Non-colon › Esophagogastric › Pancreatic › Hepatobiliary.

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)


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.


Overall Survival by Stratification Factors

16

ROW, rest of world.


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


Tumour Response



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)


Adverse Events



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??

[email protected]

Non-colon › Esophagogastric › Pancreatic › Hepatobiliary.

Documents

risk slide

resection slide

na slide

agc slide

target cyst slide

high risk n

low risk n

region of target cyst