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Gastrointestinal Cancers

CCO Independent Conference Coverage


of the 2013 Gastrointestinal Cancers Symposium*
January 24-26, 2013 San Francisco, California
*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 grants from This program program is is supported supported by by educational an educational grant from

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About These Slides


In the following slides, you will find highlights of the key studies from this meeting. Be sure to review the slide notes field for each slide for insightful commentary from our expert faculty
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Faculty
Al B. Benson III, MD, FACP
Professor of Medicine, Department of Medicine Division of Hematology/Oncology, Feinberg School of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University Chicago, Illinois

Thomas H. Cartwright, MD
Co-Chairman, US Oncology GI Research US Oncology/Ocala Oncology Ocala, Florida

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Disclosures
Al B. Benson III, MD, FACP, has disclosed that he has received consulting fees from Bayer, Celgene, Genentech, Genomic Health, and Sanofi, and funds for research support from Amgen, Astellas, Bayer, Genentech, and Gilead Sciences. Thomas H. Cartwright, MD, has disclosed that he has received consulting fees from Amgen, Bayer, Bristol-Myers Squibb, and sanofiaventis and has received fees for non-CME/CE services received directly from a commercial interest or their agents (e.g., speakers bureaus) from Amgen, Bayer, Bristol-Myers Squibb, and Genentech.

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Overview
Colorectal Cancer
First-line Bev + FOLFIRI or FOLFOXIRI in mCRC First-line Capecitabine Bev in Elderly mCRC Pts First-line Bev + Chemo Erlotinib in Unresectable mCRC Pegfilgrastim vs Placebo After First-line Chemo + Bev in Adv. CRC First-line mFOLFOX6 + Panitumumab or Bevacizumab in mCRC Biomarkers and Response to Regorafenib in mCRC Stage II Colon Cancer: Adding Recurrence Score and MMR Status to Risk Assessment

Esophageal and Stomach Cancer


Docetaxel vs ASC in Esophagogastric Cancer BSC Ramucirumab in Metastatic Gastric or GEJ Cancer

Pancreatic Cancer
Gem- or Cape-Based CRT in Locally Advanced Pancreatic Cancer Gemcitabine nab-Paclitaxel in Metastatic Pancreatic Cancer Adjuvant Gem vs S-1 in Resected Pancreatic Cancer GTX in Patients With Metastatic Pancreatic Cancer pCR, nCR Rates After Chemo + SBRT in Borderline Resectable Pancreatic Cancer

Colorectal Cancer

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Phase III TRIBE Trial: First-line Bev + FOLFIRI or FOLFOXIRI in mCRC


Stratified by PS (0-1 vs 2), center, previous adjuvant chemo Max 12 cycles

Patients with unresectable mCRC, no previous chemotherapy for advanced disease (N = 508)

FOLFIRI* + Bevacizumab 5 mg/kg (n = 256) FOLFOXIRI + Bevacizumab 5 mg/kg (n = 252)

Maintenance with 5-FU + bevacizumab until PD

*FOLFIRI: irinotecan 180 mg/m2, leucovorin 200 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2400 mg/m2 over 48 hrs, q2w FOLFOXIRI: irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, 5-FU infusion 3200 mg/m2 over 48 hrs, q2w

Primary objective: PFS Secondary endpoints: OS, safety, R0 resection, biomarkers


Loupakis F, et al. ASCO GI 2013. Abstract 336.

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TRIBE Trial of First-line Bev + FOLFIRI or FOLFOXIRI in mCRC: PFS


1.0 0.9 FOLFIRI + Bev FOLFOXIRI + Bev FOLFIRI + Bev, median PFS: 9.7 mos FOLFOXIRI + Bev, median PFS: 12.2 mos Unstratified HR: 0.73; P = .0012 Stratified HR: 0.71; P = .0006 Median follow up: 26.6 mos FOLFIRI + Bev: n = 256/progressed = 225 FOLFOXIRI + Bev: n = 252/progressed = 199 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 Pts at Risk, n FOLFIRI + Bev 256 FOLFOXIRI + Bev 252 6 198 203 12 93 125 18 42 64 24 22 27 30 10 15 36 3 8 42 0 3 48 0 1 54 0 0

Probability of PFS

Follow-up Time (Mos)

Loupakis F, et al. ASCO GI 2013. Abstract 336.

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TRIBE Trial of First-line Bev + FOLFIRI or FOLFOXIRI in mCRC: Response Rates


Best Response, % Best response PR Response Rate 80 SD Progressive disease Not assessed FOLFIRI + Bev (n = 256) 3 50 53 32 5 10 FOLFOXIRI + Bev (n = 252) 4 61 65 24 2 9 .006 P Value

% Change From Baseline

60 40 20 0 -20 -40 -60 -80 -100

FOLFIRI + Bev FOLFOXIRI + Bev Tumor shrinkage superior with FOLFOXIRI

Loupakis F, et al. ASCO GI 2013. Abstract 336.

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TRIBE Trial of First-line Bev + FOLFIRI or FOLFOXIRI in mCRC: Safety


Grade 3/4 AE, % Nausea Vomiting Diarrhea Stomatitis Neutropenia Febrile neutropenia Neurotoxicity Hypertension Venous thrombosis Arterial thrombosis Bleeding FOLFIRI + Bev (n = 254) 3 3 11 4 20 6 0 2 6 2 1 FOLFOXIRI + Bev (n = 250) 3 4 19 9 50 9 5 5 7 1 1 P Value 1.000 .492 .012 .048 < .001 .315 < .001 .157 .593 1.000 1.000 Event, % Serious AEs Fatal AEs Treatmentrelated deaths Early deaths (within 60 days from randomization) FOLFIRI + Bev (n = 254) 19.7 3.5 1.6 FOLFOXIRI + Bev (n = 250) 20.4 2.8 2.4 Compared with FOLFIRI + Bev, FOLFOXIRI + Bev increased the incidence of grade 3/4 stomatitis, diarrhea, and neutropenia, but not febrile neutropenia, serious AEs, or treatment-related deaths

2.7

3.6

Loupakis F, et al. ASCO GI 2013. Abstract 336.

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Phase III AVEX Trial: First-line Capecitabine Bev in Elderly mCRC Pts
Stratified by ECOG PS (0-1 vs 2), region

Patients aged 70 yrs or older, eligible for single-agent chemotherapy, no previous chemo for mCRC or adjuvant anti-VEGF therapy (N = 280)

Capecitabine 1000 mg/m2 BID on Days 1-14 q3w (n = 140) Capecitabine 1000 mg/m2 BID on Days 1-14 q3w + Bevacizumab 7.5 mg/kg q3w (n = 140)

Primary objective: PFS Secondary endpoints: OS, ORR, DOR, time to response, safety
Cunningham D, et al. ASCO GI 2013. Abstract 337.

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AVEX Trial of First-line Capecitabine Bev in Elderly mCRC Pts: PFS


1.0 Cape (n = 140) Cape + Bev (n = 140) 0.8 0.6 0.4 0.2 0 0 5.1 mos 2 4 6 9.1 mos 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 HR: 0.53 (95% CI: 0.41-0.69; P < .001)

Proportion Progression Free

Mos
Pts at Risk, n Cape Cape + Bev 140 121 99 80 140 109 82 56 68 38 55 41 25 13 28 9 23 6 16 13 4 4 9 2 8 1 3 1 2 1 2 1 2 1 2 1 1 1 0 1 0 0

Cunningham D, et al. ASCO GI 2013. Abstract 337.

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AVEX Trial of First-line Capecitabine Bev in Elderly mCRC Pts: ORR and AEs
Outcome, % ORR (CR + PR) Cape + Bev (n = 140) 19.3 P = .042 CR PR SD PD Disease control rate (CR + PR + SD) 2.1 17.1 55.0 10.0 74.3 P = .005 1.4 8.6 47.9 21.4 57.9 SAE Grade 3 AE Grade 5 AE Any AE leading to dose modification AE leading to discontinuation 30.6 59.0 8.2 54.5 25.4 32.4 44.1 11.8 43.4 14.0 Cape (n = 140) 10.0 AE, % Any AE Cape + Bev (n = 134) 95.5 Cape (n = 136) 95.6

Cunningham D, et al. ASCO GI 2013. Abstract 337.

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Phase III DREAM Study: First-line Bev + Chemo Erlotinib in Unresectable mCRC
Patients with untreated, unresectable mCRC, ECOG PS 2 (N = 700) FOLFOX + Bev (n = 429) CR CAPOX + Bev (n = 204) FOLFIRI + Bev (n = 67) PR SD R Bev + Erlotinib (n = 222) PD Bev (n = 224) PD

Primary endpoint: PFS Secondary endpoints: duration of disease control, OS, ORR, chemotherapy-free interval, salvage surgery rates, safety, QoL, pharmacogenetics, pharmacoeconomics Patients stratified by ECOG PS, number of metastatic sites (1 vs > 1), age, previous adjuvant chemotherapy, and baseline alkaline phosphatase

Tournigand C, et al. ASCO GI 2013. Abstract 457.

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DREAM Study of First-line Bev + Chemo Erlotinib in Unresectable mCRC: PFS


Conclusion: Induction therapy for mCRC using modified biweekly CAPOX + Bev provides similar response rates and PFS as mFOLFOX7 + Bev and FOLFIRI + Bev
100 Patients without progression, % 80 60 40 20 0 0 Regimen FOLFIRI + Bev mFOLFOX7 + Bev mCAPOX + Bev n 67 429 204 3 6 9 12 Months 15 18 21 24 FOLFIRI + Bev mFOLFOX + Bev mCAPOX + Bev

Median PFS HR (95% CI) 9.0 mo 0.94 (0.69-1.29) 8.6 mo 1.00 9.0 mo 0.99 (0.81-1.23)

P Value .723 .964

Tournigand C, et al. ASCO GI 2013. Abstract 457.

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Phase III Trial: Pegfilgrastim vs Placebo After First-line Chemo + Bev in Adv. CRC

Patients with unresectable, locally advanced or metastatic CRC who received first-line FOLFOX or FOLFIRI + bevacizumab (N = 845)

Pegfilgrastim 6 mg ~ 24 hrs after chemotherapy q2w x 4 cycles (n = 422) Placebo (n = 423)

Option to continue treatment until progression

Primary objective: incidence of grade 3/4 febrile neutropenia in cycles 1-4 Secondary endpoints: ORR, PFS, OS
Pinter T, et al. ASCO GI 2013. Abstract LBA445.

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Pegfilgrastim vs Placebo After First-line Chemo + Bev in Adv. CRC: Results


Pegfilgrastim significantly reduced the incidence of grade 3/4 febrile neutropenia in patients receiving standard chemotherapy + Bev for CRC
Result, % Placebo (n = 423) Pegfilgrastim (n = 422) 2.4 (1.1-4.3) Placebo vs Pegfilgrastim Diff = -3.3% (-6.6 to 0) OR: 0.41 (0.19-0.86) P = .014 Diff = 1.4% (-6.5 to 9.3) OR: 1.06 (0.81-1.39) P = .683 HR: 1.05 (0.88-1.26) P = .552 HR: 1.05 (0.81-1.36) P = .704

Grade 3/4 FN (95% CI)

5.7 (3.7-8.3)

ORR* (95% CI) Median PFS,* mos (95% CI) Median OS,* mos (95% CI)

56.7 (51.8-61.5)

58.1 (53.2-62.0)

10.1 (9.3-11.1) 24.6 (21.3-NR)

9.7 (9.2-10.8) 21.8 (18.5-25.6)

*Immature data. Measurable disease. Pinter T, et al. ASCO GI 2013. Abstract LBA445.

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Phase II PEAK Trial: First-line mFOLFOX6 + Panitumumab or Bevacizumab in mCRC


Panitumumab 6.0 mg/kg q2w + mFOLFOX6 q2w (n = 142) Bevacizumab 5.0 mg/kg q2w + mFOLFOX6 q2w (n = 143)

Patients with untreated mCRC, ECOG PS 0-1, and wild-type KRAS (N = 285)

Treatment until PD, death, or study withdrawal

Primary objective: PFS Secondary endpoints: OS, ORR, safety, resection rate, biomarker analysis (exploratory)
Schwartzberg LS, et al. ASCO GI 2013. Abstract 446.

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Phase II PEAK Trial of First-line mFOLFOX6 + Panit or Bev in mCRC: PFS


100 Panit + mFOLFOX6 Bev + mFOLFOX6 Panit + mFOLFOX6, n = 90/142 (63%) Median PFS: 10.9 mos (95% CI: 9.4-13.0) Bev + mFOLFOX6, n = 94/143 (66%) Median PFS: 10.1 mos (95% CI: 9.0-12.6) HR: 0.87 (95% CI: 0.65-1.17; P = .35)

Event-Free Survival (%)

90 80 70 60 50 40 30 20 10 0 0 2 4 6 8

10 12 14 16 18 20 22 24 26 28 30 32 34

Mos

PFS similar between arms ORR similar between arms: 58% for panitumumab vs 76% for bevacizumab
Schwartzberg LS, et al. ASCO GI 2013. Abstract 446.

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CORRECT Trial Analysis: Biomarkers and Response to Regorafenib in mCRC


Mutational analysis of biomarker samples in phase III CORRECT study, which compared regorafenib vs placebo in patients with progressive mCRC Genes and mutations analyzed at study entry (fresh plasma samples or tumor tissue)
KRAS (G12A, C, D, R, S, V; G13D; Q61H; A146T) PIK3CA (E542K; E545G, K; H1047L, R, Y) BRAF (V600E)

Jeffers M, et al. ASCO GI 2013. Abstract 381.

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Biomarkers and Response to Regorafenib in mCRC: OS and PFS in CORRECT Trial


KRAS-WT (plasma) KRAS-MU (plasma) KRAS-WT (tumor) KRAS-MU (tumor) PIK3CA-WT (plasma) PIK3CA-MU (plasma) PIK3CA-WT (tumor) PIK3CA-MU (tumor) KRAS-MU + PIK3CA-MU (plasma) KRAS-MU + PIK3CA-WT (plasma) KRAS-WT + PIK3CA-WT (plasma) Overall study population 0.25 0.33 KRAS-WT (plasma) KRAS-MU (plasma) KRAS-WT (tumor) KRAS-MU (tumor) PIK3CA-WT (plasma) PIK3CA-MU (plasma) PIK3CA-WT (tumor) PIK3CA-MU (tumor) KRAS-MU + PIK3CA-MU (plasma) KRAS-MU + PIK3CA-WT (plasma) KRAS-WT + PIK3CA-WT (plasma) Overall study population 0.170.2 0.250.33 0.50.67 1 1.5 2 3 4 5 6 0.5 0.67 1 1.5 2 HR (Regorafenib/Placebo) 3 4 n = 154 (130) n = 349 (311) n = 99 (82) n = 140 (128) n = 419 (366) n = 84 (75) n = 207 (180) n = 29 (26) n = 67 (60) n = 282 (251) n = 137 (115) n = 760 (671) n = 154 (71) n = 349 (205) n = 99 (55) n = 140 (82) n = 419 (224) n = 84 (52) n = 207 (123) n = 29 (15) n = 67 (40) n = 282 (165) n = 137 (59) n = 760 (432)

Regorafenib showed a trend for clinical benefit vs placebo in all subgroups analyzed However, these data suggest that neither KRAS or PIK3CA mutational status is a useful biomarker to select patients most likely to benefit from regorafenib

Jeffers M, et al. ASCO GI 2013. Abstract 381.

PFS

OS

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Stage II Colon Cancer: Adding Recurrence Score and MMR Status to Risk Assessment
In stage II colon cancer, risk assessment based on traditional clinicopathologic factors and varies widely Survey conducted to compare level of physician agreement using traditional factors alone or with addition of recurrence score (Oncotype DX) and MMR status
Data source: 20 patients with stage II colon cancer enrolled on 2 CALGB studies Conventional clinicopathologic data included T-stage, grade, LVI status, perforation/obstruction status, location, number of nodes Participants: university- and community-based oncologists
Kelley RK, et al. ASCO GI 2013. Abstract 349.

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Recurrence Score and MMR Status in Risk Assessment in Colon Cancer: Results
Addition of recurrence score result and MMR to conventional clinicopathologic criteria significantly improved agreement and decreased variability in risk assessment of stage II colon cancer Agreement in risk estimates higher among community vs university physicians
University Based 250 200 ASD 150 100 50 0 CP CP+ ASD 250 200 150 100 50 0 CP CP+ Community Based

Kelley RK, et al. ASCO GI 2013. Abstract 349.

Esophageal and Stomach Cancer

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Phase III COUGAR-02 Trial: Docetaxel vs ASC in Esophagogastric Cancer


Stratified by disease status (LA vs advanced), site (esophagus vs GEJ vs stomach), TTP (0 vs 0-3 vs 3-6 mos, ECOG PS (0-1 vs 2)

Patients with locally advanced or metastatic OGC, PS 0-2, progression within 6 mos of chemotherapy (N = 168)

Docetaxel 74 mg/m2 IV q3w + Active Symptom Control (n = 84) Active Symptom Control (n = 84)

Assess q3w for 18 wks, then q6w

Primary objective: OS Secondary endpoints: response to docetaxel, TTP, QoL, toxicity


Ford H, et al. ASCO GI 2013. Abstract LBA4.

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COUGAR-02 Trial of Docetaxel vs ASC in Esophagogastric Cancer: OS


Patients Remaining Alive (%)
100 Docetaxel ASC 75 HR: 0.67 (95% CI: 0.49-0.92; P = .01) Median Survival, Mos (95% CI) Docetaxel: 5.2 (4.1-5.9) ASC: 3.6 (3.3-4.4)

50

25

0 0 2 4 6 8 10 12 14 16 18

Mos From Randomization


Pts at Risk, n Docetaxel ASC 84 84 69 70 53 38 33 19 25 13 17 9 10 6 8 2 5 1 4 1

Ford H, et al. ASCO GI 2013. Abstract LBA4.

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COUGAR-02 Trial of Docetaxel vs ASC in Esophagogastric Cancer: Grade 3/4 AEs


AE Allergy Blood/bone marrow Neutropenia Anemia Thrombocytopenia Constitutional symptoms Gastrointestinal Infection Febrile neutropenia Neuropathy Hemorrhage/bleeding Pain
Ford H, et al. ASCO GI 2013. Abstract LBA4.

Docetaxel n % 2 3 18 22 14 18 5 6 2 3 13 16 21 26 15 19 6 7 3 4 1 1 9 11

ASC n 0 6 0 5 0 10 18 2 0 3 5 15 % 0 8 0 7 0 14 24 3 0 4 7 20

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Phase III REGARD Trial: BSC Ramucirumab in Metastatic Gastric or GEJ Cancer
Stratified by geographic region, weight loss (> vs < 10% over 3 mos), location of primary tumor (gastric vs GEJ)

Patients with metastatic gastric or GEJ adenocarcinoma progressing on first-line platinum- and/or fluoropyrimidinecontaining combination therapy, ECOG PS 0-1 (N = 355)

Ramucirumab 8 mg/kg IV q2w + BSC (n = 238) BSC + Placebo (n = 117)

Treatment until PD, unacceptable toxicity, or death

Primary objective: OS Secondary endpoints: PFS, 12-wk PFS, ORR, DOR, QoL, safety
Fuchs CS, et al. ASCO GI 2013. Abstract LBA5.

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REGARD Trial of BSC Ramucirumab in Metastatic Gastric or GEJ Cancer: OS


1.0

Proortion remaining alive

0.8 0.6 0.4 0.2 0 0 1 2 3 4 5

Ramucirumab Placebo Censored

Patients/events Median, mos (95% CI) 6-mo OS, % 12-mo OS, %

Ramucirumab 238/179 5.2 (4.4-5.7) 42 18

Placebo 117/99 3.8 (2.8-4.7) 32 11

HR: 0.776 (95% CI: 0.603-0.998; P = .0473).

6 7

8 9 10 11 12 13 14 15 16 17 18 19 20

26 27 28

Mos
Pts at Risk, n Ramucirumab 238 117 Placebo 154 66 92 34 49 20 17 7 7 4 3 2 0 1 0 0

Fuchs CS, et al. ASCO GI 2013. Abstract LBA5.

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REGARD Trial of BSC Ramucirumab in Metastatic Gastric or GEJ Cancer: PFS


1.0

Proportion without progression

0.8 0.6 0.4 0.2 0 0 1 2 3 4

Ramucirumab Placebo Censored

Patients/events Median, mos (95% CI) 12-wk PFS, %

Ramucirumab 238/199 2.1 (1.5-2.7) 40

Placebo 117/108 1.3 (1.3-1.4) 16

HR: 0.483 (95% CI: 0.376-0.620; P < .0001)

10 11 12 13 14 15 16 17

Mos
Pts at Risk, n Ramucirumab 238 213 113 65 61 45 30 18 18 117 92 27 11 7 4 2 2 2 Placebo Fuchs CS, et al. ASCO GI 2013. Abstract LBA5. 11 2 5 2 4 1 2 1 1 0 1 0 1 0 1 0 0 0

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REGARD Trial of BSC Ramucirumab in Metastatic Gastric or GEJ Cancer: AEs


Ramucirumab (n = 236) Treatment-Emergent AE, % Fatigue* Abdominal pain* Decreased appetite Vomiting Hypertension* Constipation Anemia* Dysphagia Ascites Dyspnea Back pain Any Grade 35.6 28.8 24.2 19.9 16.1 15.3 14.8 10.6 9.7 9.3 7.6 Grade 3 6.4 5.9 3.4 2.5 7.6 0.4 6.4 2.1 4.2 1.7 1.3 Placebo (n = 115) Any Grade 40.0 27.8 22.6 25.2 7.8 22.6 14.8 10.4 9.6 13.0 9.6 Grade 3 9.6 2.6 3.5 4.3 2.6 2.6 7.8 4.3 4.3 6.1 2.6

*Consolidated terms: fatigue includes asthenia; abdominal pain includes abdominal pain upper; hypertension includes elevated blood pressure; anemia includes hematocrit decreased and red blood cell decreased. No grade 4 hypertension observed among ramucirumab-treated patients. Fuchs CS, et al. ASCO GI 2013. Abstract LBA5.

Pancreatic Cancer

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Phase II SCALOP Trial: Gem- or Cape-Based CRT in Locally Advanced Pancreatic Cancer
Assess for operability

Patients with inoperable, locally advanced prostate cancer < 7 cm diameter, WHO PS 0-2 (N = 74)

GEMCAP x 4 cycles Gem 1000 mg/m2 on Days 1, 8, 15 q4w + Cape 830 mg/m2 on Days 1-21 q4w

Gem 300 mg/m2/wk IV + Radiation* 50.4 Gy in 28 fractions (n = 36) Cape 830 mg/m2/day PO M-F + Radiation* 50.4 Gy in 28 fractions (n = 38) *3D conformal or IMRT

Clinical, Ca19.9, and CT assessments at Weeks 26, 39, and 52 Primary objective: 9-mo PFS
Mukherjee S, et al. ASCO GI 2013. Abstract LBA146.

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SCALOP Trial of Gem- or Cape-Based CRT in Locally Advanced Pancreatic Cancer: PFS
1.00 Cape CRT (n = 36) Median PFS Gem CRT (n = 38) Cape: 12 Gem: 10.4 HR: 0.60 (95% CI 0.32-1.12; Median Distant PFS, Mos P = .111) Cape: 14.3 Gem: 11.9 Median Local PFS, Mos Cape: 14.6 Gem: 12.0

Proportion With PFS

0.75

0.50

0.25

0 0 Pts at Risk, n Cape CRT Gem CRT 6 12 18 Mos From Registration 17 12 4 0 24 30

36 38

33 37

0 0

0 0

Mukherjee S, et al. ASCO GI 2013. Abstract LBA146.

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SCALOP Trial of Gem- or Cape-Based CRT in Locally Advanced Pancreatic Cancer: OS


1.00 Cape CRT Gem CRT Cape + RT median OS: 15.2 mos HR: 0.39 (95% CI: 0.17-0.81; (95% CI: 13.9-19.2) 1-yr OS: 79.2% P = .012) (95% CI: 61.1-89.5) Gem + RT median OS: 13.4 mos (95% CI: 11.0-15.7) 1-yr OS: 64.2% (95% CI: 46.4-77.5)

Proportion With OS

0.75

0.50

0.25

0 0 Pts at Risk, n Capecitabine CRT 36 Gemcitabine CRT 38 6 12 18 Mos From Registration 24 20 7 2 24 30

35 37

1 0

0 0

Mukherjee S, et al. ASCO GI 2013. Abstract LBA146.

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SCALOP Trial of Gem- or Cape-Based CRT in Locally Advanced Pancreatic Cancer: AEs
Capecitabine (n = 36) Grade 3/4 Adverse Event Any CTCAE grade 3/4 Hematologic Febrile neutropenia Nonhematologic Fatigue Weight loss Diarrhea Stomatitis Nausea/vomiting Anorexia GI bleeding n 4 0 0 4 2 0 0 0 0 0 0 % 11.1 0 0 11.1 5.6 0 0 0 0 0 0 Gemcitabine (n = 38) n 14 7 1 10 4 1 3 0 3 3 0 % 36.8 18.4 2.6 26.3 10.5 2.6 7.9 0 7.9 7.0 0 .095 .007 P Value

Mukherjee S, et al. ASCO GI 2013. Abstract LBA146.

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Phase III MPACT Trial: Gemcitabine nabPaclitaxel in Metastatic Pancreatic Cancer


Stratified by KPS, region, liver metastasis

Patients with metastatic pancreatic cancer, no previous treatment for metastatic disease, KPS 70, bilirubin ULN (N = 861)

nab-Paclitaxel 125 mg/m2 IV q3w + Gemcitabine 1000 mg/m2 on Days 1, 8, 15 q4w (n = 431) Gemcitabine 1000 mg/m2/wk for 7 wks, then on Days 1, 8, 15 q4w (n = 430)

Treat until PD

Primary objective: OS Secondary endpoints: PFS, ORR, safety


Von Hoff DD, et al. ASCO GI 2013. Abstract LBA148.

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MPACT Trial of Gemcitabine nab-Paclitaxel in Metastatic Pancreatic Cancer: OS


Proportion of Surviving Patients 1.0 0.9 0.8 0.7 1.6 0.5 0.4 0.3 0.2 0.1 0 0 3 6 9 12
OS, Mos

nab-P + Gem Events, Gem n/N (%)

Median (95% CI)

75th Percentile 14.8 11.4

333/431 (77) 8.5 (7.89-9.53) 359/430 (83) 6.7 (6.01-7.23)

HR: 0.72 (95% CI: 0.617-0.835; P = .000015)

15
67 40

Pts at Risk, n nab-P + Gem 431 357 269 169 108 Gem 430 340 220 124 69

18 21 Mos
40 26 27 15

24
16 7

27
9 3

30
4 1

33
1 0

36
1 0

39
0 0

Von Hoff DD, et al. ASCO GI 2013. Abstract LBA148.

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MPACT Trial of Gemcitabine nab-Paclitaxel in Metastatic Pancreatic Cancer: PFS


1.0 0.9 0.8 0.7 1.6 0.5 0.4 0.3 0.2 0.1 0 0 3 6 Proportion of Patients Without Progression
PFS, Mos

nab-P + Gem Events, Gem n/N (%)

Median (95% CI)

75th Percentile 9.2 5.9

277/431 (64) 5.5 (4.47-5.95) 265/430 (62) 3.7 (3.61-4.04)

HR: 0.69 95% CI (0.581-0.821; P = .000024)

Pts at Risk, n nab-P + Gem 431 281 122 62 24 Gem 430 209 51 23 10 PFS Rate at nab-P + Gem Gem % Increase 6 mos 44% 25% 76% 12 mos 16% 9% 78% Von Hoff DD, et al. ASCO GI 2013. Abstract LBA148.

12 Mos

15
8 6

18
4 4

21
2 0

24
0 0

Gastrointestinal Cancers
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MPACT Trial of Gemcitabine nab-Paclitaxel in Metastatic Pancreatic Cancer: AEs


Adverse Event 1 AE leading to death, % Grade 3 hematologic AE,* % Neutropenia Leukopenia Thrombocytopenia Anemia Receipt of growth factors % Febrile neutropenia, % Grade 3 nonhematologic AE in > 5% pts, % Fatigue Peripheral neuropathy Diarrhea Grade 3 neuropathy Time to onset, median days Time to improvement by grade, median days Time to improvement to grade 1, median days Resumed nab-P, % nab-P + Gem (n = 421) 4 38 31 13 13 26 3 17 17 6 140 21 29 44 Gem (n = 402) 4 27 16 9 12 15 1 7 <1 1 113 29 ---

*Based on lab values. Based on investigator assessment of treatment-related events. Von Hoff DD, et al. ASCO GI 2013. Abstract LBA148.

Gastrointestinal Cancers
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MPACT Trial of Gem nab-Paclitaxel in Metastatic Pancreatic Cancer: Conclusions


Addition of nab-paclitaxel to gemcitabine improves survival
Across entire curve at all time points Median OS: 8.5 vs 6.7 mos with gemcitabine alone (HR: 0.72; P = .000015) 1-yr OS: 59% increase 2-yr OS: 9% vs 4%

Significant improvement in PFS, ORR, and all other efficacy endpoints with consistent improvement across subgroups Serious AEs not increased, remain acceptable and manageable Nab-paclitaxel plus gemcitabine potentially a new standard for the treatment of metastatic pancreatic cancer
Could become backbone of new regimens
Von Hoff DD, et al. ASCO GI 2013. Abstract LBA148.

Gastrointestinal Cancers
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Phase III JASPAC-01 Trial: Adjuvant Gem vs S-1 in Resected Pancreatic Cancer
Stratified by institution, residual tumor status (R0 vs R1), nodal status (N0 vs N1)

Patients with curatively resected pancreatic cancer (stage I-III), ECOG PS 0-1, no previous chemo or RT (N = 378)

Gemcitabine 1000 mg/m2 on Days 1, 8, 15, q4w 6 courses (n = 191) S-1 40-60 mg BID for 4 of 6 wks 4 courses (n = 187)

Primary endpoint: OS Secondary endpoints: RFS, safety, quality of life


Uesaka K, et al. ASCO GI 2013. Abstract 145.

Gastrointestinal Cancers
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JASPAC-01 Trial of Adjuvant Gem vs S-1 in Resected Pancreatic Cancer: OS


100 Patients remaining alive, %
S-1: 82 pts (44%) died Gem: 123 pts (64%) died 2-yr OS 70% (95% CI: 63-76)

50

2-yr OS 53% (95% CI: 46-60) Median OS: 25.5 mos HR of S-1: 0.56 (99.8% CI: 0.36-0.87; P < .0001 for noninferiority; P < .0001 for superiority, log-rank test)

0 0
Pts at Risk, n S-1 187 Gem 191

1
172 151

2
127 95

Yrs

3
68 51

4
28 16

5
1 3

Uesaka K, et al. ASCO GI 2013. Abstract 145.

Gastrointestinal Cancers
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JASPAC-01 Trial of Adjuvant Gem vs S-1 in Resected Pancreatic Cancer: AEs


Laboratory Data, % Leukocytes Hemoglobin Platelets Bilirubin AST ALT Creatinine Symptom, % Gem (n = 191) Grade 3 Grade 4 32 7 9 8 2 7 0 0.5 5 0 4 0 0 0.5 S-1 (n = 187) Grade 3 Grade 4 4 5 9 5 0 4 1 0 1 0 0.5 0 0.5 0 S-1 (n = 187) Grade 3 Grade 4 3 0 8 0 4 0 2 0 4 0.5 5 0.5 3 0 0.5 0

Gem (n = 191) Grade 3 Grade 4 Stomatitis 0 0 Anorexia 5 0.5 Nausea 2 1 Vomiting 0.5 0.5 Diarrhea 0 0 Fatigue 5 0 Fever 0.5 0 Febrile neutropenia 2 0 Uesaka K, et al. ASCO GI 2013. Abstract 145.

Gastrointestinal Cancers
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Prospective Phase II Trial: GTX in Patients With Metastatic Pancreatic Cancer


Gemcitabine/docetaxel/capecitabine (GTX) regimen
Decreases Bcl-2 and -XL expression Increases intracellular gemcitabine accumulation Inhibits MEK to ERK phosphorylation

Phase II study (N = 44) in untreated metastatic pancreatic cancer


Treatment: capecitabine 750 mg/m2 BID, on Days 1-14; gemcitabine 750 mg/m2 on Days 4, 11; docetaxel 30 mg/m2 on Days 4, 11 > 85% with liver metastases
Fine R, et al. ASCO GI 2013. Abstract 209.

Gastrointestinal Cancers
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GTX in Patients With Metastatic Pancreatic Cancer: Results


Patients remaining alive, %

Responses
ORR: 38% CR: 9% SD: 38%

100 90 80 70 60 50 40 30 20 10 0 0 6 12 18 14.5 mos

Survival (n = 42) Mo % 6 75.6 12 58.5 18 34.1 24 14.6 36 4.9

Median PFS: 6.9 mos Median OS: 14.5 mos Grade 3/4 toxicities: leucopenia, infection, neutropenia, thrombocytopenia
Fine R, et al. ASCO GI 2013. Abstract 209.

24

30

36

42

48

Mos

Gastrointestinal Cancers
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pCR, nCR Rates After Chemo + SBRT in Borderline Resectable Pancreatic Cancer
Single-institution, retrospective review of 35 patients with BRPC who completed gemcitabine-based induction therapy and 5-fraction SBRT prior to resection Each specimen assigned 2 tumor regression grade scores (CAP and MDACC) Neoadjuvant treatment with a gemcitabine-based regimen plus SBRT shown to produce
Significant pathologic response Potential OS and PFS benefit (both P = .019), based on MDACC response
Chuong M, et al. ASCO GI 2013. Abstract 221.

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