1. Best of ASCO – Colorectal & Pancreatic Cancers Best of ASCO Colorectal & Pancreatic Cancers Ali Shamseddine, MD Professor of Medicine Head of Hematology/Oncology Division American University of Beirut Medical Center

2. Best of ASCO – Colorectal & Pancreatic Cancers Adjuvant Chemotherapy in Colorectal Cancer

3. Best of ASCO – Colorectal & Pancreatic Cancers

6. Survival Results of NSABP C-07 FULV 5-FU 500 m 2 IV bolus weekly x 6 + LV 500 mg/m 2 IV weekly x 6 of each 8-week cycle x 3 (n = 1209) FLOX FULV + Oxaliplatin 85 mg/m 2 IV on Weeks 1, 3, and 5 of each 8-week cycle x 3 (n = 1200) Patients with stage II or III carcinoma of the colon stratified by number of positive lymph nodes (N = 2409) Wolmark N, et al. ASCO 2008. Abstract LBA4005.  Primary endpoint: DFS

7. Best of ASCO – Colorectal & Pancreatic Cancers C-07: Disease-Free Survival 3-Year DFS5-Year DFS FLOX (n = 1200) 76.1%69.4% P =.002 HR: 0.81 (95% CI: 0.70-0.93) FULV (n = 1209) 71.5%64.2% ∆ 4.6%5.2% Wolmark N, et al. ASCO 2008. Abstract LBA4005.

8. Best of ASCO – Colorectal & Pancreatic Cancers C-07: Overall Survival Deaths, n3-Year OS5-Year OS FLOX (n = 1200) 25980.3%77.7% P =.06 HR: 0.85 (95% CI: 0.72-1.01) FULV (n = 1209) 30178.3%73.5% ∆ 422.0%4.2% Wolmark N, et al. ASCO 2008. Abstract LBA4005.

9. Best of ASCO – Colorectal & Pancreatic Cancers Initial Safety Report of NSABP C-08 Arm A mFOLFOX6 every 2 wks x 12 doses (n = 1356) Arm B: mFOLFOX6 + Bevacizumab 5 mg/kg every 2 wks x 26 doses (n = 1354) Patients with stage II or III colon adenocarcinoma with ECOG performance score of 0/11 (N = 2710)  Patients were stratified by the number of positive lymph nodes and were randomized between Days 29 and 50 postoperatively  mFOLFOX6 regimen: leucovorin 400 mg/m 2 IV, 5-FU 400 mg/m 2 IV, 5-FU 2400 mg/m 2 over 46 hrs; oxaliplatin 85 mg/m 2 IV  Primary endpoint: DFS Allegra CJ, et al. ASCO 2008. Abstract 4006.

10. Best of ASCO – Colorectal & Pancreatic Cancers C-08: Grade 3/4 Toxicities Significantly Increased With Bevacizumab Adverse EventmFOLFOX, %mFOLFOX + Bevacizumab,% P Value Hypertension1.812.0*<.0001 Any pain6.311.1<.0001 Proteinuria0.82.7<.0001 Wound complications 0.31.7 † <.0001 Allegra CJ, et al. ASCO 2008. Abstract 4006. *5 patients had grade 4 hypertension. † All grade 3.  Median time on study: 22.4 months  No significant increases in GI perforation, hemorrhage, arterial, or venous thrombotic events, or deaths have been observed with the addition of bevacizumab

11. Best of ASCO – Colorectal & Pancreatic Cancers Metastatic Colorectal Cancer

12. Best of ASCO – Colorectal & Pancreatic Cancers CONcePT Trial Design Grothey A, et al. ASCO 2008. Abstract 4010. *Treat to failure. † 8 cycles with oxaliplatin, 8 cycles without oxaliplatin, 8 cycles with oxaliplatin. Patients with metastatic colorectal cancer (N = 140) 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)

13. Best of ASCO – Colorectal & Pancreatic Cancers CONcePT: Treat-to-Failure  Treat-to-failure –Continuous oxaliplatin (CO): 4.2 months (95% CI: 3.7-5.5) –Intermittent oxaliplatin (IO): 5.6 months (95% CI: 4.7-7.0)  Unstratified (IO relative to CO): P =.002*  Stratified by CaMg (IO relative to CO): P =.003* Grothey A, et al. ASCO 2008. Abstract 4010. *Log-rank test.

14. Best of ASCO – Colorectal & Pancreatic Cancers CONcePT: Progression-Free Survival  Treat-to-failure –Continuous oxaliplatin (CO): 7.3 months (95% CI: 6.9-NE) –Intermittent oxaliplatin (IO): 12.0 months (95% CI: 8.2-NE)  Unstratified (IO relative to CO): P =.044*  Stratified by CaMg (IO relative to CO): P =.030* Grothey A, et al. ASCO 2008. Abstract 4010. *Log-rank test.

15. Best of ASCO – Colorectal & Pancreatic Cancers Clinical practice*: Hepatic metastasectomy in patients with liver disease only Cassidy, et al. ASCO 2008 (poster) *BEAT: largest prospective trial with a predefined analysis for resectability (non-randomised study) n=107n=71n=33 15.2 20.3 14.3 n=85 12.1 n=54 15.5 n=27 11.7 25 20 15 10 5 0 Patients (%) Hepatic metastasectomy with no residual disease (R0) Hepatic metastasectomy Avastin + CTx All (n=704) Avastin + CTx Including oxaliplatin (n=349) Avastin + CTx Including irinotecan (n=230)

16. Best of ASCO – Colorectal & Pancreatic Cancers Clinical practice*: Significant improvement in 2-year OS for patients who underwent hepatic metastasectomy with R0 resection *BEAT (non-randomised study) OS = overall survival Cassidy, et al. ASCO 2008 (poster) 1.00 0.75 0.50 0.25 0 OS estimate 051015202530 Months Hepatic metastasectomy and R0 resection (n=114) Hepatic metastasectomy total (n=145) No hepatic metastasectomy (n=1,791) p<0.001 47% 89% 86%

17. Best of ASCO – Colorectal & Pancreatic Cancers FDG-PET Improves Selection of Patients With CRC Liver Metastases Wiering B, et al. ASCO 2008. Abstract 4004. CT imaging only (n = 75) CT imaging + FDG-PET (n = 75) Patients with colorectal cancer liver metastases selected for surgical treatment by imaging with CT scan (N = 150) Laparotomy Excluded by PET Findings at laparotomy and F/U Findings at laparotomy and F/U  Patients were followed for at least 3 yrs for OS and DFS –No standard chemotherapy was given postoperatively

18. Best of ASCO – Colorectal & Pancreatic Cancers  Primary endpoint: futile laparotomies, defined as a laparotomy that –Did not result in complete tumor treatment –Revealed benign disease –Did not result in DFS longer than 6 months  Secondary endpoint: OS and DFS FDG-PET Improves Selection of Patients With CRC Liver Metastases Wiering B, et al. ASCO 2008. Abstract 4004.

19. Best of ASCO – Colorectal & Pancreatic Cancers  Number of futile laparotomies was reduced from 45% to 28%  Addition of FDG-PET to the workup for surgical resection of colorectal liver metastases prevents unnecessary surgery in 1 out of 6 patients  No significant differences in OS or DFS were noted in the first 3 yrs of follow-up FDG-PET in CRC Liver Metastases: Conclusions Wiering B, et al. ASCO 2008. Abstract 4004.

20. Best of ASCO – Colorectal & Pancreatic Cancers KRAS Status and Efficacy in Metastatic Colorectal Cancer

21. Best of ASCO – Colorectal & Pancreatic Cancers KRAS Status and Efficacy of First-Line FOLFOX ± Cetuximab: OPUS  Genomic DNA was isolated from archived tumor material  KRAS mutation status of codons 12/13 was determined using a sensitive, quantitative PCR-based assay  Population with tissue available for KRAS analysis (n = 233) was representative of overall ITT population (n = 337) in terms of demographics and efficacy parameters  KRAS mutations detected in 42% (99/233) of evaluable samples Bokemeyer C, et al. ASCO 2008. Abstract 4000.

22. Best of ASCO – Colorectal & Pancreatic Cancers OPUS: Results KRAS Status Median PFS Cetuximab + FOLFOX, Mos Median PFS FOLFOX, mos HR (P Value) Overall RR Cetuximab + FOLFOX, % Overall RR FOLFOX, % P Value WT7.7 (n = 61)7.2 (n = 73)0.57 (.02)6137.01 Mutation5.5 (n = 52)8.6 (n = 47)1.83 (.02)3349.11 PFS and Response Rates by KRAS Mutation Status  The benefit from addition of cetuximab to standard treatment is higher for the population with WT KRAS  No benefit could be shown of adding cetuximab to FOLFOX for patients with KRAS mutations Bokemeyer C, et al. ASCO 2008. Abstract 4000.

23. Best of ASCO – Colorectal & Pancreatic Cancers OPUS: PFS according to K-Ras status PFS – K-Ras mutantPFS – K-Ras wild-type Progression-free time (months) Kaplan-Meier estimate 024681012 Cetuximab + FOLFOX FOLFOX Cetuximab + FOLFOX FOLFOX K-Ras mutant: HR=1.83; p=0.0192 Cetuximab + FOLFOX: 5.5 months FOLFOX: 8.6 months Kaplan-Meier estimate Progression-free time (months) 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 K-Ras wild-type: HR=0.57; p=0.016 Cetuximab + FOLFOX: 7.7 months FOLFOX: 7.2 months Bokemeyer, et al. ASCO 2008

24. Best of ASCO – Colorectal & Pancreatic Cancers KRAS and Efficacy of Irinotecan and Cetuximab in mCRC: EVEREST Patients with irinotecan- refractory metastatic cancer Cetuximab 400 mg/m 2 initial dose then 250 mg/m 2 /wk + Irinotecan 180 mg/m 2 Q2W Control Standard Cetuximab regimen (250 mg/m 2 /wk) (n = 23) Dose Escalation Cetuximab dose increases of 50 mg/m 2 Q2W up to maximum 500 mg/m 2 /wk (n = 31) Nonrandomized Standard Cetuximab regimen (250 mg/m 2 /wk) SCREENINGSCREENING Day 22 Randomized: skin toxicity grade 0/1 Not eligible for randomization: skin toxicity grade 2/3  All patients continued to receive irinotecan  Treatment until progression, unacceptable toxicity or withdrawal of consent  Skin and tumor biopsy at baseline, Week 3, and at maximum cetuximab dose in dose-escalation arm Tejpar S, et al. ASCO 2008. Abstract 4001.

25. Best of ASCO – Colorectal & Pancreatic Cancers EVEREST: PFS (ITT Population) 0 0.2 0.4 0.6 0.8 1.0 0200400600 Days PFS Estimate 800 P <.0001 KRAS mutant WT KRAS KRAS mutation present 83 days (95% CI: 75.9-90.2) 173 days (95% CI: 141.3-204.7) Tejpar S, et al. ASCO 2008. Abstract 4001. Reproduced with permission.

26. Best of ASCO – Colorectal & Pancreatic Cancers EVEREST: PFS by Treatment Group and KRAS Status 0.0 0.2 0.4 0.6 0.8 1.0 0 200400 600 800 0.0 0.2 0.4 0.6 0.8 1.0 0 200400 600 800 0.0 0.2 0.4 0.6 0.8 1.0 0 200400 600 800 Days KRAS mutant WT KRAS Control KRAS mutation present P =.014 KRAS mutant WT KRAS Dose Escalation KRAS mutation present KRAS mutant WT KRAS Nonrandomized KRAS mutation present P <.001P =.020 Tejpar S, et al. ASCO 2008. Abstract 4001. Reproduced with permission. PFS Estimate

27. Best of ASCO – Colorectal & Pancreatic Cancers Pancreatic Cancer

28. Best of ASCO – Colorectal & Pancreatic Cancers Treatment of Advanced Pancreatic Cancer Targeted Therapy beyond Erlotinib Treatment of Gemcitabine-Refractory Disease

29. Best of ASCO – Colorectal & Pancreatic Cancers

30.  Primary endpoint = overall survival  Stratified according to country, KPS (<80 vs ≥80), albumin level (<2.9g/dL vs ≥2.9g/dL) PD Previously untreated metastatic pancreatic cancer (n=600) Tarceva (100mg) + gemcitabine + Avastin (5mg/kg every 2 weeks) Tarceva (100mg) + gemcitabine + placebo KPS = Karnofsky performance status PD = progressive disease AVITA: study design

31. Best of ASCO – Colorectal & Pancreatic Cancers 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 03691215182124 Overall survival probability Time (months) 7.16.0 HR=0.89, p=0.2087 (95% CI: 0.74–1.07) Gemcitabine + Tarceva + Avastin (n=221 with events) Gemcitabine + Tarceva (n=233 with events) Vervenne W, Van Cutsem E, et al. J Clin Oncol 2008;26(Suppl. 15 Pt I): 214s (Abs. 4507) AVITA: overall survival

32. Best of ASCO – Colorectal & Pancreatic Cancers 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 PFS probability HR=0.73, p=0.0002 (95% CI: 0.61–0.86) 4.63.6 Vervenne W, Van Cutsem E, et al. J Clin Oncol 2008;26(Suppl. 15 Pt I): 214s (Abs. 4507) PFS = progression-free survival Gemcitabine + Tarceva + Avastin (n=257 with events) Gemcitabine + Tarceva (n=278 with events) 03691215182124 Time (months) AVITA: PFS

33. Best of ASCO – Colorectal & Pancreatic Cancers