Disclosures. Clinical and molecular features to guide adjuvant therapy. Personalized Medicine - Decision Tools -

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1 Disclosures Clinical and molecular features to guide adjuvant therapy Daniel Sargent Professor of Biostatistics & Oncology Mayo Clinic Consulting activities Amgen Pfizer Roche/Genentech Sanofi-Aventis Genomic Health Diagnocure 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 lowdose LV equivalent Monthly and weekly treatment equivalent Moertel et al. Ann Intern Med. 1995;122:321. Francini et al. Gastroenterol. 1994;16:899. Wolmark et al. Proc Am Soc Clin Oncol. 1996;15:25. 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. 22. Abstract 529. LV5FU2 and monthly bolus equivalent Personalized Medicine - Decision Tools - Old: Clinical parameters Patient-based Age, PS, co-morbidities, financial implications Tumor-based Stage, differentiation, number and sites of metastases ew: Molecular Biomarkers Patient-based (Pharmacogenomics) Tumor-based Colon Cancer in the Elderly Are the benefits of therapy for patients with colon cancer dependent on patient age? Do elderly patients experience greater toxicity than their younger counterparts? Sargent et al, EJM, 21 Pooled Analysis: 7 trials with surgery-alone control Study Rx regimen CCTG 5-FU/Lev 271 ECOG 5-FU/LV 415 SWOG 5-FU/Lev 936 CIC 5-FU/LV 364 FFCD 5-FU/LV 259 Siena 5-FU/LV 239 GIVIO 5-FU/LV 867 Total

2 Age<=7 Rx o Rx Years from Randomization Time to Recurrence Age>7 Rx o Rx Years from Randomization ade>=3 Rate Gra P=.15 5-FU + Leucovorin Grade>=3 Toxicity by Age Group Age<=7 Age>7 P=.99 p=.21 p=.5 ausea/vomit Diarrhea Stomatitis Leukopenia Treatment of Colorectal Cancer in Elderly Patients: ACCET Database What about newer therapies, in particular FOLFOX? Patients from the ACCET database 1,499 pts <7 years, 2,17 pts 7 years 6 phase III trials compared IV FU to combinations with irinotecan, oxaliplatin, or oral FU (capecitabine and UFT/LV) in stage II/III colon cancer Endpoints OS, DFS, TTR Elderly Patients: Efficacy of FOLFOX Pooled Analysis C-7/MOSAIC Age Endpoint* HR (95% CI) Experimental vs Control IV 5-FU/LV DFS OS TTP Deaths within 6 mos Exp vs Ctrl % (p-value) < v.81 n = 3,977 (.68,.86) (.71,.93) (.67,.86) (p=1.) 7 n = 73 Interaction of age by treatment p-value 1.4 (.8,1.35) 1.19 (.9,1.57).92 (.69,1.23) v 1.37 (p=.25) McCleary. ASCO 29. Abstract 41. * Values < 1 favor experimental arm McCleary, ASCO 29, Abstract Update of MOSAIC Trial XELOXA: phase III trial of CAPOX in the adjuvant setting o benefit in DFS with FOLFOX vs 5-FU/LV for patients > 65 yrs! Chemo/ radiotherapy-naïve stage III colon cancer R A D O M I S A T I O n=944 n=942 CAPOX Capecitabine 1,mg/m 2 b.i.d. days 1 15 Oxaliplatin 13mg/m 2 day 1 q3w duration of therapy: 24 weeks Bolus 5-FU/LV Mayo Clinic or Roswell Park Primary endpoint: disease-free survival Andre JCO 29 Schmoll HJ, et al. J Clin Oncol 27;25:

3 Conclusions: Age Younger and older patients receive same benefit from 5-FU based adjuvant therapy vs surgery alone Older patients receive short-term DFS benefit from FOLFOX that disappear with longer follow-up due to deaths from competing causes Elderly patients do not experience significantly increased toxicity 5-FU/LV an acceptable option in elderly What about Stage II Colon Cancers? 5-Year Relative Survival By AJCC Stage QUASAR: OS in patients with no clear indication for chemo (mostly stage II) 5-FU/LV vs surgery alone Patients (%) Percentage of p < Stage I Stage Stage Stage Stage Stage Stage IV IIA IIB IIIA IIIB IIIC (T 1 2 ) (T3) (T4) (T1 21) (T3 41) (Tany2) (M1) ents % of Pati yr OS difference: 2.9% Observation (n=1622) Chemotherapy (n=1617) 2 P =.2 5-year OS, Observation = 77.4% vs Chemotherapy = 8.3% Relative risk =.83 (95% CI, ) Years O Connell et al., 24. QUASAR group, Lancet 27 High-risk Stage II Colon Cancer Clinico-pathological parameters (MOSAIC) T4 tumors Obstruction/perforation Lymphatic or vascular invasion Undifferentiated histology Less than 1 (12) Ln examined Molecular parameters LOH 18q MSS Other? MOSAIC: Disease-free Survival - Final Update 5-year DFS % Data cut-off: June 26 FOLFOX4 LV5FU2 HR [95% CI] p-value ITT [.68.93].3 Stage III Δ7.5 [.65.93] Stage II High-risk stage II n=576 Low-risk stage II n=323 [ ] Δ7.2 [ ] [ ]

4 MOSAIC: OS: Stage II and Stage III Defective MMR - Colon cancer 1. p= p=.29.1% % Stage II Stage III HR [95% CI] 1. [ ].8 [.66.98] FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III Data cut-off: January 27 Overall survival (months) Andre JCO 29 lity Probabil Characterized by presence of MSI & loss of MLH1, MSH2, MSH6 or PMS2 expression ~15% of Sporadic CC, >9% loss of MLH1 Clinical Correlations: Right sided, Female, Early stage, Better prognosis Tumors: Poorly differentiated, Signet-ringcell, Lymphocytic infiltration, near diploid dmmr cells resistant to 5-FU 1,2 1 Carethers, 1999; 2 Arnold 23 Pooled data for MSI Analysis DFS/OS in Stage II dmmr Patients (=12) Trial Treatment % Stage II % dmmr FU/LEV 117 3% 14% 5-yr DFS = 47 = 55 5-yr OS IT 35 5FU/LEV 215 5% 18% FU/LV 66 19% 12% GIVIO 5FU/LV % 16% FFCD 5FU/LV % 19% CIC 5FU/LV % 15% Untreated 87% Treated 72% HR: 2.8 ( ) p=.5 Untreated 93% Treated 75% HR: 3.15 ( ) p=.3 Total % 16% Sargent ASCO 28 Sargent ASCO 28 PETACC 3: Multivariate Analysis Stage II Markers HR [95% CI] P value T4 v. T [ ].24 MSI-H v. MSS.28 [ ].89 18qLOH 1.37 [ ].38 18q Loss of Heterozygosity Associated with chromosomal instability, inversely associated with MSI. Long arm of chromosome 18 contains several genes including: DCC, SMAD-4, SMAD-2, CABLES1. Roth AD, et al. ASCO 29. 4

5 18q LOH in Stage III Colon Cancer (= 279) 18qLOH in PETACC3 18q LOH was not associated with outcome in stage III patients Stage II patients: T4 v. T [ ].24 Watanabe et al. Engl J Med. 21;344: q LOH not associated with survival in stage II patients MSI-H v. MSS 18qLOH.28 [ ] 1.37 [ ] Large Studies Assessing 18qLOH in CRC (>25) Author (Year) o. of Finding Patients Watanabe, HR=2.75 (P=.6) Halling, ull Barratt, ull Roth, ull Ogino, ull ECOG 522: Stage II Colon Cancer R A D O M I Z E High-risk: MSS and 18q LOH Low-risk: MSI or o 18q LOH FOLFOX + Bevacizumab FOLFOX + Placebo observe Genomic Health: Development and Validation of an 18-Gene RT-PCR Colon Cancer Assay Colon Cancer Technical Feasibility QUASAR Results: Recurrence Risk in Pre-specified Recurrence Risk Groups (n=711) genes 375 genes 18 genes ASCO 29 Development Studies Surgery Alone SABP C-1/C-2 (n=27) CCF (n = 765) Development Studies Surgery + 5FU/LV SABP C-4 (n=38) SABP C-6 (n=58) Selection of Final Gene List & Algorithm Validation of Analytical Methods Clinical Validation Study Stage II Colon Cancer QUASAR (n>12) Test prognostic, but not predictive! Recurrence Risk Group Range of RS Proportion of patients Low <3 43.7% Intermediate % High % Comparison of High vs. Low Recurrence Risk Groups using Cox Model: HR = 1.47 (p=.46) ent Free Proportion Eve Kaplan-Meier Estimates (95% CI) of Recurrence Risk at 3 years Recurrence Risk Group.2 Low 12% ( 9% -16%) Intermediate 18% (13%-24%) Hig 22% (16%-29%). h Years 5

6 QUASAR RESULTS: Recurrence Score, T Stage, and MMR Deficiency are Key Independent Predictors of Recurrence in Stage II Colon Cancer QUASAR Results: Recurrence Score, T Stage, and MMR Deficiency are Key Independent Predictors of Recurrence in Stage II Colon Cancer Risk of recurren nce at 3 years 45% 4% 35% 3% 25% 2% 15% 1% 5% T4 stage (13%) T3 and MMR proficient (76%) T3 and MMR deficient (11%) Multivariate Analysis % Recurrence Score Decision Algorithm in Adjuvant Therapy Resected Colon Ca Does it have to be genetics? Molecular odal examination: GCC Stage II Stage III Low-Risk o therapy! yes T4 and/or <12 Ls no dmmr no Intermed. Risk yes High-Risk * FOLFOX 5-FU/LV or Capecitabine Oncotype? Colon? *pts not considered candidates for oxaliplatin * Waldman, S. A. et al. JAMA 29;31: What about KRAS in adjuvant (wild-type) ot yet Predictive markers for Adjuvant Therapy PETACC 8 Stage III colon cancer (=24) Intergroup 147 Stage III colon cancer (=36) FOLFOX4 6m FOLFOX4 6m + Cetuximab 6m mfolfox6 6m mfolfox6 6m + Cetuximab 6m Fit elderly patients benefit from 5-FU/LV o evidence of further benefit from adding Oxali but confirmatory data await MSI a validated predictive marker in stage II disease MSI-H/dMMR stage II patients should not be treated Additional markers in active development 6