1. Peri-Operative Chemotherapy Is the Best Approach Wells Messersmith, MD, FACP Professor Director, Gastrointestinal Medical Oncology Program Program co-Leader, Developmental Therapeutics University of Colorado Cancer Center

2. Conflict of Interest: 1.No employment, speaker’s bureaus, stock ownership, royalties, patents, etc 2.Data Safety Monitoring Board for OncoMed 3. PI or Local PI of clinical trials by Genentech/Roche, GSK, Pfizer, Millenium, Bayer, Onconova, and NIH/CTEP.

3. Rationale for Neoadjuvant Therapy Convert unresectable patients to resectable Assess biology/chemo-responsiveness of disease Treat micro-metastatic disease (which chemotherapy can cure) as soon as possible Potentially decrease surgical complications by making surgery more feasible Potential downsides: hepatotoxicity; complications; complete response can hide metastatic sites; fear of “lost opportunity” if progression; etc

4. What we know Liver resection can cure patients (although no randomized trials) Response rates to modern combination regimens are very high (40-80%) Chemo is feasible and safe in 1 st line setting What we don’t know Optimal chemo regimens (e.g., biologics?) Optimal sequencing and # cycles Optimal patient selection (predictive markers)

5. Peri-Operative FOLFOX for Hepatic Metastases (for patients with initially resectable disease) Nordlinger, ASCO 2005; Nordlinger, Lancet Oncology 2013;14:1208-15 n = 364, resectable liver metastases Primary endpoint: disease-free survival (DFS) FOLFOX4 6 cycles (3m) Surgery No chemotherapy SurgeryFOLFOX4 6 cycles (3m) EORTC 40983 Important toxicity data: only small increase in peri- operative complications with chemo, although only 63% in chemo group received it post-operatively n=182 (171 eligible)

6. EORTC 40983: Peri-Op FOLFOX for Liver Mets Nordlinger, Lancet Oncology 2013;14:1208-15 Overall Survival HR=0.88 (p=0.34) mOS, 61m vs 54m Absolute difference: 3.4% Progression-Free Survival HR=0.81 (p=0.068) (p=0.035 for eligible pts) mPFS, 20m vs 12.5m Absolute difference: 8.2% No survival advantage to peri-operative chemo!

7. Key Points for EORTC 40983 (1) No overall survival benefit to adding chemotherapy to surgery for resectable liver metastases – OS was not primary endpoint; study underpowered – HR for PFS (~0.8), and absolute benefit of ~4% in eligible patients, is similar to stage III trials (MOSAIC, C-07) Note: a 360-patient study in stage III disease would show the same thing! Most adjuvant trials enroll > 2000 patients.

8. Key Points for EORTC 40983 (2) Difficult to accrue these studies; survival studies with 1000’s patients (as in stage III) are unlikely Peri-operative chemotherapy generally safe and well-tolerated Only ~4-7% of patients developed extrahepatic disease while receiving chemotherapy (too much hype as a “good patient selector”?) Fewer patients receive chemotherapy after surgery (thus, similar to rectal cancer; we treat up front so patients can tolerate better)

9. Report drugs toxicity % Rubbia-Brandt 5-FU/ sinusoidal51% total Ann Oncol 2004, n=153 Ox congestion78% oxali Fernandez 5-FU/ steato- 64% I + O J AM C Surg 2005, n=37 Ox / I hepatitis10% 5-FU Karoui 5-FU/ sinusoidal49% chemo Ann Surg 2006, n=67 Ox / I dilation 14% no chemo Aloia 5-FU vascular52% chemo JCO 2006, n=75 Ox changes18% no chemo Chemotherapy Liver Toxicity: Selected Reports Ox = oxaliplatin; I = Irinotecan

10. Chemotherapy Liver Toxicity: Selected Reports Karoui, Ann Surg 2006 Influence of Number of Cycles of Pre-Op Chemo on Morbidity More is not better! But some is OK!

11. METHEP Trial: randomized phase II trial of regimens for initially unresectable* mCRC Ychou, ASCO 2008; Ychou, Ann Surg Oncol 2013;20: 4289-4297 n = 122 Primary endpoint: Response rate after 4 cycles “standard” chemo *Definitions: Not optimally resectable (but potentially resectable) was defined as complex hepatectomy, “risky”, close contact with major vascular structures n=92 n=30 “Intensified” chemo High dose FOLFIRI FOLFOX7 FOLFIRINOX FOLFOX4 FOLFIRI 15 32 30 n=

12. METHEP Trial Ychou, Ann Surg Oncol 2013;20: 4289-4297 Lesson #1: FOLFIRINOX appears more active than other regimens (mOS>48m; all others <30m; RR=57%) Lesson #2: Patients who undergo R0/R1 resections do much better than non- operated, or R2 (visible disease left behind)

13. Randomized phase II trial of chemo +/- cetuximab for initially unresectable* mCRC Ye, J Clin Oncol 2013 Jun 1;31(16):1931-8 n = 138, KRAS WT Primary endpoint: Rate of conversion to resectability FOLFOX or FOLFIRI *Definitions: “declared unresectable by a multi- disciplinary team including 3 liver surgeons and a radiologist” n=70 n=68 FOLFOX or FOLFIRI & cetuximab

14. Improved survival with Cetx in phase II trial: initially unresectable liver-confined mCRC Ye, J Clin Oncol 2013 Jun 1;31(16):1931-8 Note difference between the (negative) “New EPOC” study, which was perioperative adjuvant Ctx trial, and this one.

15. Biologics as adjuvant therapy: 0 for 4! - NSABP C-08 mFOLFOX6 +/- bevacizumab (12 mos) - N0147 FOLFOX +/- cetuximab (US Intergroup) - AVANTFOLFOX4 vs FOLFOX + bevacizumab vs XELOX + bevacizumab - New EPOCFOLFOX +/- Cetuximab (Liver Mets) (HR=1.49; Primose, J Clin Oncol 31, 2013 (suppl; #3504 )

16. Trials for Unresectable Liver Mets METHEP2 (PRODIGE 14, NCT01442935 ) – Cetuximab (KRAS WT) or Bevacizumab (MT) with FOLFIRINOX vs FOLFOX/FOLFIRI CELIM2 (Dresden; NCT01802645 ) – Cetx/FOLFOXIRI vs cetx/FOLFIRI (KRAS WT) – FOLFOXIRI +/- Bev FOLFOX/Cetux (Korea/Samsung; NCT00743678 ) mFOLFOX7/Cetux (NSABP FC-6; NCT00803647 ) Many others

17. Trials for Resectable Liver Mets Université Catholique de Louvain( NCT01858662 ) – Cetuximab (KRAS WT) with either FOLFOX or FOLFIRI; pCR is primary endpoint BOS-2 ( EORTC-40091; NCT01508000 ) – FOLFOX alone, or with Panitumumab (KRAS WT) or Bevacizumab (KRAS MT) PANTER ( CTC-A10-005; NCT01266187 ) – FOLFOX/Ctx x 12w-> Surgery -> FOLFOX/Ctx x 12w vs. – Surgery -> FOLFOX/Ctx x 24w

18. Conclusions -Liver resection of colorectal metastases appears highly effective in selected patients -“Conversion” therapy (converting unresectable to resectable) is increasingly feasible given high response rates of modern regimens -Unclear whether we should be using regimens for metastatic disease (e.g. biologics) versus adjuvant regiments (no biologics) -Overtreatment can increase complications and costs -A multi-disciplinary approach involving surgical oncologists at diagnosis in potentially curative cases is important