A Report from ASCO-GI 2008 and ASCO 2007 Up-to-Date Review of the Treatment of Adjuvant Colorectal Cancer Axel Grothey, MD Professor of Oncology Mayo Clinic College of Medicine Rochester, MN Axel Grothey, MD Professor of Oncology Mayo Clinic College of Medicine Rochester, MN

History of Adjuvant Therapy of Colon Cancer 5-FU/lev superior to surgery alone 5-FU/LV superior to surgery alone 5-FU/LV superior to 5- FU/lev 6- and 12-month treatment cycles equivalent Lev unnecessary High-dose and low- dose LV equivalent Monthly and weekly treatment equivalent LV5FU2 and monthly bolus equivalent Moertel et al. Ann Intern Med. 1995;122:321. Francini et al. Gastroenterol. 1994;106:899. Wolmark et al. Proc Am Soc Clin Oncol. 1996;15:205. Abstract O’Connell et al. J Clin Oncol. 1998;16:295. Haller et al. Proc Am Soc Clin Oncol. 1998;17:256a. Abstract 982. Andre et al. Proc Am Soc Clin Oncol Abstract 529.

3 Year DFS vs 5 Year OS 5-yr OS = * 3-yr DFS May 05, 2004: ODAC recommends 3-yr DFS as new regulatory endpoint for FULL approval in adjuvant colon cancer Sargent, et al. J Clin Oncol 2005;23:8664–8670.

5-FU: Historical Standard in the Adjuvant Setting 1 IMPACT Investigators, Lancet 1995;345:939–44. 2 Wolmark N, et al. J Clin Oncol 1993;11:1879–87. 3 QUASAR Group. Lancet 2000;355:1588–96. 4 André T, et al. J Clin Oncol 2003;21:2896– year disease-free survival (%) Observation 1 5-FU/high-dose LV (Mayo) 2 5-FU/low-dose LV (Mayo) 3 LV5FU2 4 Stage II and III colon cancer patients 6 months 5-FU/LV (Mayo)

Beyond 5-FU in the Adjuvant Setting Completed studies: Oxaliplatin (MOSAIC, NSABP C-07) Irinotecan (CALGB 89803, ACCORD-2, PETACC-3) Capecitabine (X-ACT) Ongoing studies: CAPOX (XELOXA) Bevacizumab (NSABP C-08, AVANT, E5202) Cetuximab (N0147, PETACC-8) Completed studies: Oxaliplatin (MOSAIC, NSABP C-07) Irinotecan (CALGB 89803, ACCORD-2, PETACC-3) Capecitabine (X-ACT) Ongoing studies: CAPOX (XELOXA) Bevacizumab (NSABP C-08, AVANT, E5202) Cetuximab (N0147, PETACC-8)

MOSAIC: Study Design Primary end-point: disease-free survival Secondary end-points: safety, overall survival R LV5FU2 FOLFOX4 (LV5FU2 + oxaliplatin 85 mg/m²) (N =1,123) LV5FU2, Leucovorin 200 mg/m 2 iv over 2 hours followed by 5-fluorouracil 400 mg/m 2 bolus and 5-fluorouracil 600 mg/m 2 iv over 22 hours on Days 1 and 2, every 14 days; FOLFOX4, LV5FU2 + oxaliplatin 85 mg/m 2 iv over 2 hours on Day 1 N = 2,246 Enrollment:Oct 1998–Jan 2001 (146 centres; 20 countries) Completely resected colon cancer Stage II, 40%; Stage III, 60% Age 18–75 years KPS ≥60 No prior chemotherapy

Disease-free Survival: ITT Data cut-off: June 2006 Disease-free survival (months) FOLFOX4 LV5FU2 Probability Events FOLFOX4 304/1,123 (27.1%) LV5FU2 360/1,123 (32.1%) HR [95% CI]: 0.80 [0.68–0.93] 5.9% P = % De Gramont A, et al. ASCO Abstract #4007.

Disease-free Survival: Stage II and Stage III Patients Data cut-off: June 2006 HR [95% CI] P - value Stage II 0.84 [0.62–1.14] Stage III 0.78 [0.65–0.93] FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III Months Probability % 7.5% P = P = De Gramont A, et al. ASCO Abstract #4007.

MOSAIC: Disease-free Survival – Final Update 5-year DFS % HR [95% CI]P - value FOLFOX4LV5FU2 ITT (overall population) [0.68 – 0.93] Stage III [0.65 – 0.93] Stage II [0.62 – 1.14] High-risk stage II N = [0.52 – 1.06] — Low-risk stage II N = [0.66–2.26] — Data cut-off: June 2006 De Gramont A, et al. ASCO Abstract #4007.

“High-risk” Stage II Colon Cancer Clinico-pathological parameters (MOSAIC) - T4 tumors - Obstruction/perforation - Lymphatic or vascular invasion - Undifferentiated histology - Less than 10 (12) Ln examined Molecular parameters - LOH 18q - MSS - Other? Clinico-pathological parameters (MOSAIC) - T4 tumors - Obstruction/perforation - Lymphatic or vascular invasion - Undifferentiated histology - Less than 10 (12) Ln examined Molecular parameters - LOH 18q - MSS - Other? De Gramont A, et al. ASCO Abstract #4007.

Long-term Safety (% patients) FOLFOX 5.3 LV5FU2 5.7 Data cut-off: January 2007 Second cancer Peripheral Sensory Neuropathy Evaluable patients N = 811 Grade 084.3% Grade 112.0% Grade 22.8% Grade 30.7% De Gramont A, et al. ASCO Abstract #4007.

Overall Survival: ITT Data cut-off: January 2007 Overall survival (months) FOLFOX4 LV5FU2 Probability Events FOLFOX4 243/1,123 (21.6%) LV5FU2 279/1,123 (24.8%) HR [95% CI]: 0.85 [0.72–1.01] 2.6% P = yrs: 78.6% vs. 76.0% De Gramont A, et al. ASCO Abstract #4007.

Overall Survival: Stage II and Stage III Data cut-off: January 2007 FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III Overall survival (months) Probability HR [95% CI] Stage II 1.00 [0.71–1.42] Stage III 0.80 [0.66–0.98] 0.1% 4.4% P = P = De Gramont A, et al. ASCO Abstract #4007.

Take-Home Messages MOSAIC DFS benefit for FOLFOX is maintained over 5 years Significant OS benefit for stage III, but NOT for unselected stage II patients “High-risk” stage II with trend toward better DFS with FOLFOX, but clinical consequence unclear No increased rate of secondary cancers, but more deaths of cancer in FOLFOX group (21 vs. 11) Even 4 years after FOLFOX, 3.5% of patients still have grade 2/3 neurotoxicity (+12% grade 1)  FOLFOX is standard adjuvant therapy for stage III and can be considered for high-risk stage II CC DFS benefit for FOLFOX is maintained over 5 years Significant OS benefit for stage III, but NOT for unselected stage II patients “High-risk” stage II with trend toward better DFS with FOLFOX, but clinical consequence unclear No increased rate of secondary cancers, but more deaths of cancer in FOLFOX group (21 vs. 11) Even 4 years after FOLFOX, 3.5% of patients still have grade 2/3 neurotoxicity (+12% grade 1)  FOLFOX is standard adjuvant therapy for stage III and can be considered for high-risk stage II CC

FU Rest LV500 FU500 Rest LV500 OHP 852hr 500 Week R NSABP C-07 x3 N = 2,407 Endpoint 3yr DFS Accrual 02/ /02 RP FLOX Kuebler JP, et al. J Clin Oncol 2007;25:2198–2204.

Ev # 3yr DFS FLOX % FULV % P < HR: 0.79 [0.67 – 0.93] 21 % risk reduction C-07: DFS Kuebler JP, et al. J Clin Oncol 2007;25:2198–2204.

3y DFS Δ HR C % 4.9 % 0.79 MOSAIC 77.9 % 5.1 % 0.77 C-07 and MOSAIC - Oxaliplatin benefit De Gramont A, et al. ASCO Abstract #4007. Kuebler JP, et al. J Clin Oncol 2007;25:2198–2204.

Cross-Study Comparison Toxicity: MOSAIC / C-07 FOLFOX 4 (MOSAIC) FLOX (C-07) Gr 3-4 Neutropenia 41% (2% neut. fever) 4% (?) Gr 3-4 Diarrhea 11%38% Gr 3 Neuro (cum oxali) 12.4% (1,020 mg/m 2 ) 8% (765 mg/m 2 ) All Cause Mortality0.5%1% De Gramont A, et al. ASCO Abstract #4007. Kuebler JP, et al. J Clin Oncol 2007;25:2198–2204.

Abstract 347 Ramanathan RK, André T, Rothenberg ML, de Gramont A, Tournigand C, Goldberg RM, Gupta S Diabetes Mellitus and the Incidence and Time to Onset of Oxaliplatin-Induced Peripheral Sensory Neuropathy (PSN) in Patients with Colorectal Cancer: A Pooled Analysis of Three Randomized Studies

Pooled Analysis Data from 3 randomized clinical trials including FOLFOX4 EFC3313 (MOSAIC): 5-FU and LV (LV5–FU2) + oxaliplatin as adjuvant therapy in CRC EFC4584: Three-arm study of LV5–FU2, LV5–FU2 with oxaliplatin, or oxaliplatin alone as second-line therapy of metastatic CRC EFC2962: Phase II/III study of LV5FU2 + oxaliplatin first-line PSN data from the overall study population with or without diabetes were analyzed for: Incidence and time to onset of PSN Trends indicating clinically relevant differences in the incidence and severity of PSN Data from 3 randomized clinical trials including FOLFOX4 EFC3313 (MOSAIC): 5-FU and LV (LV5–FU2) + oxaliplatin as adjuvant therapy in CRC EFC4584: Three-arm study of LV5–FU2, LV5–FU2 with oxaliplatin, or oxaliplatin alone as second-line therapy of metastatic CRC EFC2962: Phase II/III study of LV5FU2 + oxaliplatin first-line PSN data from the overall study population with or without diabetes were analyzed for: Incidence and time to onset of PSN Trends indicating clinically relevant differences in the incidence and severity of PSN Ramanathan 2008 ASCO GI abstract # 347

Incidence and Severity of PSN PSN All Patients (N = 1,585) DM Patients (N = 135) Grade Grade Grade Ramanathan 2008 ASCO GI abstract # 347

Probability of PSN by Cumulative Dose EFC3313: any grade EFC3313: grade ≥ 3 EFC4584: any grade EFC4584: grade ≥ 3 Ramanathan 2008 ASCO GI abstract # 347

Conclusions FOLFOX in Diabetics In CRC trials with FOLFOX4 no difference in: - the probability of developing PSN nor - the severity of grade between all treated patients and the subset with diabetes mellitus was observed This data suggests patients with diabetes mellitus have no increased risk of developing cumulative neurotoxicity In CRC trials with FOLFOX4 no difference in: - the probability of developing PSN nor - the severity of grade between all treated patients and the subset with diabetes mellitus was observed This data suggests patients with diabetes mellitus have no increased risk of developing cumulative neurotoxicity Ramanathan 2008 ASCO GI abstract # 347

CALGB 89803: DFS and OS Not Improved with IFL in Stage III Colon Cancer Saltz L, et al. J Clin Oncol 2007;25:3456–61 OS = overall survival; IFL = irinotecan, 5-FU plus leucovorin Proportion disease-free Proportion surviving Years NEvents FU/LV IFL P (stratified) = 0.85 (1-sided) NEvents FU/LV IFL P (stratified) = 0.74 (1-sided) FU/LV IFL FU/LV IFL

ACCORD-02 Irinotecan in High-risk Stage III Colon Cancer 400 patients with resected high risk stage III colon cancer (N2 or N1 with occlusion/perforation) Accrual completed in Spring 2002 Stratified: - Center - N stage - Delay to chemotherapy - Age 400 patients with resected high risk stage III colon cancer (N2 or N1 with occlusion/perforation) Accrual completed in Spring 2002 Stratified: - Center - N stage - Delay to chemotherapy - Age RANDOMIZE RANDOMIZE LV5FU2 FOLFIRI: LV5FU2 CPT mg/m 2 on day 1 12 cycles planned Ychou M, et al. J Clin Oncol 2005;(Suppl. 16):246s (Abstract 3502)

ACCORD-02: DFS Not Improved with FOLFIRI in High-risk Colon Cancer Ychou M, et al. J Clin Oncol 2005;(Suppl. 16):246s (Abstract 3502) Years Estimated probability HR = 1.19 (95% CI: 0.90–1.59) P = 0.22 LV5FU2 60 FOLFIRI 51 3-year DFS (%)

Stratification: Stage II vs. III Center RANDOMIZATIONRANDOMIZATION Day 1Day 2 FA 200 mg/m 2 5-FU bolus 400 mg/m 2 5-FU CI 600 mg/m 2 Day 1Day 2 Irinotecan 180 mg/m 2 LV5FU2 as above F IF Repeat q 2 weeks for 12 Cycles PETACC-3: Study Design 210 pts treated with AIO regimen ± irinotecan within given centers will be presented later. Van Cutsem E, et al. J Clin Oncol 2005; 23:(Suppl. 16):3s (Abstract LBA8)

PETACC-3: Results Stage III HR (95% CI) P-value DFS ( ) RFS ( ) Van Cutsem E, et al. J Clin Oncol 2005; 23:(Suppl. 16):3s (Abstract LBA8)

PETACC-3: DFS not significantly improved with FOLFIRI in stage III Van Cutsem E, et al. J Clin Oncol 2005; 23:(Suppl. 16):3s (Abstract LBA8) Estimated probability Months FOLFIRI 1, FU/LV 1, HR=0.89 (95% CI: 0.77–1.11) P = year DFS (%) DFS = disease free survival HR = hazard ratio; CI = confidence interval N

X-ACT Trial - Design Endpoints - DFS - RFS - overall survival (OS) - tolerability (NCIC CTG) - pharmacoeconomics - quality of life (QoL) Chemo-naïve stage III colon cancer, resection  8 weeks Capecitabine 1 250mg/m 2 twice daily, d1–14, q21d N = 1,004 Bolus 5-FU / LV 5-FU 425mg/m 2 plus LV 20mg/m 2, d1–5, q28d N = 983 Recruitment 1998– weeks Twelves et al., N Engl J Med 2005

X-ACT: 5-year DFS (median follow-up 6.8 years) 5-year DFS (%) Capecitabine 1, FU/LV Months HR = 0.88 (95% CI: 0.77–1.01) NI margin ITT population Estimated probability ITT (intent-to-treat) population; NI = non-inferiority Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB) 102 N Test of non-inferiority P < Test of superiority P =

X-ACT: 5-year OS (median follow-up 6.8 years) HR = 0.86 (95% CI: 0.74–1.01) NI margin 1.14 ITT population Months Estimated probability Test of non-inferiority P = Test of superiority P = year OS (%) Capecitabine 1, FU/LV N Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)

Neutropenia Nausea/ vomiting Stomatitis Diarrhea Febrile neutropenia HFS Patients (%) Scheithauer W, et al. Ann Oncol 2003;14:1735–43 * * * * *P < HFS = hand foot syndrome Capecitabine (N = 993) 5-FU/LV(N = 974) Grade 3/4 adverse events X-ACT: Improved Safety with Capecitabine

Chemo/ radiotherapy-naïve stage III colon cancer Bolus 5-FU/LV Mayo Clinic or Roswell Park CAPOX Capecitabine 1,000mg/m 2 b.i.d. days 1–15 Oxaliplatin 130mg/m 2 day 1 q3w Schmoll HJ, et al. J Clin Oncol 2007;25:4217–23 XELOXA: Phase III Trial of CAPOX in the Adjuvant Setting Primary endpoint: disease-free survival N = 944 N = 942 RANDOMISATIONRANDOMISATION Duration of therapy: 24 weeks

Grade 3/4 Adverse Events Patients (%) CAPOX 1 (N = 938) FOLFOX4 2 (N = 1,108) FLOX 3 (N = 1,200) Cross-trial comparison *Not reported Neutropenia Nausea Stomatitis Diarrhea Febrile neutropenia HFS Vomiting Neurosensory 1 Schmiegel WH, et al. J Clin Oncol 2007;25(Suppl. 18):172s (Abstract 4034) 2 André T, et al. N Engl J Med 2004;350:2343–51 3 Wolmark N, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):246s (Abstract LBA 3500) * Adjuvant CAPOX: Toxicity Compared with FOLFOX and FLOX **

Ongoing US Cooperative Group Trials Adjuvant Therapy of Colon Cancer Stage III colon cancer (N = 2,300) Stage II/III colon cancer (N = 2,400) mFOLFOX6 6m mFOLFOX6 6m + Bevacizumab 12m Intergroup N0147 NSABP C-08 mFOLFOX6 6m mFOLFOX6 6m + Cetuximab 6m Accrual completed

Should Patients with Stage II Colon Cancer Receive Adjuvant Therapy? Direct evidence of randomized trials Meta-analyses Identification of “high-risk” patients Direct evidence of randomized trials Meta-analyses Identification of “high-risk” patients

Approximate Number of Patients Needed to Detect a Realistic Treatment Benefit* Dukes’ B Dukes’ C No. of No. of Survival ARR Patients Survival ARR Patients At 3-years 85% 2.5% 8,000 65% 5.2% 3,400 At 4-years 80% 3.3% 5,800 58% 6.0% 2,800 At 5-years 75% 4.0% 4,700 50% 6.6% 2,400 Abbreviation: ARR = absolute risk reduction For 90% power of detecting the treatment benefit using two-tailed significance tests at the 5% level, assuming the true relative risk reduction is 18% for both Dukes’ B and Dukes’ C. Buyse, Piedbois, 2001

QUASAR: Study Design Clear indication for chemotherapy (N = 4,320) 2 x 2 randomization to 5-FU with low- or high-dose LV and Lev or placebo Chemotherapy (N = 1,622)* Observation (N = 1,617) No clear indication for chemotherapy (mainly stage II) (N = 3,239) RANDOMIZERANDOMIZE Colon or rectal cancer Stage I-III Complete resection with no evidence of residual disease * Prior to 10/1997 chemotherapy patients were randomized as in clear indication arm; after 10/1997 patients received 5-FU/low-dose LV. QUASAR Group, Lancet 2007

% of Patients QUASAR: Overall Survival in Patients with “no clear indication for chemo” P =.02 5-year OS, Observation = 77.4% vs Chemotherapy = 80.3% Relative risk = 0.83 (95% CI, ) Years QUSAR group, Lancet Observation (N = 1,622) Chemotherapy (N = 1,617) 5-yr OS difference: 2.9%

ASCO Guidelines 2004 Direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer. Patients and oncologists who accept the relative benefit in stage III disease as adequate indirect evidence of benefit for stage II disease are justified in considering the use of adjuvant chemotherapy, particularly for those patients with high-risk stage II disease. The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences. Patients with stage II disease should be encouraged to participate in randomized trials. Direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer. Patients and oncologists who accept the relative benefit in stage III disease as adequate indirect evidence of benefit for stage II disease are justified in considering the use of adjuvant chemotherapy, particularly for those patients with high-risk stage II disease. The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences. Patients with stage II disease should be encouraged to participate in randomized trials. Benson et al. J Clin Oncol. 2004

“High-risk” Stage II Colon Cancer Clinico-pathological parameters T4 tumors Obstruction/perforation Lymphatic or vascular invasion Undifferentiated histology Less than 10 (12) Ln examined Molecular parameters LOH 18q MSS Other? Clinico-pathological parameters T4 tumors Obstruction/perforation Lymphatic or vascular invasion Undifferentiated histology Less than 10 (12) Ln examined Molecular parameters LOH 18q MSS Other?

Analysis of Molecular Markers in Patients with Stage III Colon Cancer Watanbe T, et al. N Engl J Med 344(16); , 2001

Colon Stage II – Adjuvant E5202: High Risk Stage II R e g is t e r Tumor block assessment for 18q/MSI High Risk MSS + 18q LOH MSI-L + 18q LOH Low Risk MSS, no 18q LOH MSI-L, no 18q LOH MSI-H +/- 18q LOH Observation mFOLFOX6 + bevacizumab R Expect 2 weeks for tissue review N = 3,610

What is the Standard Adjuvant Therapy in Colon Cancer ? FOLFOX is the standard adjuvant therapy in stage III and high-risk stage II colon cancer Capecitabine (UFT,S1?) for patients who are not considered candidates for oxaliplatin Irinotecan-based combinations are NOT options in the adjuvant setting XELOX data eagerly awaited Bevacizumab and Cetuximab are under investigation FOLFOX is the standard adjuvant therapy in stage III and high-risk stage II colon cancer Capecitabine (UFT,S1?) for patients who are not considered candidates for oxaliplatin Irinotecan-based combinations are NOT options in the adjuvant setting XELOX data eagerly awaited Bevacizumab and Cetuximab are under investigation