Adjuvant therapy in colon cancer Christophe Louvet Hôpital St-Antoine Paris, France Beyrouth, 14/11/08

Incidence of colorectal cancer in the U. S Incidence of colorectal cancer in the U.S. and Western Europe 2006 (n~300,000) Adjuvant Chemotherapy = Option Stage I 24% Stage II 26% Stage IV 22% Stage III 29% Adjuvant Chemotherapy = Standard

When there was no 5FU…. 3-year DFS~50% Stage III

When there was only 5FU…. 3-year DFS < 67%

X-ACT trial in adjuvant treatment of stage III colon cancer 1° endpoint: disease-free survival (DFS) 2° endpoints overall survival (OS) relapse-free survival (RFS) tolerability (NCIC CTG) pharmacoeconomics QoL Capecitabine 1250mg/m2 twice daily, d1–14, q21d n=1004 Bolus 5-FU/LV 5-FU 425mg/m2 plus LV 20mg/m2, d1–5, q28d n=983 Recruitment 1998–2001 24 weeks Chemo-naïve stage III, resection £8 weeks Twelves et al., ECCO 2007

Disease-free survival: 5-year update – median follow-up 6.8 years Capecitabine (n=1 004) 60.8% 5-FU/LV (n=983) 56.7% Estimated probability 1.0 0.8 0.6 0.4 0.2 0.0 6 42 48 78 96 Months HR=0.88 (95% CI: 0.77–1.01) NI margin 1.20 12 18 24 30 36 54 60 66 72 84 90 Test of non-inferiority p<0.0001 Test of superiority p=0.0682 Twelves et al., ECCO 2007 ITT population

Overall survival: 5-year update – median follow-up 6.8 years Capecitabine (n=1 004) 71.4% 5-FU/LV (n=983) 68.4% 1.0 0.8 0.6 0.4 0.2 0.0 6 42 48 78 96 12 18 24 30 36 54 60 66 72 84 90 Estimated probability Months HR=0.86 (95% CI: 0.74–1.01) NI margin 1.14 Test of non-inferiority p=0.000116 Test of superiority p=0.06 Twelves et al., ECCO 2007 ITT population

Fluoropyrimidine monotherapy DFS in stage III CRC 80 67 70 65 64 62 61 60 52 50 44 DFS (%) 40 30 20 10 Moertel IMPACT IMPACT Punt Fields Andre X-ACT Observation Fluoropyrimidine monotherapy

Irinotecan Irinotecan Irinotecan hydrochloride SN-38 2 H 3 SN-38 N-H HO + Carboxylesterases Piperidinopiperidine

VanCutsem, ASCO 2005

Adjuvant Therapy DFS New standard 5FU bolus + LV LV5FU2 Capecitabine 5FU+lev LV5FU/iri IFL better safety

trans-l-diaminocyclohexane oxalatoplatinum Oxaliplatin oxaliplatin Diaminocyclohexane (DACH) carrier ligand NH2 O C Pt O C NH2 O trans-l-diaminocyclohexane oxalatoplatinum OXALIPLATIN

MOSAIC (FOLFOX4): Disease-Free Survival (all population) 3 years (April 20031) 5 years (June 20062) FOLFOX4 (n=1123) LV5FU2 (n=1123) Median follow-up, months 37.9 37.8 73.5 73.4 Events (%) 21.1 26.1 27.1 32.1 DFS (%) 78.2 72.9 73.3 67.4 HR 0.77 0.80 [95% CI] [0.65–0.91] [0.68–0.93] p-value 0.002 0.003 1. Andre, et al. N Engl J Med 2004;350:2343–2351 2. De Gramont et al. ASCO 2007. Abstract 4007.

5 Yrs Disease-free Survival: Stage II and Stage III Patients HR [95% CI] p-value Stage II 0.84 [0.62–1.14] 0.258 Stage III 0.78 [0.65–0.93] 0.005 FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III Months Probability 1.0 0.8 0.6 0.4 0.2 0.9 0.7 0.5 0.3 0.1 6 12 18 24 60 30 36 42 48 54 66 72 p=0.258 3.8% p=0.005 7.5% Data cut-off: June 2006 De Gramont et al. ASCO 2007. Abstract 4007.

Disease-free Survival in Stage III Patients: N1 & N2 1.0 0.9 0.8 7.2% 0.7 0.6 11.5% DFS probability 0.5 0.4 FOLFOX4 – 443 N1 LV5FU2 – 443 N1 FOLFOX4 – 229 N2 LV5FU2 – 232 N2 HR: 0.76 0.3 0.2 HR: 0.72 0.1 0.0 6 12 18 24 30 36 42 48 54 60 66 Data cut-off: January 16, 2005 Months

MOSAIC: OS with 6 years minimum follow-up (2008) 1.0 p=0.996 0.9 0.1% 0.8 p=0.023 0.7 4.4% 0.6 Probability 0.5 0.4 HR [95% CI] Stage II 1.00 [0.71–1.42] Stage III 0.80 [0.66–0.98] FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III 0.3 0.2 0.1 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Data cut-off: January 2007 De Gramont et al. ASCO 2007. Abstract 4007.

Safety results: toxicity per patient NCI Grade 3 FOLFOX4 LV5FU2 Patients (%) (n=1108) (n=1111) Thrombocytopenia 1.7 0.4 Neutropenia 41.1 (Grade 4: 12.2) 4.7 Febrile neutropenia/sepsis 1.8 0.2 Diarrhoea 10.8 6.7 Stomatitis 2.7 2.2 Vomiting 5.9 1.4 Allergy 3.0 0.2 Alopecia (Grade 2) 5.0 5.0 All-cause mortality 0.5 0.5 Andre T et al; N Engl J Med, 2004 Jun 3;350(23):2343-51

Long-term Safety Second cancer Peripheral Sensory Neuropathy 5.3 5.7 (% patients) FOLFOX 5.3 LV5FU2 5.7 Second cancer Peripheral Sensory Neuropathy Evaluable patients n=811 Grade 0 84.3% Grade 1 12.0% Grade 2 2.8% Grade 3 0.7% Data cut-off: January 2007

Eloxatin combinations: NSABP C-07 Primary endpoint: 3-year DFS 5-FU/LV 5-FU: 500 mg/m2 iv bolus weekly x 6 LV: 500 mg/m2 iv weekly x 6 each 8-week cycle x 3, n=1207 2492 patients with stage II and III colon cancer R FLOX 5-FU/LV + oxaliplatin 85 mg/m2 iv on Weeks 1, 3 and 5 of each 8-week cycle x 3, n=1200 P.Kuebler et al. JCO,2007,2198-2204

Eloxatin combinations: NSABP C-07 3-year DFS 1.0 21% risk reduction for FLOX 0.9 0.8 0.7 4.9% Probability 0.6 0.5 3-year DFS 0.4 76.5% 71.6% FU/LV FLOX 0.3 0.2 Hazard ratio: 0.79 (95% CI: 0.67–0.93) p<0.004 0.1 1 2 3 4 Time (years) P.Kuebler et al. JCO,June 2007,2198-2204

LV/5FU bolus (Mayo or RPMI) XELOX NO16968 LV/5FU bolus (Mayo or RPMI) Closed april 2004 R 24 weeks XELOX stage III 24 weeks n = 1864 Xeloda is firmly established as first-line treatment for MCRC, leading to the question, ‘Can Xeloda replace 5-FU in the adjuvant setting? Potential benefits: tumor-targeted action, improved tolerability, convenient oral therapy, cost savings An open-label, multinational, randomised, phase III trial, the Xeloda Adjuvant Chemotherapy Trial (X-ACT), evaluated Xeloda versus bolus 5-FU/LV as adjuvant treatment for Dukes’ C colon cancer [1,2]. Primary objective: to demonstrate at least equivalent disease-free survival with Xeloda versus 5-FU/LV, in an event-driven analysis. Secondary objectives: superiority and confirmatory analyses (subgroups, multivariate), relapse-free survival, overall survival, safety, QoL, and pharmacoeconomics. Between November 1998 and November 2001, 1 987 patients were enrolled from 164 centres worldwide. 1. Scheithauer W et al. Ann Oncol 2003;14:1735–43. 2. Cassidy J et al. Proc Am Soc Clin Oncol 2004 (Abst 1403). 1st endpoint: disease-free survival (DFS) Results : end of 2008

XELOX vs bolus 5-FU/LV: main grade 3–4 treatment-related toxicities 30 XELOX 25 5-FU/LV 20 Patients (%) 15 10 5 HFS Diarrhoea Nausea Vomiting Stomatitis Neutropenia Neurosensory Febr. neutropenia Schmoll et al, J Clin Oncol 2007

Adjuvant Therapy ? DFS New standard FLOX XELOX FOLFOX4 5FU bolus + LV LV5FU2 Capecitabine 5FU+lev LV5FU/iri IFL better safety

Fluoropyrimidine monotherapy 3y-DFS in stage III CRC 78 76 80 67 70 65 64 62 61 60 52 50 44 DFS (%) 40 30 20 10 C07 FLOX Moertel IMPACT IMPACT Punt Fields Andre X-ACT MOSAIC FOLFOX4 Observation Fluoropyrimidine monotherapy Ox-based

Quick & Simple & Reliable 'Uncertain indication' for chemotherapy (3239 patients ’94 -’03) Randomize Observation (n=1617) 5-FU/LV ± Lev (n=1622) Quasar Collaborative group-Lancet 2007;370:2020-29

QUASAR: Survival n deaths 5yS p Chemo 1622 311 80.3 0.008 None 1617 370 77.4 Quasar Collaborative group-Lancet 2007;370:2020-29

MOSAIC: high-risk stage II patients 64% of stage II patients were defined as high-risk: T4 Bowel obstruction Tumour perforation Poorly differentiated tumour Venous invasion Number of examined lymph nodes <10

5 Yrs Disease-free Survival: High-risk Stage II Patients 1.0 0.9 0.8 7.2% 0.7 FOLFOX4 n=286 LV5FU2 n=290 0.6 Probability 0.5 3-year 5-year FOLFOX4 85.4% 82.1% LV5FU2 80.4% 74.9% HR [95% CI]: 0.74 [0.52–1.06] 0.4 0.3 0.2 0.1 6 12 18 24 30 36 42 48 54 60 66 72 Disease-free survival (months) Exploratory analysis De Gramont et al. ASCO 2007. Abstract 4007.

Future directions: E5202 R Planned n=3125 mFOLFOX6 High-risk (MSS and 18q LOH) Stage II colon cancer R mFOLFOX6 + bevacizumab SURGERY Tumour block risk assessment based on biology (18q/MSI) Low-risk (MSI or no loss of 18q LOH) Observation Planned n=3125

When there was only chemotherapy… 3-year DFS<74%

BEVACIZUMAB VEGF VEGFR

R NSABP C08 mFOLFOX6 12 cycles mFOLFOX6 + Bev Bev 12 cycles 6 months stage II-III (n=2700) 12 cycles 6 months Xeloda is firmly established as first-line treatment for MCRC, leading to the question, ‘Can Xeloda replace 5-FU in the adjuvant setting? Potential benefits: tumor-targeted action, improved tolerability, convenient oral therapy, cost savings An open-label, multinational, randomised, phase III trial, the Xeloda Adjuvant Chemotherapy Trial (X-ACT), evaluated Xeloda versus bolus 5-FU/LV as adjuvant treatment for Dukes’ C colon cancer [1,2]. Primary objective: to demonstrate at least equivalent disease-free survival with Xeloda versus 5-FU/LV, in an event-driven analysis. Secondary objectives: superiority and confirmatory analyses (subgroups, multivariate), relapse-free survival, overall survival, safety, QoL, and pharmacoeconomics. Between November 1998 and November 2001, 1 987 patients were enrolled from 164 centres worldwide. 1. Scheithauer W et al. Ann Oncol 2003;14:1735–43. 2. Cassidy J et al. Proc Am Soc Clin Oncol 2004 (Abst 1403). 1st endpoint: disease-free survival (DFS) Closed octobre 2006

R AVANT BO17920 study Primary endpoint: disease-free survival FOLFOX4 Observation R FOLFOX4 + Beva. (5mg/kg q 2 weeks) Beva. mono (7.5mg/kg q 3 weeks) Stage II/III colon cancer (n=3450) XELOX + Beva. (7.5mg/kg q3 weeks) Beva. mono (7.5mg/kg q3 weeks) Duration of treatment 24 weeks 24 weeks Primary endpoint: disease-free survival Secondary endpoints: safety, overall survival, pharmacoeconomics, pharmacodynamics, convenience and satisfaction with chemotherapy

Capecitabine + Bevacizumab Phase III adjuvant trial in high-risk stage II/III colon cancer (QUASAR-2) Capecitabine R Capecitabine + Bevacizumab Stage II-III N=3510 Ongoing trial phase III trial in patients with high-risk stage II/III colon cancer. Over 30 patients with colon cancer have been enrolled to date. Primary endpoint: disease-free survival. Secondary endpoints include survival and tolerability analyses. 24 weeks 1st endpoint: disease-free survival (DFS) Secondary endpoint: safety, overall survival

CETUXIMAB EGFR1

R Modified Intergroup N0147 mFOLFOX6 24 weeks mFOLFOX6 + Cetuximab Stage III 24 weeks Xeloda is firmly established as first-line treatment for MCRC, leading to the question, ‘Can Xeloda replace 5-FU in the adjuvant setting? Potential benefits: tumor-targeted action, improved tolerability, convenient oral therapy, cost savings An open-label, multinational, randomised, phase III trial, the Xeloda Adjuvant Chemotherapy Trial (X-ACT), evaluated Xeloda versus bolus 5-FU/LV as adjuvant treatment for Dukes’ C colon cancer [1,2]. Primary objective: to demonstrate at least equivalent disease-free survival with Xeloda versus 5-FU/LV, in an event-driven analysis. Secondary objectives: superiority and confirmatory analyses (subgroups, multivariate), relapse-free survival, overall survival, safety, QoL, and pharmacoeconomics. Between November 1998 and November 2001, 1 987 patients were enrolled from 164 centres worldwide. 1. Scheithauer W et al. Ann Oncol 2003;14:1735–43. 2. Cassidy J et al. Proc Am Soc Clin Oncol 2004 (Abst 1403). 1st endpoint: disease-free survival (DFS)

R PETACC-8 - ACCORD - Merck FOLFOX4 24 weeks FOLFOX4 + Cetuximab stage III 24 weeks Xeloda is firmly established as first-line treatment for MCRC, leading to the question, ‘Can Xeloda replace 5-FU in the adjuvant setting? Potential benefits: tumor-targeted action, improved tolerability, convenient oral therapy, cost savings An open-label, multinational, randomised, phase III trial, the Xeloda Adjuvant Chemotherapy Trial (X-ACT), evaluated Xeloda versus bolus 5-FU/LV as adjuvant treatment for Dukes’ C colon cancer [1,2]. Primary objective: to demonstrate at least equivalent disease-free survival with Xeloda versus 5-FU/LV, in an event-driven analysis. Secondary objectives: superiority and confirmatory analyses (subgroups, multivariate), relapse-free survival, overall survival, safety, QoL, and pharmacoeconomics. Between November 1998 and November 2001, 1 987 patients were enrolled from 164 centres worldwide. 1. Scheithauer W et al. Ann Oncol 2003;14:1735–43. 2. Cassidy J et al. Proc Am Soc Clin Oncol 2004 (Abst 1403). 1st endpoint: disease-free survival (DFS) Now restricted to k-ras WT patients

Advances in the Adjuvant treatment of colon cancer 1990 5-FU + levamisole better than BSC 1998 6 months = 12 months 1998 levamisole of no additional benefit 1998 high-dose LV = low-dose LV 1998 Weekly = monthly schedule 1998 MOSAIC Adjuvant study starts 2001 Elderly benefit 2004 Capecitabine and UFT equivalence to IV 5FU 2004 QUASAR data for Dukes B 2004 MOSAIC (NSABP C-07) new standard of care Dukes C 2005 Irinotecan preliminary data / PETACC-3 2005 Targeted (Bevacizumab/ Cetuximab) agent studies start 2007-8 MOSAIC Overall Survival data ACCENT DATABASE

New guidelines for adjuvant treatment of colon cancer: NCCN 2006 T1, N0, M0 and T2, N0, M0 (stage I) No chemotherapy T3, M0, N0 (stage II, no high-risk features) Consider single-agent fluoropyrimidine or 5-FU/LV + oxaliplatin N0 high risk and Stage III FOLFOX (XELOX) NCCN Clinical Practice Guidelines in Oncology v2.2006.