Cco Gi 2008 Cr Slideset

January 25-27, 2008 Orlando, Florida CCO Independent Conference Coverage of the 2008 Gastrointestinal Cancers Symposium* *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

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These slides accompany CCO’s online Independent Conference Coverage of the 2008 Gastrointestinal Cancers Symposium
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Alan P. Venook, MD Professor of Clinical Medicine Department of Hematology and Oncology Division of Medical Oncology University of California, San Francisco San 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.

PACCE Trial Oxaliplatin Arm: PFS Median (Months) Ox-CT/Bev + Pmab Ox-CT/Bev 0 2 4 6 8 12 10 Hecht JR, et al. GI Cancers Symposium 2008. Abstract 273. 11.1 9.6 59 52 PFS Events, % 1.27 (1.05-1.53) Ox-CT/Bev + Pmab -- Ox-CT/Bev HR (95% CI) Regimen

PACCE Trial Oxaliplatin Arm: Toxicity
More serious adverse events reported with panitumumab plus oxaliplatin chemotherapy/bevacizumab
Skin toxicity most frequent
Hecht JR, et al. GI Cancers Symposium 2008. Abstract 273. 38 60 Any serious adverse event Grade 3/4 toxicity < 6 17
Dehydration
24 24
Neutropenia
4 < 6 10 13 1 Ox-CT/Bev ( n = 397) 10 11 18 24 36 Ox-CT/Bev + Pmab (n = 407)
Nausea
Grade 3/4 Toxicity, %
Skin toxicity
Diarrhea
Infections
Low potassium

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

PACCE Trial Irinotecan Arm Patients with metastatic 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 Hecht JR, et al. GI Cancers Symposium 2008. Abstract 279.

PACCE Trial Irinotecan Arm: PFS Hecht JR, et al. GI Cancers Symposium 2008. Abstract 279. 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 Censored No Pmab Censored Pmab 115 74 23 7 1 0 0 0 0 4 1 2 7 6 6 23 32 34 19 76 29 0 0 115 0 5 10 15 20 25 Months 0 20 40 60 80 100 Patients (%)

PACCE Trial Irinotecan Arm: Toxicity
More serious adverse events when panitumumab added to irinotecan chemotherapy/bevacizumab
Skin toxicity most frequent
Hecht JR, et al. GI Cancers Symposium 2008. Abstract 279. Grade 3/4 toxicity 33 54 Any serious adverse event 9 14
Infections
21 17
Neutropenia
4 6 6 9 0 Iri-CT/Bev ( n = 113) 11 12 14 28 37 Iri-CT/Bev + Pmab (n = 111 )
Nausea
Toxicity, %
Skin toxicity
Diarrhea
Dehydration
Low potassium

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)
Hecht JR, et al. GI Cancers Symposium 2008. Abstract 279.

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
Neutropenia and diarrhea more frequent in 5-FU/ irinotecan arm
Toxicity manageable, investigators concluded
Mitry E, et al. GI Cancers Symposium 2008. Abstract 281. 48 16 Any grade 3/4 toxicity 98 93 Any adverse event 57 57 Death 16 9 28 5-FU/IR (n = 67) 0 1 1 5-FU (n = 75 ) Toxicity, %
Neutropenia
Neutropenia with fever
Diarrhea

CONcePT Trial Design Hochster HS, et al. GI Cancers Symposium 2008. Abstract 280. Patients with metastatic 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 + Ca 2+ /Mg 2+ (n = 35) Intermittent Oxaliplatin † mFOLFOX7 + bevacizumab + placebo (n = 36) Intermittent Oxaliplatin † mFOLFOX7 + bevacizumab + Ca 2+ /Mg 2+ (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)
Hochster HS, et al. GI Cancers Symposium 2008. Abstract 280. 21 36 45 43 46 48 48 39 32 16 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. Patients, %

CONcePT Trial: Summary
Prophylactic Ca 2+ /Mg 2+ did not influence tumor response
Trend toward shorter time to first response with prophylactic Ca 2+ /Mg 2+
32.7 weeks with placebo vs 24.0 weeks with Ca 2+ /Mg 2+
Trend toward higher response rates with intermittent oxaliplatin (intent-to-treat population)
Without Ca 2+ /Mg 2+ : 45% (intermittent) vs 21% (continuous)
With Ca 2+ /Mg 2+ : 34% (intermittent) vs 29% (continuous)
Results on peripheral sensory neuropathy pending
Hochster HS, et al. GI Cancers Symposium 2008. Abstract 280.

X-ACT Trial Design Twelves C, et al. GI Cancers Symposium 2008. Abstract 274. Bolus 5-FU/Leucovorin 5-FU 425 mg/m 2 + LV 20 mg/m 2 on Days 1-5, every 28 days (n = 983) Capecitabine 1250 mg/m 2 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 Twelves C, et al. GI Cancers Symposium 2008. Abstract 274. 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 < .0001 Test of superiority: P = .0682 Estimated Probability HR: 0.88 (95% CI: 0.77-1.01) NI margin: 1.20 Capecitabine (n = 1004) 5-FU/LV (n = 983) 5-Year DFS 60.8% 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
Twelves C, et al. GI Cancers Symposium 2008. Abstract 274.

Adherence to Follow-up Guidelines After Curative Resection
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
Cooper GS, et al. GI Cancers Symposium 2008. Abstract 284.

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
Adherence to Follow-up Guidelines: Results 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 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 Amado RG, et al. GI Cancers Symposium 2008. Abstract 278.
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 + BSC BSC alone 7.4 7.3 HR: 0.99 (95% CI: 0.73-1.36) Proportion Event Free Weeks 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 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 Proportion Event Free Weeks 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Pmab + BSC BSC alone 12.3 7.3 Median PFS Median PFS

OS by KRAS Status and Treatment Amado RG, et al. GI Cancers Symposium 2008. Abstract 278. Median OS (Months) 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
Amado RG, et al. GI Cancers Symposium 2008. Abstract 278.

Circulating Tumor Cells Predict Survival
Baseline CTCs in metastatic colorectal cancer patients entering new systemic therapy predicts PFS and OS
Cohen SJ, et al. GI Cancers Symposium 2008. Abstract 299. < .0001 9.5 23.6 .0008 5.6 8.5 187 ECOG PS 0 .0155 9.4 15.0 .0738 4.7 7.0 210 ECOG PS 1-2 .0001 12.1 23.1 .0880 7.7 8.7 213 Age < 65 yrs .0005 10.5 18.6 .0178 6.3 8.6 235 Bevacizumab < .0001 7.4 14.8 < .0001 2.8 7.1 200 Age ≥ 65 yrs < .0001 6.2 14.8 .0016 2.3 5.4 117 Second/third-line treatment .0001 5.9 15.9 < .0001 2.3 6.7 99 Irinotecan 18.1 17.3 21.2 < 3 CTC Median OS, Mos 11.6 9.5 11.6 ≥ 3CTC .0008 < .0001 .0001 P Value Median PFS, Mos Oxaliplatin Liver metastasis First-line treatment Parameter 242 302 296 n .1200 7.5 8.7 4.2 6.3 ≥ 3CTC .0002 .0246 P Value 8.5 8.7 < 3 CTC

Genes Predictive for Colon Cancer Recurrence
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
Lavery I, et al. GI Cancers Symposium 2008. Abstract 302.

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 for Advanced-Stage Colorectal Cancer Diagnosis

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. Patients (%) 0 20 40 60 80 100 BMI > 25 Central Adiposity DeMeester Score Metabolic Syndrome Elevated CRP Barrett’s Esophagus GERD P = .007 P = .05 P = .04

Barrett’s Esophagus and Metabolic Syndrome: Summary
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
Power DG, et al. GI Cancers Symposium 2008. Abstract 2.

OE02 Update: Design Allum WH, et al. GI Cancers Symposium 2008. Abstract 9. Preoperative Chemotherapy Then Surgery Cisplatin 80 mg/m 2 on Day 1 + 5-FU 1 g/m 2 /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
DFS from randomization + 6 months
Allum WH, et al. GI Cancers Symposium 2008. Abstract 9. 02 00 121 162 83 115 65 85 50 67 41 54 32 41 26 33 17 21 8 14 No. at risk 0.75 1.00 0.50 0.25 0 Survival 0 1 4 6 8 9 Years DFS by Treatment Arm HR: 0.82 (95% CI: 0.71-0.95; P = .003) Chemotherapy then surgery Surgery alone Surgery alone Chemotherapy then surgery 7 5 2 3

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) Survival Rate 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 96 108 120

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/m 2 on Days 1-5 Cisplatin 80 mg/m 2 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/Cisplatin 5-FU 800 mg/m 2 on Days 1-5 Cisplatin 80 mg/m 2 on Day 1

JCOG 9907: PFS, OS Ando N, et al. GI Cancers Symposium 2008. Abstract 10. Second Interim Analysis Unadjusted 2-sided log-rank P = .013 HR by Cox model: 0.64 (95% CI: 0.45-0.91; P = .014) Unadjusted 1-sided stratified Log- rank P = .0444 > .0254 (alpha) HR: 0.76 (94.91% CI: 0.56-1.04) OS Postop 5-yr OS: 38.4% Preop 5-yr OS: 60.1% Years After Randomization 0 1 2 3 4 5 6 7 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 PFS Postop median PFS: 2 yrs Preop median PFS: 3 yrs Years After Randomization 0 1 2 3 4 5 6 7 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

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

Second-Line Cetuximab in Esophageal Cancer: SWOG Phase II Trial
Survival benefit of second-line cetuximab in patients with metastatic esophageal adenocarcinoma
Cetuximab treatment regimen
Initial dose: 400 mg/m 2 IV
Subsequent doses: 250 mg/m 2 IV over 1 hour every 7 days
Adverse events observed in 64% of patients
Considered manageable
Approximately 50% of patients had dose modification
Gold PJ, et al. GI Cancers Symposium 2008. Abstract 96.

Second-Line Cetuximab in Esophageal Cancer SWOG Phase II Trial: Results
Primary endpoint — 23 patients surviving > 6 months — not met
6-month survival rate: 36%
Gold PJ, et al. GI Cancers Symposium 2008. Abstract 96. 4 1.8 1.8 0 1 2 3 4 OS PFS TTF Months 0 20 40 60 80 100 Not evaluable PD SD PR Response Rate (%) 5% 7% 11% 76% N = 55

Phase III IRIS Study: Design Imamura H, et al. GI Cancers Symposium 2008. Abstract 5. S-1 Oral Fluoropyrimidine 80 mg/m 2 /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/m 2 /day IV on Days 1 and 15 + S-1 80 mg/m 2 /day given on Days 1-21, every 5 weeks (n = 155 ) Median follow-up 10.4 months Median follow-up 12.6 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
Imamura H, et al. GI Cancers Symposium 2008. Abstract 5. 27 41 38 43 32 13 0 20 40 60 80 100 S-1 (n = 93) IRIS (n = 94) Not evaluable PD SD PR Response Rate (%)

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
Imamura H, et al. GI Cancers Symposium 2008. Abstract 5. .2327 12.8 10.5 OS, mos 44.9 3.6 S-1 (n = 160) 52.0 1-yr survival, % .1565 4.5 Time to treatment failure, mos P Value IRIS (n = 155) Outcome

AMC 0201 Adjuvant Mitomycin C: Design Kang Y, et al. GI Cancers Symposium 2008. Abstract 6. Mf Mitomycin C 20 mg/m 2 + short-term Doxifluridine 600 mg/m 2 /day x 3 cycles (n = 424) Chemotherapy-naive patients aged 18-70 years with advanced gastric cancer and D2 dissection, M0 (N = 855) MFP Mitomycin C + long-term Doxifluridine x 14 cycles + Cisplatin 60 mg/m 2 on Day 1, every 4 weeks x 6 months (n = 431) Median follow-up 3.2 years Randomization 3-6 weeks postsurgery

AMC 0201 Adjuvant Mitomycin C: Recurrence-Free Survival Kang Y, et al. GI Cancers Symposium 2008. Abstract 6. HR: 1.067 (95% CI: 0.845-1.346) Log-rank test: P = .59 Recurrence-Free Proportion Months 0 0 0.2 0.4 0.6 0.8 1.0 12 24 36 48 60 72 MFP Mf 58.1 63.3 5-yr RFS 32.4 31.6 Total recurrence 64.9 67.0 3-yr RFS MFP (n = 431) Mf (n = 424) Outcome, %

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

Phase II Trial of Sorafenib in Imatinib- and Sunitinib-Resistant GIST Nimeiri HS, et al. GI Cancers Symposium 2008. Abstract 7. 3 1 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 Patients (n)

Conclusions
Sorafenib proves active in imatinib- and imatinib/sunitinib- resistant GIST patients
Overall sorafenib well tolerated, but dose reductions frequent
Accrual ongoing
Phase II Trial of Sorafenib in Imatinib- and Sunitinib-Resistant GIST: PFS, OS Nimeiri HS, et al. GI Cancers Symposium 2008. Abstract 7. 5.1-open 13.0 Median OS, mos 62 5.3 All Patients (N = 24) 37-78 1-yr survival, % 3.2-open Median PFS, mos 95% CI Survival

ACOSOG Z9000: Phase II Study of Adjuvant Imatinib in GIST
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
DeMatteo RP, et al. GI Cancers Symposium 2008. Abstract 8.

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 C min Quartiles Demetri GD, et al. GI Cancers Symposium 2008. Abstract 3.
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
7 (19) 29 (81) Q2-Q3, n (%) (n = 36) Q4, n (%) (n = 19) Q1, n (%) (n = 18) 3 (16) 6 (33) PD/unknown 16 (84) 12 (67) CR + PR + SD Imatinib C min Quartiles (n = 73) Response

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

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 months
Picozzi VJ, et al. GI Cancers Symposium 2008. Abstract 125. 8
Febrile neutropenia
12
Thrombocytopenia
39
Neutropenia
Hematologic toxicity 24
Stomatitis
30
Anorexia
36
Nausea
Gastrointestinal toxicity 22
Vomiting
25
Diarrhea
27
Dehydration
ACOSOG Toxicity, %

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 Survival (%) 0 1 2 3 Time (Yrs) 18-month OS 67%

Adjuvant Chemoradiation in Pancreatic Adenocarcinoma
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
Hsu CC, et al. GI Cancers Symposium 2008. Abstract 124.

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 0.2 Survival, proportion 0 1 2 3 4 5 Follow-up (Yrs) mOS 2-yr OS 5-yr OS CRT 21.1 mo 44.7% 22.3% Obs 15.5 mo 34.6% 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
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
McWilliams RR, et al. GI Cancers Symposium 2008. Abstract 187.

CFTR Mutation and Risk of Pancreatic Cancer: Incidence and Age of Onset McWilliams RR, et al. GI Cancers Symposium 2008. Abstract 187. CFTR carrier Noncarrier 0 12 24 36 48 60 72 Overall Ever Smokers Never Smokers Age of Pancreatic Cancer Onset (Yrs) 0 2 4 6 8 < 60 < 55 < 50 Incidence of CFTR Mutation (%) 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
McWilliams RR, et al. GI Cancers Symposium 2008. Abstract 187.

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

Combined SNP Genotypes and Survival Javle MM, et al. GI Cancers Symposium 2008. Abstract 126. 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 Cumulative Survival, % 100 80 60 40 20 0 0 20 40 60 80 100 Time (Mos) Cumulative Survival, % 3 1-2 0 100 80 60 40 20 0 0 20 40 60 80 100 Time (Mos) 3 1-2 0

SNPs and Gemcitabine: OS by Genotype Javle MM, et al. GI Cancers Symposium 2008. Abstract 126. 0 10 20 30 40 CC CT TT AA AG GG CDA C111T RRM1 G42A Median OS (Mos) n = 48 n = 17 n = 3 n = 15 n = 56 n = 97

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

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 1 21 days Gemcitabine Days 1 and 8 1000 mg/m2 Bevacizumab Days 1 and 15 10 mg/kg Cycle 2 28 days Gemcitabine Days 1, 8, and 15 1000 mg/m2 Bevacizumab Days 8 and 21 10 mg/kg Radiotherapy Days 1-5, 8-12, 15-19 Cycle 3 21 days Gemcitabine Days 1 and 8 1000 mg/m2 Bevacizumab Day 8 10 mg/kg

Pancreatic Cancer: Gemcitabine and Bevacizumab Plus Radiation Small W, et al. GI Cancers Symposium 2008. Abstract 131. 53 48 36 45
1-yr OS, %
6 5 4 15
Progressed or died, n
67 50 38 68
6-mo PFS, %
10.0 11.8 10.2 10.2
Median duration, mos
PFS NA 11.8 10.2 11.8
Median duration, mos
OS 36 50 38 41
1-yr PFS, %
13 82 All (N = 29) 4 71 Resectable (n = 7) 5 75 Unresectable (n = 12) 4
Died, n
89 Borderline (n = 10)
6-mo OS, %
Survival

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

SHARP: Sorafenib in Patients With Advanced HCC and HCV Infection Bolondi L, et al. GI Cancers Symposium 2008. Abstract 129.
Post hoc analysis of subpopulation in phase III trial of sorafenib vs placebo
14.0 7.6 44.1 Sorafenib (n = 93) HCV-Positive Patients 7.9 2.8 30.6 Placebo (n = 85) 10.7 5.5 43.5 Sorafenib (n = 299) Overall SHARP Population 2.8 Median TTP, mos 7.9 31.6 Placebo (n = 303) Median OS, mos Disease recurrence, % Outcome

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) Median (Wks) Child-Pugh B (n = 7)

Sorafenib Plus Doxorubicin in HCC Phase II Study: Design Abou-Alfa GK, et al. GI Cancers Symposium 2008. Abstract 128. Treatment-naive patients with advanced HCC, Child-Pugh A, and ECOG PS 0-2 (N = 96) Placebo/Doxorubicin* Doxorubicin 60 mg/m 2 IV every 21 days (n = 49) Sorafenib/Doxorubicin* Sorafenib 400 mg twice daily Doxorubicin 60 mg/m 2 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 Abou-Alfa GK, et al. GI Cancers Symposium 2008. Abstract 128. 4.8 6.5 2.8 8.6 13.8 6.9 0 3 6 9 12 15 TTP OS PFS Placebo Sorafenib Median (Mos) ( P = .0129) ( P = .076)

Retrospective analysis of SEER database
Surgery and Adjuvant Radiation in Cholangiocarcinomas (CCA): Survival Shinohara ET, et al. GI Cancers Symposium 2008. Abstract 143. 4 8 12 16 Radiation and Surgery Surgery Radiation No Treatment Extrahepatic CCA Intrahepatic CCA Median OS (Mos) n = 701 n = 1372 n = 475 n = 2210 n = 286 n = 948 n = 396 n = 2209 0

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
Shinohara ET, et al. GI Cancers Symposium 2008. Abstract 143. 0.59-0.77 0.68 0.58-0.75 0.66
Radiation
0.44-0.54 0.49 0.47-0.57 0.52
Surgery
0.34-0.47 0.40 0.42-0.52 0.47
Radiation and surgery
1.21-1.53 1.31 1.13-1.50 1.30 Black vs white 0.59 0.48 HR Extrahepatic CCA 0.54-0.65 0.43-0.53 95% CI 0.66 0.51 HR Intrahepatic CCA Multivariate Analysis 0.46-0.56 Localized vs distant disease 0.60-0.73 95% CI Regional vs distant disease Treatment vs no treatment Factor

Capsule Summaries featuring expert discussion and commentary in key
topic areas in gastrointestinal cancers
Colorectal Cancers
Esophageal and Gastric Cancers
clinicaloptions.com/GI2008
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Cco Gi 2008 Cr Slideset

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