How to treat a patient with stage III Colon Cancer in 2013 Aimery de Gramont Barcelona July 6, 2013

Colo-rectal Cancer World Incidence: 1 234 000 (rank 3) World Deaths: 608 000 (rank 4) Globocan 2007 Colon/Colorectum: 75% Colon Cancer Stages AJCC 2010

State of the Art Standard Adjuvant Therapy Stage III Biomarkers Adjuvant Therapy - Elderly Decision Algorithm Ongoing Trials

State of the Art Standard Adjuvant Therapy Stage III Adjuvant Therapy Elderly Biomarkers Decision Algorithm Ongoing Trials

There is an adjuvant therapy for colon cancer! The first step (1990)

Oxaliplatin plus 5FU is better than 5FU alone! The second step (2004) MOSAIC NSABP C07 Kuebler JCO 2007 XELOXA NO16968 Haller JCO 2011

Oxaliplatin Trials - Efficacy Stage III MOSAIC C07 XELOXA Δ DFS 7.5% 7.8% 6.3% HR DFS 0.78 0.80 Δ OS 4.2% 3.4% HR OS 0.85 0.87 N1 DFS HR 0.84 0.73 N2 DFS HR 0.70

MOSAIC – 4+ Lymph Nodes 12.7% 11.8% 13.5% Disease-free Survival FOLFOX 12 24 36 48 60 72 84 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 LV5FU2 FOLFOX months Disease-free Survival 8

Oxaliplatin Trials - Safety Grade 3/4 FOLFOX4 N=1123 FLOX N=1247 XELOX N=944 mFOLFOX6 N=1321 Neutropenia 40% NR 9% 33% Febrile N. <2% >2% <1% Platelets 2% 5% 3% Diarrhea 11% 38% 19% 10% Nausea 16% Hand-Foot S. Neuropathy 12% 8% 14% 60D Mortality 3 (0.3%) 15 (1.2%) 9 (1.0%)

The disillusion of targeted therapies in adjuvant colon cancer therapy Bevacizumab NSABP C08 Allegra JCO 2010 AVANT Lancet Oncol 2012 Cetuximab N0 147 Alberts JAMA 2012 PETACC8 Taieb WGIC 2012

State of the Art Standard Adjuvant Therapy Stage III Biomarkers Adjuvant Therapy Elderly Decision Algorithm Ongoing Trials

Different biology between stage II and III. The need of Biomarkers Different biology between stage II and III. Markers Stage II Stage III HR§ p value* T Stage (T4 vs T3) 2.8 0.0001 1.6 0.0006 N Stage (N2 vs N1) N/A 2.2 <0.0001 Histologic Grade (3-4 vs 1-2) 0.6 0.55 1.4 0.07 Age (>60 vs ≤60) 1.8 0.026 1.1 0.3 MSI (High vs Stable) 0.027 0.7 0.12 p53 (High) 0.27 1.3 0.015 SMAD4 (any loss) 1.0 0.9 0.0002 Treatment, Sex, Site, KRAS, BRAF,TS, 18qLOH (Stage II: HR 1.4, p=0.33), hTERT: not significant * p values from the Wald test in a multiivariate Cox regression § HR = hazard ratio Roth A et al. ASCO 2009

DFS in dMMR patients, pooled data Stage II (N=102) Stage III (N=63) 5 yr DFS 5 yr DFS Untreated 87% Treated 72% HR: 2.80 (0.98-8.97) p=0.05 Untreated 62% Treated 67% HR: 1.08 (0.44-2.68) p=0.86 Sargent, JCO 2009

DFS in Stage III dMMR patients Fluoropyrimidine Stage III (N=63) FOLFOX4 Stage III (N=47) 5 yr DFS Untreated 62% Treated 67% HR: 1.08 (0.44-2.68) p=0.86 Sargent, JCO 2009 Fléjou, ASCO 2013

State of the Art Standard Adjuvant Therapy Stage III Biomarkers Adjuvant Therapy Elderly Decision Algorithm Ongoing Trials

Elderly - ACCENT Hazard ratio (95% CI) DFS OS ACCENT analysis4† <70 years, n=3877 0.77 (0.68,0.86) 0.81 (0.71,0.93) ≥70 years, n=703 1.04 (0.80,1.35) 1.19 (0.90,1.57) Values <1 favor oxaliplatin-based therapy vs. 5-FU/LV. McCleary et al. ASCO 2009 (poster 4010) 16

> 70 Years MOSAIC C0-7 OS OS DFS Interaction P=0.0391 Years LV5FU FLOX OS OS DFS Interaction P=0.0391 2 4 6 8 Years

Elderly XELOXA Hazard ratio (95% CIs)* DFS OS NO16968 <70 years, n=1477 0.79 (0.66,0.94) 0.86 (0.69,1.08) ≥70 years, n=409 0.87 (0.63,1.18) 0.94 (0.66,1.34) Haller ASCO GI 2011 18

DFS RFS MOSAIC OS S post R JCO 2012

Role of Gender in Elderly Patients DFS

Stage IIIC (4+LN) in Elderly Patients OS 18% DFS 17%

State of the Art Standard Adjuvant Therapy Stage III Biomarkers Adjuvant Therapy Elderly Decision Algorithm Ongoing Trials

When cure rate without oxaliplatin is 50% Most patients want to be treated if they can have an absolute survival benfit of more then 3% When cure rate without oxaliplatin is 50% % When cure rate without oxaliplatin is 80% % Benefit of oxaliplatin Benefit of oxaliplatin Love, ASCO 2007

AJCC7 (2010). Summary of changes T4a (Tumor penetrates the surface of the visceral peritoneum) T4b (Tumor directly invades or is histologically adherent to other organs or structures) N1c T1-2 N0 with tumor deposit(s)(TD) N1a (metastasis in 1 regional node) N1b (metastasis in 2–3 nodes) N2a (metastasis in 4–6 nodes) N2b (metastasis in 7 or more nodes) Stage II is subdivided into IIA (T3N0), IIB (T4aN0), IIC (T4bN0) Stage III: T4bN1 has been reclassified from IIIB to IIIC T1N2a has been reclassified as IIIA T1N2b,T2N2a-b and T3N2a have all been reclassified as IIIB M1 has been subdivided into M1a for single metastatic site vs. M1b for multiple metastatic sites

DFS Stage III (AJCC not applicable) * * * previous AJCC

DFS AJCC Stage IIIA N=56 N=46

DFS AJCC Stage IIIB

DFS AJCC Stage IIIC

Will Rogers’effect Recent trials vs. MOSAIC in Stage III 2004 XELOXA 2011 NCCTG N0147 2012 AVANT Regimen LV5FU2 FOLFOX4 XELOX mFOLFOX6 3yr OS 81.3% 84.3% 86%* 87.9% 90%* * from curves FOLFOX4 MOSAIC vs. FOLFOX4 AVANT 3-yr DFS 5-yr OS 3-yr DFS <4LN 3-yr DFS ≥4LN MOSAIC 73% 76% 71,8% 56,2% AVANT 77% 85%* 85% 66% * preliminary results MOSAIC data Haller, et al. JCO 2011 Alberts, et al. JAMA 2012 Lancet Oncol 2012

Decision Algorithm in Stage III Adjuvant Therapy Risk <15% Potential Benefit<3% Stage IIIA 5FU/cap RS Risk 15-25% Potential Benefit>3% FOLFOX XELOX Stage IIIB* Stage IIIB T3N2a-b* Stage IIIC Elderly (M75, F80) Risk >25% Potential Benefit>5% FOLFOX XELOX Prexisting neuropathy Frail patients Elderly (M75, F80) Stage IIIA-B 5FU/cap

State of the Art Standard Adjuvant Therapy Stage III Biomarkers Adjuvant Therapy Elderly Decision Algorithm Ongoing Trials

Incidence of Neurosensory Symptoms during Treatment and Follow-up after FOLFOX Evaluable patients n=811 at 4 years Grade 0 84.3% Grade 1 12.0% Grade 2 2.8% Grade 3 0.7% Andre et al J Clin Oncol. 2009 Jul 1;27(19):3109-16.

Relapse-free Survival by Adjuvant Treatment Arms 6 Months of bolus 5FU/LV vs. 3 months of Continuous Infusion 5FU Relapse-free survival by treatment arms in all patients. 5-FU, 5-fluorouracil; PVI, protracted venous infusion; LV, leucovorin. Chau I et al. Ann Onco 2005

R IDEA – Meta-Analysis TOSCA SCOT GERCOR CALGB HORG JAPAN mFOLFOX6/XELOX TOSCA N= 3249 R 12/8 cycles mFOLFOX6/XELOX SCOT stage II-III 6/4 cycles N= 3656 Non inferiority trial (HR<1.1 – N 10500) 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). N= 9101 (Nov 2012) GERCOR CALGB HORG JAPAN N= 1136 N= 590 N= 470 Started 35

Ongoing Trials (June 2013) CALGB 80702: Phase III Trial of 6 vs. 12 Treatments of Adjuvant Folfox Plus Celecoxib or Placebo for Patients with Resected Stage III Colon Cancer N=2500 ASCOLT: Aspirin vs Placebo Stage II-III Colon & Rectum N=2660 Asia CHALLENGE: Colon Health + Life-Long Exercise Change trial NSABP: Rosuvastatin vs Placebo Stage I-II polyps and recurrence N=1740 Japan: UFT +/- PSK stage IIIAB n=300 UK: CAPOX vs no therapy locally advanced rectal cancer N=800 France: follow-up vs laparotomy+HIPEC High-risk peritoneal N=130

5 year Recurrence Risk based on Recurrence Score Category New Biomarkers Detection of guanylyl cyclase C mRNA in lymph nodes of resected stage II colorectal cancer is highly correlated with the risk of tumor recurrence Hyslop CCR 2011 Molecular signatures: Oncotype Dx Colon 12 5 year Recurrence Risk based on Recurrence Score Category Low Intermediate High Stage IIIA/B 21% 29% 38% Stage IIIC 40% 51% 64% NSABP C07 – O’Connell et al ASCO 2012 Abstract 3512

Molecular Classification of Colon Cancer Stage II-III Salazar, et al. ASCO 2013

What is the signal to launch an adjuvant trial? Drug Preclinical model Metastatic trial Adjuvant study Results Levamisole No Yes Positive LV5FU Phase III Irinotecan Negative Oxaliplatin Phase III (PFS) Interferon α Phase II Edrecolomab Cetuximab Bevacizumab

R COLADJ 2012 Antiangiogenic Agent X mFOLFOX6 6-12 cycles Control ASCO 2018 40

Conclusions: Decision Algorithm Prexisting neuropathy Frail patients Elderly (M75, F80) Stage IIIA-B Stage IIIA Stage IIIB* Stage IIIB T3N2a-b* Stage IIIC Elderly (M75, F80) Risk <15% Potential Benefit<3% Risk 15-25% Benefit>3% Risk >25% Benefit>5% 5FU/cap FOLFOX XELOX RS