Cco Gi 2008 Cr Slideset

CCO IndependentConference Coverageof the 2008 Gastrointestinal Cancers Symposium*

January 25-27, 2008Orlando, Florida

*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.

This program is supported by educational grants from

clinicaloptions.com/oncology

CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium

DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

About These Slides

These slides accompany CCO’s online Independent Conference Coverage of the 2008 Gastrointestinal Cancers Symposium

Our thanks to the presenters who gave permission to include their original data

The full program is available on the Clinical Care Options for Hematology/Oncology Web site: clinicaloptions.com/GI2008

Users are encouraged to use these slides in their own presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent

These slides may not be published or posted online without permission from Clinical Care Options



Alan P. Venook, MDProfessor of Clinical MedicineDepartment of Hematology and OncologyDivision of Medical OncologyUniversity of California, San FranciscoSan Francisco, California

Faculty Participating in Slide Development



Contents

Colorectal Cancers

Esophageal and Stomach Cancers

– Esophageal cancers

– Gastric Cancer

– Gastrointestinal Stromal Tumors (GIST)

Pancreas, Small Bowel, and Hepatobiliary Tract Cancers– Pancreatic Cancer

– Hepatocellular Carcinoma

– Cholangiocarcinomas

Colorectal Cancers



PACCE Trial: Oxaliplatin Arm

Patients with metastatic

colorectal cancer and ECOG ≤ 1

(N = 823)Oxaliplatin-CT (eg, FOLFOX)/Bevacizumab + Panitumumab

(n = 413)

Interim analysis at 231 PFS events

Panitumumab discontinued

Oxaliplatin-CT (eg, FOLFOX)/Bevacizumab

(n = 410)

Median follow-up:54 weeks

Hecht JR, et al. GI Cancers Symposium 2008. Abstract 273.



11.1

9.6

PACCE Trial Oxaliplatin Arm: PFS

Regimen PFSEvents, %

HR(95% CI)

Ox-CT/Bev 52 --

Ox-CT/Bev + Pmab

591.27

(1.05-1.53)

Med

ian

(M

on

ths)

Ox-CT/Bev + Pmab Ox-CT/Bev0

2

4

6

8

12

10




PACCE Trial Oxaliplatin Arm: Toxicity

More serious adverse events reported with panitumumab plus oxaliplatin chemotherapy/bevacizumab

– Skin toxicity most frequent

Grade 3/4 Toxicity, % Ox-CT/Bev + Pmab(n = 407)

Ox-CT/Bev ( n = 397)

Any serious adverse event 60 38

Grade 3/4 toxicity

Skin toxicity 36 1

Diarrhea 24 13

Neutropenia 24 24

Infections 18 10

Dehydration 17 < 6

Nausea 11 < 6

Low potassium 10 4Hecht JR, et al. GI Cancers Symposium 2008. Abstract 273.



PACCE Trial Oxaliplatin Arm: Summary


Adding panitumumab to oxaliplatin chemotherapy with bevacizumab did not prolong PFS

– 9.6 (panitumumab) vs 11.1 months (no panitumumab)

Trend toward inferior PFS and OS

Toxicity frequent in both arms; incidence of serious adverse events higher with oxaliplatin chemotherapy/ bevacizumab/panitumumab

– 60% (panitumumab) vs 38% (no panitumumab)

Majority of patients in both arms withdrew from study due to nonprogressive events



PACCE Trial Irinotecan Arm


colorectal cancer and ECOG ≤ 1

(N = 230)

Irinotecan chemotherapy (eg FOLFIRI)/Bevacizumab

(n = 115)

Irinotecan chemotherapy (eg FOLFIRI)/

Bevacizumab +Panitumumab

(n = 115)

Median follow-up:9 months




PACCE Trial Irinotecan Arm: PFS


PFS Events, n (%) Median, mos (95%CI)

54 (47)

43 (37)

10.1 (8.2-13.7)

11.7 (9.0-13.2)

Pmab + Bev/Iri-CT

Bev/Iri-CT

HR: 1.21 (95% CI: 0.80-1.82)**Descriptive only

CensoredNo PmabCensored

Pmab 115 74 23 7 1 0000

4127

66

2332

34

197629

0

0115

0 5 10 15 20 25Months

0

20

40

60

80

100

Pat

ien

ts (

%)



PACCE Trial Irinotecan Arm: Toxicity

More serious adverse events when panitumumab added to irinotecan chemotherapy/bevacizumab

Skin toxicity most frequent

Toxicity, % Iri-CT/Bev + Pmab(n = 111 )

Iri-CT/Bev( n = 113)

Any serious adverse event 54 33

Grade 3/4 toxicity

Skin toxicity 37 0 Diarrhea 28 9 Neutropenia 17 21 Dehydration 14 6 Infections 14 9 Nausea 12 6 Low potassium 11 4




PACCE Trial Irinotecan Arm: Summary

Adding panitumumab to irinotecan chemotherapy and bevacizumab did not prolong PFS

– 10.1 (panitumumab) vs 11.7 months (no panitumumab)

Toxicity frequent in both arms; incidence of serious adverse events higher in patients receiving panitumumab

– 54% (panitumumab) vs 33% (no panitumumab)




FFCD 2001-02 Trial: 5-FU ± Irinotecan

One arm of a 2-arm of randomized phase III trial compared 5-FU/irinotecan with 5-FU alone in frontline therapy in elderly patients (75 years of age or older) with metastatic colorectal cancer

– Interim descriptive analysis (N = 142 patients followed ≥ 8 weeks)

Response by RECIST criteria high with a 5-FU/irinotecan regimen compared with 5-FU alone in frontline therapy

– ORR: 88% for 5-FU/irinotecan vs 69% for 5-FU alone

PD more prevalent in 5-FU-alone arm

– 25% for 5-FU vs 9% for 5-FU/irinotecan

60-day mortality: 12.7%

– Primary cause of death: disease progression

Mitry E, et al. GI Cancers Symposium 2008. Abstract 281.



FFCD 2001-02 Trial: Toxicity

Toxicity, % 5-FU(n = 75 )

5-FU/IR(n = 67)

Any adverse event 93 98

Any grade 3/4 toxicity 16 48

Neutropenia 1 28

Neutropenia with fever 1 9

Diarrhea 0 16

Death 57 57

Neutropenia and diarrhea more frequent in 5-FU/irinotecan arm

Toxicity manageable, investigators concluded

Mitry E, et al. GI Cancers Symposium 2008. Abstract 281.



CONcePT Trial Design

Hochster HS, et al. GI Cancers Symposium 2008. Abstract 280.


colorectal cancer

(N = 140)

*Treat to failure. †8 cycles with oxaliplatin, 8 cycles without oxaliplatin, 8 cycles with oxaliplatin.

Continuous Oxaliplatin*mFOLFOX7 + bevacizumab +

placebo(n = 34)

Continuous Oxaliplatin*mFOLFOX7 + bevacizumab +

Ca2+/Mg2+

(n = 35)

Intermittent Oxaliplatin†

mFOLFOX7 + bevacizumab +placebo(n = 36)

Intermittent Oxaliplatin†

mFOLFOX7 + bevacizumab +Ca2+/Mg2+

(n = 35)



CONcePT Trial Results: Sequentially Confirmed* Responses Trend toward better response with intermittent oxaliplatin

compared with continuous oxaliplatin dosing (evaluable patients)

– OR: 1.96 (95% CI: 0.86-4.54; P = .089)


2136

45 43

46

4848

39

3216 7

18

0

25

50

75

100

Placebo Ca+/Mg+ Placebo Ca+/Mg+

Continuous Oxaliplatin Intermittent Oxaliplatin

PD

SD

PR

*Responses confirmed by RECIST criteria on sequential assessments.

Pat

ient

s, %



CONcePT Trial: Summary


Prophylactic Ca2+/Mg2+ did not influence tumor response

Trend toward shorter time to first response with prophylactic Ca2+/Mg2+

– 32.7 weeks with placebo vs 24.0 weeks with Ca2+/Mg2+

Trend toward higher response rates with intermittent oxaliplatin (intent-to-treat population)

– Without Ca2+/Mg2+: 45% (intermittent) vs 21% (continuous)

– With Ca2+/Mg2+: 34% (intermittent) vs 29% (continuous)

Results on peripheral sensory neuropathy pending



X-ACT Trial Design

Twelves C, et al. GI Cancers Symposium 2008. Abstract 274.

Bolus 5-FU/Leucovorin5-FU 425 mg/m2 +

LV 20 mg/m2 on Days 1-5, every 28 days

(n = 983)

Capecitabine1250 mg/m2 twice daily on

Days 1-14, every 21 days

(n = 1004)

Chemotherapy-naive patients with

operable stage III colorectal cancer and resection ≤ 8 weeks

(N = 1987)

Median follow-up: 6.8 years



X-ACT Trial: 5-Year DFS


0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Months

0

0.2

0.4

0.6

0.8

1.0

Test of noninferiority: P < .0001Test of superiority: P = .0682

Est

imat

ed P

rob

abili

ty

HR: 0.88 (95% CI: 0.77-1.01)NI margin: 1.20

Capecitabine (n = 1004)5-FU/LV (n = 983)

5-Year DFS60.8%

56.7%

ITT population



X-ACT Trial Key Findings


Trend toward superior 5-year DFS and OS with capecitabine treatment

– DFS: 60.8% vs 56.7% (P = .0682)

– OS: 68.4% vs 71.4% (P = .06)

Hand-foot syndrome common toxicity with capecitabine

– Associated with higher DFS and OS

– Possible clinical marker for optimal capecitabine exposure



Adherence to Follow-up Guidelines After Curative Resection

Cooper GS, et al. GI Cancers Symposium 2008. Abstract 284.

Guidelines

– ≥ 2 office visits each year

– ≥ 2 CEA tests each year

– > 1 colonoscopy within 3 years

– Yearly CT scans for poorly differentiated cancer

Medicare claims evaluated between 1992 and 2001

– Adherence to guidelines between 6 and 42 months after diagnosis

– 33,906 patients identified



9.9% of patients met guidelines

77.2% did not meet guidelines

12.9% of patients were in excess of guidelines; met guidelines but also had CT scan for other level of differentiation and/or PET scan

Older age and local stage cancer predicted under use of guidelines

Cooper GS, et al. GI Cancers Symposium 2008. Abstract 284.

0 20 40 60 80 100

Office Visits

Colonoscopy

CES

CT Poorly Differentiated

CT Other Level of Differentiation

PET Scan

Adherence to Follow-up Guidelines: Results

Patients, %



KRAS Status and Response to Panitumumab: Phase III Trial Analysis

Amado RG, et al. GI Cancers Symposium 2008. Abstract 278.

Panitumumab 6 mg/kg every 2 weeks +Best Supportive Care

(n = 231)

Best Supportive Care*(n = 232)

Colorectal cancer patients stratified by

ECOG 0-1 vs 2 and region

(N = 463)

*Optional crossover to panitumumab upon disease progression.



PFS by KRAS Status and Treatment


The relative effect of panitumumab vs best supportive care was significantly greater in patients with WT vs mutant KRAS

The quantitative-interaction test comparing the magnitude of the relative treatment effect on PFS between WT and mutant KRAS was statistically significant (P < .0001)

PFS was significantly greater for panitumumab treatment compared with best supportive care in the WT KRAS group (stratified log-rank test: P < .0001).

Mutant KRAS WT KRAS

Pmab + BSCBSC alone

7.47.3

HR: 0.99(95% CI: 0.73-1.36)

Pro

po

rtio

n E

ven

t F

ree

Weeks

00.10.20.30.40.50.60.70.80.91.0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

HR: 0.45 (95% CI: 0.34-0.59)

Stratified log-rank test: P < .0001

Pro

po

rtio

n E

ven

t F

ree

Weeks

00.10.20.30.40.50.60.70.80.91.0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Pmab + BSCBSC alone

12.37.3

Median PFSMedian PFS



OS by KRAS Status and Treatment


Med

ian

OS

(M

on

ths) 8.1

7.6

4.9 4.4

0

2

4

6

8

10

WT KRAS WT KRAS Mutant KRAS Mutant KRAS

Pmab BSC Pmab BSC



KRAS Mutation Status and Response to Panitumumab: Summary OS shorter in patients with KRAS mutation regardless of treatment

– HR: 0.67 (95% CI: 0.55-0.82)

Incidence of disease progression following panitumumab nearly 2-fold higher in patients with mutant KRAS

– 70% for mutant KRAS vs 36% for WT KRAS

Panitumumab monotherapy appears effective only in patients WT KRAS

KRAS mutational status does not influence PFS following best supportive care

KRAS genotyping recommended for metastatic colorectal cancer patients




Circulating Tumor Cells Predict Survival

Parameter n Median PFS, Mos Median OS, Mos

< 3 CTC ≥ 3CTC P Value < 3 CTC ≥ 3CTC P Value

First-line treatment 296 8.7 6.3 .0246 21.2 11.6 .0001

Second/third-line treatment 117 5.4 2.3 .0016 14.8 6.2 < .0001

Liver metastasis 302 8.5 4.2 .0002 17.3 9.5 < .0001

Oxaliplatin 242 8.7 7.5 .1200 18.1 11.6 .0008

Irinotecan 99 6.7 2.3 < .0001 15.9 5.9 .0001

Bevacizumab 235 8.6 6.3 .0178 18.6 10.5 .0005

Age ≥ 65 yrs 200 7.1 2.8 < .0001 14.8 7.4 < .0001

Age < 65 yrs 213 8.7 7.7 .0880 23.1 12.1 .0001

ECOG PS 0 187 8.5 5.6 .0008 23.6 9.5 < .0001

ECOG PS 1-2 210 7.0 4.7 .0738 15.0 9.4 .0155

Cohen SJ, et al. GI Cancers Symposium 2008. Abstract 299.

Baseline CTCs in metastatic colorectal cancer patients entering new systemic therapy predicts PFS and OS



Genes Predictive for Colon Cancer Recurrence

Lavery I, et al. GI Cancers Symposium 2008. Abstract 302.

NSABP C-01/C-02 observational arm (N = 765)

Patients treated with surgery alone

59 genes prognostic for disease recurrence

– Up to an 11-fold difference in risk between individual expressed genes

– Genes involved in a number of biological pathways including cell cycle regulation, cell proliferation, and invasion

Multigene algorithm developed and will be validated



Insurance Status and Colorectal Cancer Stage at Diagnosis Analysis of data from National Cancer Data Base

N = 493,419; 50 years of age or older

Uninsured and Medicaid patients 100% and 50%, respectively, more likely to be diagnosed with late-stage colorectal cancer

Halpern MT, et al. GI Cancers Symposium 2008. Abstract 275

0.0

0.5

1.0

1.5

2.0

2.5

Uninsured Medicaid Medicare < 65 Yrs

Medicare> 65 Yrs

Stage II vs I

Stage III/IV vs I

OR

fo

r A

dva

nce

d-S

tag

e C

olo

rect

al C

ance

r D

iag

no

sis



Insurance Status and Colorectal Cancer Stage at Diagnosis: Summary Uninsured and Medicaid patients at risk for late-stage colorectal

cancer diagnosis

Supplementing Medicare with private insurance reduces this risk

Groups more likely to be diagnosed with advanced-stage colorectal cancer include

– Blacks

– Females

– Persons with low socioeconomic or education status

– Persons receiving care at nonteaching/research hospitals

Underserved populations need better access to screening and better screening

Halpern MT, et al. GI Cancers Symposium 2008. Abstract 275

Esophagus and Stomach Cancers



Barrett’s Esophagus and Metabolic Syndrome N = 180: 102 Barrett’s Esophagus and 78 GERD

Mean age 56 years

Power DG, et al. GI Cancers Symposium 2008. Abstract 2.

Pat

ien

ts (

%)

0

20

40

60

80

100

BMI > 25 CentralAdiposity

DeMeesterScore

MetabolicSyndrome

ElevatedCRP

Barrett’s Esophagus

GERDP = .007

P = .05

P = .04



Barrett’s Esophagus and Metabolic Syndrome: Summary

Power DG, et al. GI Cancers Symposium 2008. Abstract 2.

Metabolic syndrome prevalent in Barrett’s Esophagus (46%) and GERD (32%) patients

High prevalence of long segment Barrett’s Esophagus (> 3 cm) in patients with

– Central adiposity (93%)

– Metabolic syndrome (62%)

– BMI > 30 (42%)

– Hyperinsulinemia (20%)

– Elevated IL-4 (4%)

Inflammation and insulin resistance due to metabolic syndrome may contribute to Barrett’s Esophagus progression to adenocarcinoma



OE02 Update: Design

Allum WH, et al. GI Cancers Symposium 2008. Abstract 9.

Preoperative Chemotherapy Then Surgery

Cisplatin 80 mg/m2 on Day 1 +5-FU 1 g/m2/day for 4 days,

two 4-day courses 3 weeks apart

(n = 400 )Patients with resectable

esophageal cancer

(N = 802)

Median follow-up:5.9 years

Surgery Alone(n = 402)

Median follow-up:6.1 years



OE02 Update: DFS

Allum WH, et al. GI Cancers Symposium 2008. Abstract 9.

0200

121162

83115

6585

5067

4154

3241

2633

1721

814

No. at risk

0.75

1.00

0.50

0.25

0

Su

rviv

al

0 1 4 6 8 9Years

DFS by Treatment Arm

HR: 0.82 (95% CI: 0.71-0.95; P = .003)

Chemotherapy then surgery

Surgery alone

Surgery aloneChemotherapy

then surgery752 3

DFS from randomization + 6 months



OE02 Update: Results

5-year OS

– 17% surgery alone vs 23% chemotherapy then surgery (P = .03)

Survival rates dependent on resection status but not histology

3-year survival by MRC

– R0: 42%

– R1: 18%

– R2: 9%

– Unresected: 1%Allum WH, et al. GI Cancers Symposium 2008. Abstract 9.

Survival by Resection Status (All Patients)

Su

rviv

al R

ate

Months From Randomization

R0

R1

R2

Unresected

1.0

0.8

0.6

0.4

0.2

0

0 12 24 36 48 60 72 84 96 108120



JCOG 9907: Study Design

Ando N, et al. GI Cancers Symposium 2008. Abstract 10.

Treatment-naive patients aged younger

than 75 years with squamous cell carcinoma of

thoracic esophagus,T1-3/N0-1/M0, and

ECOG PS 0-2

(N = 330)

5-FU/Cisplatin 5-FU 800 mg/m2 on

Days 1-5Cisplatin 80 mg/m2 on

Day 1(n = 164)

Surgery Transthoracic

esophagectomy with lymphadenectomy ≥ D2

(n = 166)

Postoperative chemotherapy

Preoperative chemotherapy

Surgery Transthoracic

esophagectomy with lymphadenectomy ≥ D2

5-FU/Cisplatin5-FU 800 mg/m2 on

Days 1-5Cisplatin 80 mg/m2 on

Day 1



JCOG 9907: PFS, OS


Second Interim Analysis

Unadjusted 2-sided log-rank P = .013HR by Cox model: 0.64 (95% CI: 0.45-0.91; P = .014)

Unadjusted 1-sided stratifiedLog- rank P = .0444 > .0254 (alpha)HR: 0.76 (94.91% CI: 0.56-1.04)

OS

Postop5-yr OS: 38.4%

Preop 5-yr OS: 60.1%

Years After Randomization

0 1 2 3 4 5 6 70.00.10.20.30.40.50.60.70.80.91.0

PFS

Postopmedian PFS: 2 yrs

Preop median PFS: 3 yrs

Years After Randomization

0 1 2 3 4 5 6 70.00.10.20.30.40.50.60.70.80.91.0



JCOG 9907: Summary


Survival benefit with preoperative chemotherapy

Fewer patients in postoperative chemotherapy arm received chemotherapy

– 70.5% postoperative vs 88.4% preoperative

2-fold greater incidence of grade 3/4 mucositis and leucopenia in postoperative chemotherapy group

Preoperative chemotherapy provided greater benefit for patients with stage II disease

Preoperative chemotherapy led to downstaging and R0 resection and therefore is recommended for patients with resectable (stage II/III) esophageal cancer



Second-Line Cetuximab in Esophageal Cancer: SWOG Phase II Trial

Gold PJ, et al. GI Cancers Symposium 2008. Abstract 96.

Survival benefit of second-line cetuximab in patients with metastatic esophageal adenocarcinoma

Cetuximab treatment regimen

– Initial dose: 400 mg/m2 IV

– Subsequent doses: 250 mg/m2 IV over 1 hour every 7 days

Adverse events observed in 64% of patients

– Considered manageable

– Approximately 50% of patients had dose modification



Second-Line Cetuximab in Esophageal Cancer SWOG Phase II Trial: Results

Gold PJ, et al. GI Cancers Symposium 2008. Abstract 96.

4

1.8 1.8

0

1

2

3

4

OS PFS TTF

Mo

nth

s

0

20

40

60

80

100 Not evaluablePDSDPR

Res

po

nse

Rat

e (%

)5%

7%

11%

76%

N = 55

Primary endpoint—23 patients surviving > 6 months—not met

6-month survival rate: 36%



Phase III IRIS Study: Design

Imamura H, et al. GI Cancers Symposium 2008. Abstract 5.

S-1Oral Fluoropyrimidine

80 mg/m2/day on Days 1-28, every 6 weeks

(n = 160)Patients aged 20-75 years

with nonresectable and advanced gastric

cancer and ECOG PS 0-2

(N = 315)

Irinotecan + S-1 (IRIS)Irinotecan 80 mg/m2/day IV

on Days 1 and 15 +S-1 80 mg/m2/day given on Days 1-21, every 5 weeks

(n = 155 )

Median follow-up10.4 months

Median follow-up12.6 months



Phase III IRIS Study: Response by RECIST 187 patients evaluated for objective response

ORR higher in IRIS (P = .035). ORR represents PR rate—no CR observed


2741

38

43

3213

0

20

40

60

80

100

S-1(n = 93)

IRIS(n = 94)

Not evaluable

PD

SD

PR

Res

po

nse

Rat

e (%

)



Phase III IRIS Study: Survival Results

Higher response rates with IRIS treatment equated to slightly longer time to treatment failure, but not to significantly longer OS

Outcome S-1(n = 160)

IRIS(n = 155)

P Value

Time to treatment failure, mos 3.6 4.5 .1565

OS, mos 10.5 12.8 .2327

1-yr survival, % 44.9 52.0




AMC 0201 Adjuvant Mitomycin C: Design

Kang Y, et al. GI Cancers Symposium 2008. Abstract 6.

MfMitomycin C 20 mg/m2 + short-term Doxifluridine600 mg/m2/day x 3 cycles

(n = 424)Chemotherapy-naive patients aged 18-70 years with

advanced gastric cancer and D2 dissection, M0

(N = 855)

MFPMitomycin C +

long-term Doxifluridine x 14 cycles +

Cisplatin 60 mg/m2 on Day 1, every 4 weeks x 6 months

(n = 431)

Median follow-up3.2 years

Randomization 3-6 weeks postsurgery



AMC 0201 Adjuvant Mitomycin C: Recurrence-Free Survival


Outcome, % Mf(n = 424)

MFP(n = 431)

3-yr RFS 67.0 64.9

5-yr RFS 63.3 58.1

Total recurrence 31.6 32.4

HR: 1.067 (95% CI: 0.845-1.346)Log-rank test: P = .59

Rec

urr

ence

-Fre

e P

rop

ort

ion

Months

00

0.2

0.4

0.6

0.8

1.0

12 24 36 48 60 72

MFPMf



Adjuvant Mitomycin C: Summary

Extending doxifluridine and adding cisplatin to adjuvant mitomycin C safe, but efficacy not improved

5-year recurrence-free survival and OS rates similar between treatment arms

– Recurrence-free survival: 63.3% in Mf arm vs 58.1% in MFP arm

– OS: 64.5% in Mf arm vs 64.8% in MFP arm

More than 30% of patients in each arm had disease recurrences, the majority of which were distant




Nimeiri HS, et al. GI Cancers Symposium 2008. Abstract 7.

31 2

14

3

11

0

5

10

15

20

Overall(N = 24)

IM-RES(n = 6)

IM/SU-RES(n = 18)

SD

PR

ORR 71%

ORR 67%

ORR 72%

ORR

Pat

ien

ts (

n)

Phase II Trial of Sorafenib in Imatinib- and Sunitinib-Resistant GIST



Survival All Patients(N = 24)

95% CI

Median PFS, mos 5.3 3.2-open

Median OS, mos 13.0 5.1-open

1-yr survival, % 62 37-78

Conclusions

Sorafenib proves active in imatinib- and imatinib/sunitinib- resistant GIST patients

Overall sorafenib well tolerated, but dose reductions frequent

Accrual ongoing

Nimeiri HS, et al. GI Cancers Symposium 2008. Abstract 7.

Phase II Trial of Sorafenib in Imatinib- and Sunitinib-Resistant GIST: PFS, OS



ACOSOG Z9000: Phase II Study of Adjuvant Imatinib in GIST

DeMatteo RP, et al. GI Cancers Symposium 2008. Abstract 8.

High-risk GIST patients (N = 107)

– Multiple lesions or ≥ 10 cm

– KIT positive

Oral imatinib initiated after surgery (median 59 days)

– 400 mg/day for 12 months

No severe adverse events

– < 20% had grade 3 toxicity

Overall survival 99% at 1 year, 97% at 2 years and at 3 years

Recurrence-free survival 94% at 1 year, 73% at 2 years, 61% at 3 years

– Recurrence rate high among patients with KIT exon 9 mutation

Recurrence-free survival prolonged vs historical controls



Imatinib Pharmacokinetics and Response in GIST Patients (Trial B2222)

Demetri GD, et al. GI Cancers Symposium 2008. Abstract 3.

Imatinib 400 mg/day

(n = 73)GIST patients

(N = 147) Imatinib 600 mg/day

(n = 74 )

Imatinib 800 mg/day

Imatinib 800 mg/day

PD

PD

PK data collected prospectively

Correlation with clinical outcomes analyzed retrospectively



Response to Imatinib in GIST by Cmin Quartiles


Response Imatinib Cmin Quartiles (n = 73)

Q1, n (%)(n = 18)

Q2-Q3, n (%)(n = 36)

Q4, n (%)(n = 19)

CR + PR + SD 12 (67) 29 (81) 16 (84)

PD/unknown 6 (33) 7 (19) 3 (16)

Patients in lowest imatinib exposure quartile (Q1) had shorter TTP (median: 11.3 months) than patients in the upper 3 quartiles (30.6 months; P = .0029)

Patients in lowest imatinib exposure quartile (Q1) exhibited somewhat lower rates of clinical benefit (ie, CR + PR + SD) than patients in the upper 3 quartiles



Trial B2222: Summary

Survival not different between treatment arms

– Median PFS: 57 months; median OS: 21 months

– OS varied by KIT exon 11 mutation

– OS: 63 months with KIT exon 11 and 8 months with no mutation (P = .005)

Trend toward higher rates of clinical benefit with higher imatinib exposure

– Q1: 67%; Q2/3: 81%; Q4: 84%

Higher imatinib exposure provided greater clinical benefit for patients with KIT exon 11 mutation

– Q1 67% vs Q2/3 + Q4 100% (P = .009)


Pancreas, Small Bowel, and Hepatobiliary Tract Cancers



ACOSOG Z05031: Chemoradiation in Resected Pancreatic Cancer Patients Chemoradiation regimen

– Radiation 5040 cGy/cisplatin/5-FU

– Postchemoradiation 5-FU

Phase II study

93 patients planned; 89 patients accrued; 80 evaluable

Study accrual terminated due to toxicity concerns

Median follow-up: 28 monthsPicozzi VJ, et al. GI Cancers Symposium 2008. Abstract 125.

Toxicity, % ACOSOG

Gastrointestinal toxicity

Nausea 36

Anorexia 30

Dehydration 27

Diarrhea 25

Stomatitis 24

Vomiting 22

Hematologic toxicity

Neutropenia 39

Febrile neutropenia 8

Thrombocytopenia 12



Chemoradiation in Resected Pancreatic Cancer Patients: OS

Picozzi VJ, et al. GI Cancers Symposium 2008. Abstract 125.

18-month OS 67%90

100

80

70

60

50

40

30

20

10

0

Su

rviv

al (

%)

0 1 2 3

Time (Yrs)

18-month OS 67%



Adjuvant Chemoradiation in Pancreatic Adenocarcinoma

Hsu CC, et al. GI Cancers Symposium 2008. Abstract 124.

Retrospective analysis of 2 patient arms

– Johns Hopkins (n = 618)

– Mayo Clinic (n = 474)

Patients underwent pancreaticoduodenectomy, followed by chemoradiation or observation

– One half of the patients (53.4%) received 5-FU–based adjuvant chemoradiation

Median OS: 18.8 months



Adjuvant Chemoradiation in Pancreatic Adenocarcinoma: Survival

Hsu CC, et al. GI Cancers Symposium 2008. Abstract 124.

0

0.8

1.0

0.6

0.4

0.2Su

rviv

al, p

rop

ort

ion

0 1 2 3 4 5

Follow-up (Yrs)

mOS2-yr OS5-yr OS

CRT21.1 mo44.7%22.3%

Obs15.5 mo34.6%16.1%

(P < .001)

Observation only (n= 509) Adjuvant chemoradiation (n = 583)

RR: 0.74 (95% CI 0.62-0.87)



CFTR Mutation and Risk of Pancreatic Cancer

McWilliams RR, et al. GI Cancers Symposium 2008. Abstract 187.

CFTR gene mutations associated with other pancreatic diseases; association to pancreatic cancer unknown

Case-control study

– Patients (n = 948) recruited through Mayo Clinic Pancreas Biospecimen Resource from 2000-2006

– Controls (n = 13,340) derived from prenatal counseling samples

– Analysis limited to white patients/controls due to higher frequency of CFTR gene mutations



CFTR Mutation and Risk of Pancreatic Cancer: Incidence and Age of Onset


CFTR carrier Noncarrier

0

12

24

36

48

60

72

Overall EverSmokers

NeverSmokers

Ag

e o

f P

ancr

eati

c C

ance

r O

nse

t (Y

rs)

0

2

4

6

8

< 60 < 55 < 50

Inci

den

ce o

f C

FT

R M

uta

tio

n (

%)

Age (Yrs)



CFTR Mutation and Risk of Pancreatic Cancer: Summary


Carrying just 1 CFTR mutation increases risk for pancreatic cancer

Age of onset of pancreatic cancer influenced by smoking in CFTR mutation carriers only

Known CFTR carriers should be counseled not to smoke



Javle MM, et al. GI Cancers Symposium 2008. Abstract 126.

SNPs in 8 genes involved in gemcitabine metabolism

– Cytidine deaminase (CDA)

– Deoxycytidine kinase (dCK)

– Ribonucleotide reductase (RRM1)

– Deoxycytidylate deaminase (DCTD)

– Human concentrative (hCNT) 1, 2, and 3

– Equilibrative nucleoside transporter (hENT1)

SNPs and Gemcitabine Activity and Toxicity



Combined SNP Genotypes and Survival


Combined Genotype: hCNT1 (16AA/AG); hCNT2 (17CC);

hENT1 (913CC)Number of alleles: P = .008

Combined Genotype: CDA (111C); CDA (76AA); RRM1 (42GG); DCTD (47AG)

Number of alleles: P = .052

Cu

mu

lati

ve S

urv

ival

, %

100

80

60

40

20

00 20 40 60 80 100

Time (Mos)

Cu

mu

lati

ve S

urv

ival

, %

3 1-2

0

100

80

60

40

20

00 20 40 60 80 100

Time (Mos)

3 1-2

0




0

10

20

30

40

CC CT TT AA AG GG

CDA C111T RRM1 G42A

Med

ian

OS

(M

os)

n = 48 n = 17 n = 3n = 15n = 56 n = 97

SNPs and Gemcitabine: OS by Genotype



SNPs and Gemcitabine Activity and Toxicity: Summary


Genetic variants of genes involved in gemcitabine metabolism have prognostic value in gemcitabine treatment of pancreatic cancer

SNPs associated with lower drug toxicity correlated with poor efficacy

– CDA 111CC and dCK 1205TT alleles associated with poor survival but a lower incidence of neutropenia

Tailored therapy according to genetics on horizon



Pancreatic Cancer: Gemcitabine and Bevacizumab Plus Radiation Phase II study of preoperative therapy

Patients with localized pancreatic cancer (N = 29)

– ECOG PS 0-1

Small W, et al. GI Cancers Symposium 2008. Abstract 131.

Cycle 121 days

Gemcitabine Days 1 and 8 1000 mg/m2

Bevacizumab Days 1 and 15

10 mg/kg

Cycle 228 days

Gemcitabine Days 1, 8, and 15

1000 mg/m2Bevacizumab Days 8 and 21

10 mg/kgRadiotherapy

Days 1-5, 8-12, 15-19

Cycle 321 days

GemcitabineDays 1 and 81000 mg/m2

BevacizumabDay 8

10 mg/kg



Pancreatic Cancer: Gemcitabine and Bevacizumab Plus Radiation


Survival All(N = 29)

Resectable(n = 7)

Unresectable(n = 12)

Borderline(n = 10)

PFS

Median duration, mos 10.2 10.2 11.8 10.0

6-mo PFS, % 68 38 50 67

1-yr PFS, % 41 38 50 36

Progressed or died, n 15 4 5 6

OS

Median duration, mos 11.8 10.2 11.8 NA

6-mo OS, % 82 71 75 89

1-yr OS, % 45 36 48 53

Died, n 13 4 5 4



Pancreatic Cancer: Gemcitabine and Bevacizumab Plus Radiation Chemoradiation combination of gemcitabine/

bevacizumab/radiation well tolerated

– Only 1 patient did not complete 3 cycles of therapy

Radiographic CR seen in 2 patients

– CR (2), PR (3), SD (18), PD (5)

6 patients underwent resection; 2 had pathologic CR (33%)




SHARP: Sorafenib in Patients With Advanced HCC and HCV Infection

Bolondi L, et al. GI Cancers Symposium 2008. Abstract 129.

Outcome

HCV-Positive Patients

Overall SHARP Population

Sorafenib(n = 93)

Placebo(n = 85)

Sorafenib(n = 299)

Placebo(n = 303)

Disease recurrence, % 44.1 30.6 43.5 31.6

Median TTP, mos 7.6 2.8 5.5 2.8

Median OS, mos 14.0 7.9 10.7 7.9

Post hoc analysis of subpopulation in phase III trial of sorafenib vs placebo



Sorafenib in Patients With HCC and Child-Pugh A and B Cirrhosis Phase II study

Sorafenib 400 mg twice daily

Areas under the curve

– Child-Pugh A 25.4 mg/hour/L and Child-Pugh B 30.3 mg/hour/L

Abou-Alfa GK, et al. GI Cancers Symposium 2008. Abstract 140.

0

10

20

30

40

50

TTP OS

Child-Pugh A (n = 21)

Med

ian

(W

ks)

Child-Pugh B (n = 7)



Sorafenib Plus Doxorubicin in HCC Phase II Study: Design


Treatment-naive patients with advanced HCC,Child-Pugh A, and

ECOG PS 0-2

(N = 96)

Placebo/Doxorubicin*Doxorubicin 60 mg/m2 IV

every 21 days(n = 49)

Sorafenib/Doxorubicin*Sorafenib 400 mg twice daily

Doxorubicin 60 mg/m2 IV every 21 days

(n = 47)

*After 18 weeks, patients allowed to continue on single-agent sorafenib or placebo until disease progression.



Sorafenib Plus Doxorubicin in HCC Phase II Study: Results


4.86.5

2.8

8.6

13.8

6.9

0

3

6

9

12

15

TTP OS PFS

Placebo

Sorafenib

Med

ian

(M

os)

(P = .0129)

(P = .076)



Retrospective analysis of SEER database

Shinohara ET, et al. GI Cancers Symposium 2008. Abstract 143.

4

8

12

16

Radiationand Surgery

Surgery Radiation No Treatment

Extrahepatic CCA

Intrahepatic CCA

Med

ian

OS

(M

os)

n = 701

n = 1372 n = 475

n = 2210

n = 286

n = 948n = 396

n = 2209

0

Surgery and Adjuvant Radiation in Cholangiocarcinomas (CCA): Survival



Surgery and Adjuvant Radiation in CCA: Prognostic Factors Treatment, race, and stage independent predictors for survival in multivariate

analysis for extrahepatic and intrahepatic CCA

Year of diagnosis independent predictor of survival for intrahepatic CCA only

Multivariate Analysis Extrahepatic CCA Intrahepatic CCA

Factor HR 95% CI HR 95% CI

Treatment vs no treatment

Radiation and surgery 0.47 0.42-0.52 0.40 0.34-0.47

Surgery 0.52 0.47-0.57 0.49 0.44-0.54

Radiation 0.66 0.58-0.75 0.68 0.59-0.77

Black vs white 1.30 1.13-1.50 1.31 1.21-1.53

Localized vs distant disease 0.48 0.43-0.53 0.51 0.46-0.56

Regional vs distant disease 0.59 0.54-0.65 0.66 0.60-0.73

Shinohara ET, et al. GI Cancers Symposium 2008. Abstract 143.

Capsule Summaries featuring expert discussion and commentary in keytopic areas in gastrointestinal cancers

Colorectal Cancers

Esophageal and Gastric Cancers

Pancreas, Small Bowel, and Hepatobiliary Tract Cancers

clinicaloptions.com/GI2008

Go Online for More CCO Coverage of This Conference!

http://www.clinicaloptions.com/GI2008

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