PDAC in a
region separate from the target cyst
Target cyst characteristicsVariable Resection >6 mos
adenoma/borderlinei.e. LOW RISKN=57 (59%)
Resection >6mosHGD/invasivei.e. HIGH RISKN=40 (41%)
P value
IPMN location, n(%) Head Body/tail Head/body Diffuse
32(56)23(40)2(4)0(0)
25(62)14(35)0(0)1(2)
0.70
IPMN size, cm, median
2.1 3 0.01
IPMN subtype, n(%) Main Branch Mixed
10(18)39(68)8(14)
17(42)11(27)12(30)
<0.001
Target cyst characteristics
Variable Resection >6 mos adenoma/borderlinei.e. LOW RISK(N=57)
Resection >6mosHGD/invasivei.e. HIGH RISK(N=40)
P value
Degree of dysplasia, N(%) Adenoma BorderlineHigh gr dysplasia Invasive
16(28)41(72)0(0)0(0)
0(0)0(0)22(55)18(45)
N/A
Subtype, N(%)
Tubular Colloid MixedOther Uknown
N/A
11(61)4(22)2(11)0(0)1(6)
N/A
Objectives
Identify patients with IPMN who underwent resection › Define pathologic characteristics of target cyst› Define the risk of developing a PDAC in a
region separate from the target cyst
Bottom Line Of 158 patients ≥6 mos after diagnosis
› 97 came to resection› Invasive carcinoma in 18 pts, representing
11% of those being followed 19% of those who came to resection
› Of those with invasive carcinoma, 5 pts developed PDAC in region other than target cyst, representing 3.2% of those being followed 5.2% of those who came to resection
Conclusions Surveillance strategies for patients with
IPMN should consider risk of malignancy to not only the region of target cyst, but to entire gland
Patients with invasive components in their target cyst are at risk for PDAC in a separate region, and may need closer surveillance
More studies needed to further define this risk
Hepatobiliary
Sorafenib or placebo in combination with transarterial
chemoembolization (TACE) with doxorubicin-eluting beads
(DEBDOX) for intermediate-stage hcc: Phase II, randomized,
double-blind SPACE trial
Riccardo Lencioni, MDPisa University, Italy
Background TACE is std of care for intermediate stage hcc TACE with DEBDOX has shown advantages in
efficacy and safety over conventional TACE› Reduces peak concentration and total systemic
exposure to doxorubicin fewer AEs Several phase II trials suggest a synergistic
effect between sorafenib and TACE› TACE in these trials was heterogenous› Large global trial needed to test the combo of TACE
and Sorafenib with a controlled TACE regimen
Study objective and design
Objective› To evaluate the efficacy and safety of Sorafenib
in combination with TACE using DEBDOX in patients with intermediate-stage hcc
Design› Randomized, double-blind, placebo-controlled
phase II 85 centres, 13 countries Efficacy assessments performed on ITT
population Safety assessments performed on all pts that
received at least one dose of study drug
Study objective and design
Stratification factors› Geographic region
Europe North America Asia Pacific
› AFP <400 vs ≥400
Sorafenib 400mg bid
Matching Placebo
Study SchemaInclusion Criteria • Unresectable, multinodular,
asymptomatic HCC• Child-Pugh A
without ascites or encephalopathy
• ECOG PS of 0
Exclusion Criteria • Diffuse HCC, vascular
invasion, extrahepatic spread (VI/EHS)
• Contraindication to hepatic embolization procedures
• Planned liver transplantation• Previous local therapy
to target lesion• Prior TACE, prior systemic
therapy
RANDOMIZE
Primary Endpoint• Time to progression
(by central review)
Secondary Endpoints • Overall survival• Time to VI/EHS• Time to untreatable
progression• Safety
1 3 5 7 9 11 13 15 17 19
TACETACE(optional)(optional)
ImagingImaging
Cycle no(=4 weeks)Cycle no
(=4 weeks)
n=307n=307
n=154n=154
n=153n=153
• First TACE with DEBDOX performed 3-7 days after first day of treatment with sorafenib or placebo
• Subsequent TACE with DEBDOX performed on day 1 (±4 days) of cycles 3, 7, and 13, and every 6 cycles thereafter
• Patients allowed optional TACE sessions between cycles 7 and 13 and cycles 13 and 19, if deemed necessary by the investigator 63
Baseline Patient CharacteristicsSorafenib (n=154) , % Placebo (n=153), %
Median age at enrolment (yrs)
64.5 63.0
Male 87.7 82.4
Etiology
Hep B 35.7 32.7
Hep C 25.3 26.8
Alcohol 17.5 19.6
HCC proven by biopsy 39.0 43.8
Liver cirrhosis present
85.6 90.3
Geographic region
Europe 50.6 51.6
North America 11.0 11.1
Asia 38.3 37.3
Baseline Patient Characteristics
Sorafenib (n=154) , % Placebo (n=153), %
AFP
<400 ng/mL 73.4 73.2
≥400 ng/mL 26.6 26.8
Child-Pugh score
5 63.6 68.6
6 35.7 30.7
TTP by Central ReviewPrimary Endpoint
66
HR: 0.79795% Cl: 0.588, 1.08P = 0.072
SorafenibMedian: 169 days95% Cl: 166, 219 days
PlaceboMedian: 166 days95% Cl: 113, 168 days
Time to Vascular Invasion/Extrahepatic SpreadSecondary Endpoint
67
HR: 0.62195% Cl: 0.321, 1.200P = 0.076
SorafenibMedian: NR
PlaceboMedian: NR
Overall SurvivalSecondary Endpoint
68
HR: 0.89895% Cl: 0.606, 1.33P = 0.295
SorafenibMedian: NR95% Cl: 554 days, NR
PlaceboMedian: NR95% Cl: 562 days, NR
Secondary endpoints
TTUP› Defined as time to the inability of a patient
to further receive/benefit from TACE: Failure to achieve objective response after at
least two TACE sessions Appearance of contraindications to TACE
Vascular invasion Extrahepatic spread Sustained ascites Sustained Child-Pugh B Clinical progression to ECOG≥2 Plt count <60
TTUP by Investigator Assessment Secondary Endpoint
70
HR: 1.58695% Cl: 1.200, 2.096P = 0.999
SorafenibMedian: 95 days95% Cl: 62, 113 days
PlaceboMedian: 224 days95% Cl: 158, 288 days
Time to untreatable progression
TTUP longer in placebo group› What does this mean?
Patients on sorafenib more likely to come off treatment Mainly due to developing contraindications to TACE (ie
hepatic dysfunction, poor PS, low plt likely sorafenib S/Es)
When looking at Asian vs Non-Asian patients:› Asian pts had longer TTUP in Sorafenib group
Is TACE + Sorafenib more tolerable and/or efficacious in Asians??
Summary of Study Drug AdministrationAsian vs Non-Asian Populations
72
• Patients stopped sorafenib earlier than placebo in Western countries (median 17 vs 28 weeks), whereas sorafenib was given longer than placebo in Asian countries (median 30 vs 18 weeks)
Asian vs non-asian analysisAssessment Asian (n=104) Non-asian (n=200)
Sorafenib (n=54)
Placebo (n=50)
Sorafenib (n=99)
Placebo (n=101)
Median Tx duration with study drug, wks
30.0 25.8 17.4 27.9
% of pts that received 1 TACE
24.1 22.0 42.4 17.8
% of pts that received 2 TACE
35.2 32.0 35.4 40.6
% of pts that received >2 TACE
38.9 44.0 20.2 39.7
% of pts that received TACE after SPACE
28.8 19.3 33.7 32.3
TTP HR 95% CI p value
0.7200.457-1.1350.078
0.8650.576-1.32.43
OS HR 95% CI p value
0.6770.355-1.2920.117
1.0620.646-1.7450.594
Adverse eventsAdverse Event Sorafenib (n=153), % Placebo (n=151), %
All grade Grade 3/4 All grade Grade 3/4
Diarrhea 52.9 3.9/0 17.2 0.7/0
HFSR 46.4 9.2/0 6.6 1.3/0
Fatigue 43.1 9.8/1.3 33.1 4.6/0.7
Nausea 37.9 0.7/0 39.1 0.7/0
Anorexia 30.7 2.0/0 20.5 0.7/0
Hypertension 30.1 16.3/0 16.6 9.3/0
SPACE - Conclusions Primary endpoint of TTP was met
› HR 0.797, p=0.072 (one-sided alpha 0.15) TACE + DEBDOX was feasible and well-
tolerated Duration of sorafenib was longer in Asian arm,
associated with greater efficacy (TTP, OS)› These positive signals in Asian population require
further phase III studies Currently not enough data to change practice
› Current std of care is to treat with Sorafenib after TACE fails
Thank you! Questions??