Impact of older age on the efficacy of newer adjuvant therapies in >12,500 patients with stage II / III colon cancer: Findings from the ACCENT Database N. Jackson McCleary, J.A. Meyerhardt, E. Green, G. Yothers, A. de Gramont, E. Van Cutsem, M. O’Connell, C.J. Twelves, L.B. Saltz, D.J. Sargent for the ACCENT collaborative group

Treatment of Colorectal Cancer in Elderly Patients Metastatic setting Folprecht JCO 2008 - N=2,692 (22%  70 yrs) 4 trials of irinotecan-based therapy Improved PFS, trend to improved OS for elderly w/addition of irinotecan Goldberg JCO 2006 - N=3,742 (16%  70 yrs) 4 trials of oxaliplatin-based therapy Similar survival benefit and toxicity in age subgroups **Pooled analyses in metastatic setting showed improved or similar survival benefit for older pts receiving combination vs IV FU/LV **Suggests older patients derive benefit from adjuvant therapy after surgery **Formed basis of ACCENT data group

Treatment of Colorectal Cancer in Elderly Patients Adjuvant setting Sargent NEJM 2001 – N=3351 (15%  70 yrs) 7 trials of 5-FU + levamisole/leucovorin v surgery No significant interaction observed between age and efficacy of treatment **Pooled analyses in metastatic setting showed improved or similar survival benefit for older pts receiving combination vs IV FU/LV **Suggests older patients derive benefit from adjuvant therapy after surgery **Formed basis of ACCENT data group

The Adjuvant Colon Cancer End Points (ACCENT) Group Established in 2003 A collection of individual patient data from trials in the US, Canada, Australia and Europe Original objective - to validate DFS as a surrogate endpoint in adjuvant colon cancer trials O'Connell MJ, et al. JCO 2008; Sargent DJ, et al. JCO 2007; Sargent DJ, et al. JCO 2005

ACCENT update: 6 trials added Accrual Period # pts % pts ≥70 yrs Experimental treatment arm† % stage III‡ MOSAIC 1998-01 2246 14 FOLFOX4 60 NSABP C-07 2000-02 2434 16 FLOX 71 CALGB 89803 1999-01 1263 24 IFL 98 PETACC-3 3186 13 FOLFIRI NSABP C-06 1997-99 1557 23 Uracil/tegafur 53 X-ACT 1983 20 Capecitabine 100 † Compared to control arm of intravenous 5-flourouracil (IV 5-FU) and leucovorin (LV) ‡ Remaining patients were stage II or unknown Recently added data from 6 newer studies evaluating the survival benefit of either intravenous (IV) FU combination chemotherapy or oral FU chemotherapy compared to standard IV FU/LV monotherapy in stage II and III CRC Abbreviations: MOSAIC, Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer; XACT, Xeloda in Adjuvant Colon Cancer Therapy; NSABP, National Surgical Adjuvant Breast and Bowel Project; CALGB, Cancer and Leukemia Group B; PETACC, Pan-European Trials in Adjuvant Colon Cancer; FOLFOX, infusional 5-FU/LV + oxaliplatin; FLOX, bolus IV 5-fluorouracil (FU)/ leucovorin (LV) + oxaliplatin; IFL, bolus IV 5-FU/LV + irinotecan; FOLFIRI, infusional 5-FU/LV + irinotecan † Compared to control arm of intravenous 5-flourouracil (IV 5-FU) and leucovorin (LV) ‡ Remaining patients were stage II or unknown

Pooled data: 6 adjuvant trials 12,669 pts, Accrual from 1997-2002 17% ≥70 years Available data Age Gender Disease stage Treatment arm Survival and recurrence status at last follow-up ACCENT does not collect toxicity data Data on grade 3 or 4 toxicity is not consistently available across all studies -- not included in this analysis.

Objective Determine impact of age (prospectively specified age 70 threshold), on benefit of chemotherapy in the adjuvant setting for colon cancer Disease-free survival (DFS) Time from randomization to the first event of either recurrent disease or death Overall survival (OS) Time from randomization to death from any cause Time-to-recurrence (TTR) Time to colon cancer recurrence, where deaths without recurrence are censored at the time of death **Age 70 cutpoint was prospectively specified.

Statistical considerations Pooled individual patient data from 6 trials Pre-specified age grouping: Age < 70 or > 70 Secondary analysis with STEPP model Hazard ratios calculated using Cox proportional hazards regression model Stratified by original trial Adjust for gender, treatment arm, stage Test age-by-treatment interaction Age cut-off of 70 was selected to be consistent with other studies in the literature evaluating the impact of chemotherapy regimens on older patients with colorectal cancer

Baseline characteristics – pooled data <70 years (%) N=10,499 ≥70 years (%) N=2,170 Gender Female 45 44 Male 55 56 Stage II 26 23 III 74 77 Treatment arm Control 50 52 Experimental 48 Patient enrollment and characteristics In the 6 trials included in these analyses, 10,499 subjects are <70 years and 2,170 ≥70 years. There were no appreciable differences in age, stage of disease or treatment assignment by age, though 3% more patients < 70 years had stage II than III disease compared to those ≥ 70 years (Table 2).

Efficacy – overall population Age Endpoint HR (95% CI) Experimental v Control IV 5 FU/LV Deaths within 6 mo Exp v Control % (p-value) DFS* OS* TTR* <70 n = 10,499 0.85 (0.80,0.91) 0.86 (0.79,0.92) 0.84 (0.79,0.91) 0.89 v 0.79 (p=0.58) ≥ 70 n = 2,170 1.11 (0.97,1.27) 1.14 (0.98,1.32) 1.13 (0.97,1.32) 2.71 v 2.11 (p=0.37) Interaction of age by treatment p-value 0.005 0.004 **VALUES >1 favor control therapy, <1 favors experimental. **Statistically significant (p<0.05) Age*Treatment interaction term indicates that treatment effect differs by age. **Lack of survival benefit among older v younger pts NOT due to early deaths (within first 6 months of treatment). In analyses that combined data from all 6 trials (combination and oral FU regimens versus standard IV 5-FU/LV), older patients did not receive any statistically significant benefit from combination therapy or oral FU in terms of overall survival (HR 1.13, 95% CI 0.96-1.32)), disease-free survival (HR 1.11, 95% CI 0.97-1.28) or time-to-recurrence (HR 1.13, 95% 0.97-1.32). In contrast, patients who were younger than age 70 did experience statistically significant improvements in all three endpoints with the experimental regimens compared to standard IV FU/LV. The test for interaction between age and treatment was statistically significant for all three endpoints (p interaction = 0.010 for OS, 0.011 for DFS, and 0.012 for TTR). The differential effects of therapy by age was not accounted for by the different rates of deaths within 6 months in the older age group randomized to the experimental treatment arm vs. control (2.71 vs. 2.11%; p=0.4). * Values < 1 favor experimental arm

Efficacy – oxaliplatin-based therapy Age Endpoint HR (95% CI) Experimental v Control IV 5-FU/LV Deaths within 6 mo Exp v Control % (p-value) DFS* OS* TTR* <70 n = 3,977 0.77 (0.68,0.86) 0.81 (0.71,0.93) 0.76 (0.67,0.86) 0.81 v 0.81 (p=1.0) ≥ 70 n = 703 1.04 (0.80,1.35) 1.19 (0.90,1.57) 0.92 (0.69,1.23) 2.57 v 1.37 (p=0.25) Interaction of age by treatment p-value 0.016 0.037 0.21 When analyzed by the drug class of the experimental treatment arm, no statistically significant benefits for overall survival, disease-free survival or time-to-recurrence were detected for older subjects receiving oxaliplatin-based, irinotecan-based or oral fluoropyrimidine-based therapy compared to control IV 5-FU/LV (Table 3). In contrast, younger patients experienced statistically significant improvement in all three outcomes with oxaliplatin- and irinotecan-based therapies, while oral FU had point estimates suggestive of a benefit, although the confidence intervals included the null hypothesis. * Values < 1 favor experimental arm

Efficacy – oral fluoropyrimidines Age Endpoint HR (95% CI) Exp v Control IV 5-FU/LV Deaths within 6 mo Exp v Control % (p-value) DFS* OS* TTR* <70 n = 2,785 0.89 (0.79,1.0) 0.87 (0.76,1.0) 0.90 1.0 vs 1.3 (p=0.50) ≥ 70 n = 755 1.13 (0.90,1.42) 1.17 (0.92,1.48) 1.16 (0.90,1.50) 1.7 vs 2.5 (p=0.43) Interaction of age by treatment p-value 0.10 0.06 0.13 When analyzed by the drug class of the experimental treatment arm, no statistically significant benefits for overall survival, disease-free survival or time-to-recurrence were detected for older subjects receiving oxaliplatin-based, irinotecan-based or oral fluoropyrimidine-based therapy compared to control IV 5-FU/LV (Table 3). In contrast, younger patients experienced statistically significant improvement in all three outcomes with oxaliplatin- and irinotecan-based therapies, while oral FU had point estimates suggestive of a benefit, although the confidence intervals included the null hypothesis. * Values < 1 favor experimental arm

Forest Plots of Hazard Ratios Disease-Free Survival To reiterate graphically, these forest plots depict no alteration of treatment effect by age. **These associations are further illustrated by forest plots organized by drug class (Figure 1).

Forest Plots of Hazard Ratios Overall Survival

Forest Plots of Hazard Ratios Time to Recurrence

What if restricted to stage III disease? Stage II disease comprised 25% of overall cohort X-ACT and CALGB 89803 limited to stage III pts Disease-Free survival p interaction = 0.062 p interaction = 0.005 Tested whether the subset of older patients with stage III disease benefited from newer therapies. Eligibility criteria of two of the trials (X-ACT and CALGB 89803) were limited to stage III patients Pts with stage II disease comprised 25% of the overall cohort Removing pts with stage II disease from the analysis -- the point estimates by drug class for DFS for older pts, comparing experimental to control arms, were all greater than 1

What if age modeled differently? Exploratory Analysis Subpopulation Treatment Effect Pattern Plot (STEPP) analysis Method for estimating treatment benefit for a sequence of patient subgroups defined by a characteristic of interest, such as age, without set cut points Can enhance interpretation of for individual patient decision-making. Definition of STEPP: displays the patterns of treatment effects within randomized clinical trials or datasets from meta-analyses to identify features that predict responsiveness to the treatments under study without relying on retrospective subset analysis. Allows validation of cutoff points/thresholds for treatment effects. Gelber. Breast, 2003; Bonetti. Stat Med 2009.

STEPP analysis – Overall population age cutoff validation for observed lack of added treatment effect 0.0 20.0 40.0 60.0 80.0 100.0 37 42 47 52 57 62 67 72 Age 3 Year DFS Control Experimental P=value = 0.038

STEPP analysis – Oxaliplatin-based therapy age cutoff validation for observed lack of added treatment effect Presenting oxaliplatin-based therapy plot given frequency of use of Oxaliplatin in the US.

Limitations Lack of … Toxicity data Dose-intensity Comorbidity data …may confound interaction between age & newer adjuvant chemotherapy regimens **Lack of consistent toxicity data May be more critical if the point estimates for the older patients was at least less than 1 so that clinicians can weigh the risk – benefit ratio **Lack data on dose-intensity or proportion of dose delivered compared to the total dose planned unable to comment on the extent to which the amount of actual dose received may account for lack of benefit among older patients receiving adjuvant therapy **Lack mechanistic explanation ?impact of comorbidity ?impact of functional decline Dewys WD, et al. Am J Med 1980; Eagles JM, et al. BMJ 1990; Landi F ZG, et al. J Am Geriatr Soc 1999; Lee Y et al. J Epidemiol Community Health 2000; Satariano WA, et al. Ann Intern Med 1994; Wedding U, et al. J Cancer Res Clin Oncol 2007.

Toxicity and Dose-Intensity Issue In recent C-08 (FOLFOX +/- Bevacizumab), advanced age was associated with significantly greater grade 3+ toxicities in both treatment arms Dose intensity for patients age > 60 was significantly less for 5-FU and oxaliplatin than < 60 (p < 0.001) Toxicity Age < 70 Age > 70 Gr 3+ ANC 35% 57% Gr 3+ fatigue 7% 15% Gr 3+ dehydration 3% 11% Gr 3+ diarrhea 10% 16% Febrile neutropenia 1% 3.5% All grade 3+ 73% 81% **Lack of consistent toxicity data May be more critical if the point estimates for the older patients was at least less than 1 so that clinicians can weigh the risk – benefit ratio **Lack data on dose-intensity or proportion of dose delivered compared to the total dose planned unable to comment on the extent to which the amount of actual dose received may account for lack of benefit among older patients receiving adjuvant therapy **Lack mechanistic explanation ?impact of comorbidity ?impact of functional decline Allegra CJ et al JCO online ahead of print May 4, 2009

Implications of individual study design The 6 included adjuvant trials tested regimens beyond variations in IV 5-FU/LV dosing schedule 4 trials (MOSAIC, NSABP C07, CALGB 89803 and PETACC-3) designed to demonstrate superiority of experimental regimen in improving DFS or OS compared to standard IV FU/LV Do not demonstrate superiority of experimental regimen in subset of older patients 2 trials (X-ACT and NSABP C06) designed to demonstrate non-inferiority of oral fluoropyrimidine therapy compared to standard IV FU/LV Data support that oral fluoropyrimidines are non-inferior both older and younger patients ***Since the oral fluoropyrimidines trials were designed as non-inferiority trials, these data are supportive of the conclusion that the oral therapy is non-inferior for disease-free and overall survival for patients at least 70 years old. – this analysis does not lead to different conclusion regarding treatment effect when analyzed by age. ***When stratified by age, neither patients < 70 years or ≥ 70 years had a statistically inferior outcome compared to control therapy; the confidence intervals for patients ≥ 70 years crossed the null hypothesis for disease-free and overall survival.

Conclusions Newer adjuvant regimens were not associated with a significant benefit in DFS, OS, or TTR compared to standard IV 5-FU/LV in pts > 70 years A key question that must be addressed is whether subgroups of > 70 would benefit from combination therapy Lack of significant interaction for TTR for age and treatment in oxaliplatin-based trials suggests competing risks Oxaliplatin may reduce risk of early recurrence but does not translate into DFS or OS benefit due to deaths from other causes *** In the ACCENT database, an international collaboration to pool individual patient data from phase III adjuvant chemotherapy trials for colon cancer, older patients (at least 70 years old) did not appear to gain a statistically significant advantage in DFS, OS, TTR with newer adjuvant regimens compared to standard intravenous 5-FU and leucovorin **This observation held true regardless of stage at diagnosis or experimental treatment received (oxaliplatin, irinotecan or oral fluoropyrimidine). In contrast, patients under the age of 70 had statistically significant improvement in disease-free and overall survival with either oxaliplatin-based or irinotecan-based chemotherapy combinations and near significant improvement with oral fluoropyrimdines. ** Do not contradict the Sargent NEJM 2001 findings of benefit of postoperative FU/LV vs. surgery alone for older pts Current analysis had chemotherapy in both arms Data do not show any additional survival benefit for older patients receiving combination or oral FU therapy Questions the additive risk vs. benefit of newer chemotherapy agents in the adjuvant setting for older CRC patients, particularly given the increased rates of toxicity attributable to combination therapies

Conclusions These data do not contradict early studies of benefit of adjuvant therapy with 5-flurouracil and leucovorin vs surgery alone in elderly patients *** In the ACCENT database, an international collaboration to pool individual patient data from phase III adjuvant chemotherapy trials for colon cancer, older patients (at least 70 years old) did not appear to gain a statistically significant advantage in DFS, OS, TTR with newer adjuvant regimens compared to standard intravenous 5-FU and leucovorin **This observation held true regardless of stage at diagnosis or experimental treatment received (oxaliplatin, irinotecan or oral fluoropyrimidine). In contrast, patients under the age of 70 had statistically significant improvement in disease-free and overall survival with either oxaliplatin-based or irinotecan-based chemotherapy combinations and near significant improvement with oral fluoropyrimdines. ** Do not contradict the Sargent NEJM 2001 findings of benefit of postoperative FU/LV vs. surgery alone for older pts Current analysis had chemotherapy in both arms Data do not show any additional survival benefit for older patients receiving combination or oral FU therapy Questions the additive risk vs. benefit of newer chemotherapy agents in the adjuvant setting for older CRC patients, particularly given the increased rates of toxicity attributable to combination therapies

With gratitude… ACCENT Collaborators: S Wieand, G Yothers, M O’Connell, N Wolmark – NSABP J Benedetti, C Blanke – SWOG; C O’Callaghan – NCIC R Labianca – Ospedali Riuniti (Italy) D Haller, P Catalano, A Benson – ECOG JF Seitz – University of the Mediterranean (France) G Francini – University of Siena (Italy) A de Gramont, T Andre – GERCOR R Goldberg, J Meyerhardt, N Jackson, L Saltz – CALGB M Buyse – IDDI (Belgium); R Gray, D Kerr – QUASAR D Sargent, A Grothey, S Alberts, E Green, Q Shi –Mayo Clinic C Twelves -University of Bradford (UK) J Cassidy – University of Glasgow (UK) F Sirzen – Roche ; L Cisar - Pfizer E Van Cutsem –University Hospital Gasthuisberg (Belgium); A Sobrero - Ospedale San Martino (Italy) ASCO Young Investigator’s Award 2008-09 to Dr. Jackson- McCleary Hartford Foundation