1. Post G.I. ASCO Update: Colorectal Cancer Ronald Burkes, M.D.

2. Disclosure of Potential Conflicts of Interest Dr. Ronald Burkes Amgen Inc., Eli Lilly and Company, Hoffmann-La Roche, AstraZeneca, Sanofi- Aventis Advisory board: Honoraria:Amgen Inc., Eli Lilly and Company, Hoffmann-La Roche, AstraZeneca, Sanofi-Aventis Speaker:Amgen Inc., Eli Lilly and Company, Hoffmann-La Roche, AstraZeneca

3. Objective(s)  Review what was new and interesting from G.I. ASCO, 2012  Put these results in perspective  Studies to be reviewed:  181 study – FOLFIRI +/- Panitumumab as 2 nd -line treatment of mCRC  NCIC CO.20 study – Cetuximab +/-Brivanib in KRAS WT mCRC (3 rd -line)  CORRECT trial – BSC +/- Regorafenib in mCRC (4 th -line)  XELOXA trial (N016968) – role of adjuvant XELOX for stage III CRC  ACCORD 12 trial – Capox in rectal cancer  Assessment of the prognostic and predictive value of mutant KRAS codons 12 & 13

12. FOLFIRI +/- Panitumumab as 2 nd -line Therapy of mCRC: 181 study Sobrero GI ASCO (#387), 2012 FOLFIRI + P 303 FOLFIRI 284 HR/p-value RR36%9.8% PFS (mos)6.74.9.82/.023 OS (mos)14.512.5.92/.37 Post Rx EGFR MoAb 12%34% OS (mos) by ST (2-4 vs 0-1) 16.4 vs 8.412.7.5 vs 1.48

13. Comments: 181  Final analysis is consistent with the primary analysis  There is an improvement in PFS and RR but not OS  Not likely to be used as a 2 nd -line option since no OS but may be appropriate for some pts when response is necessary (? still potentially resectable)  Rash/efficacy interaction seems to be important, but not well understood  The inability to mount a skin reaction to an anti- EGFR antibody seems to be associated with a shorter survival → what should we do with patients who don’t develop a rash (should they stop the anti-EGFR MoAb) ?

15.  Brivanib – anti-VEGFR2 inhibitor and also targets fibroblast growth receptors

25. Cetuximab +/- Brivanib in Refractory KRAS WT mCRC: NCIC CO.20 Siu GI ASCO (#386), 2012 Cetux + Ber 376 Cetux + Pl 374 HR/p-value OS (mos)8.88.1.88/.12 PFS (mos)53.4.72/<.0001 RR13.6%7.2%.004 DI cetux57%83% AEs (gr3/4)78%53% D/C Cetux/Br8%/22%4%/3%

26. Comments: CO.20  PFS and RR benefit but no OS benefit (primary endpoint!) → no significant x-over  Toxicity of the combination may have confounded efficacy → DI; D/C Rx 2 0 AEs  Potential biological antagonism → PACCE and CAIRO-2  Unlikely to gain regulatory approval and/or use in combination with cetuximab  Phase III HCC monotherapy trials are ongoing

30.  NB: no PS 2 patients on study

37. BSC +/- Regorafinib in Refractory mCRC: CORRECT Trial (no PS2, no x-over) Grothey GI ASCO (#385), 2012 Regorafinib 505 BSC 255 HR/p-value KRAS mut54.1%61.6% MST (mos)6.45.77/.0052 PFS (mos)1.91.7.49/<.00001 RR/DCR1%/44.8%.4%/15.3%p<.000001 Toxicity H/F, ↑BP, Diarrhea D/C 2 0 AEs8.2%1%

38. Comments: CORRECT OS and PFS benefit –Statistically significant –Clinically meaningful –Toxicity profile not insiginificant (H/F, diarrhea, fatigue, ↑BP) but acceptable –Lack of x-over helped achieve endpoints Clinical impact –Likely to become an available standard for refractory mCRC – when??? (unmet need) –Role in PS 2 patients is unknown –Role of continuous dosing is unknown

46. X-ACT vs XELOXA CapeMayoHR/pBolusXeloxHR/p N1004983942944 DFS60.8%56.7%.88/<.0001(.068)59.8%66.1%.8/.0038 OS71.4%68.4%.86/<.0001(.06)70%75%.83/.038 X-ACTXELOXA Twelves GI ASCO (#274), 2008

50. Comments: XELOXA  XELOX improves DFS and OS compared to bolus 5-FU in patients with stage III colon cancer (median follow-up of 7 years)  Benefit is less in patients > 70 years  XELOX should be considered a treatment option in the adjuvant therapy of stage III colon cancer  q3weeks  less infusion time (impact on chemo unit)  less need for central lines  it is not for everyone – keep a close watch for toxicity

56. Capecitabine + RT(45) vs Capox + RT (50) in Rectal Cancer: ACCORD 12 Trial Gerard GI ASCO (#389), 2012 Cape 45 299 Capox 50 299 DFS (3 yrs)68.3%73.7% OS (3 yrs)87.6%88.3% pCR13.9%19.2% Local recurrence6.1%4.7% Systemic recurrence25%21% Diarrhea gr ¾11%25%

57. Comments: ACCORD 12  This study introduced 3 changes to the approach to the pre-operative therapy of rectal cancer  Oxaliplatin increases toxicity (diarrhea) without any significant impact on ypCR (not a radiosensitizer), local or systemic recurrences, DFS and OS  50Gy/5 weeks compatible with surgery and also increased the CRM negative rate  Capecitabine has the same activity as 5-FU

66. Comments: KRAS Mutation Analysis in mCRC Peeters GI ASCO (#383), 2012  Patients with mCRC that harbor most of the common codon 12 and 13 mutant KRAS alleles are unlikely to benefit from panitumumab therapy  Currently only mCRC patients with WT KRAS tumors should be treated with anti-EGFR MoAbs