IDEA: Pooled Analysis of Adjuvant Oxaliplatin for 3 vs 6 Mos in Stage III Colon Cancer CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois *Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

IDEA: Background Standard of care in stage III CC: 6 mos with oxaliplatin-based tx (FOLFOX4/modified FOLFOX6, CAPOX)[1] Neurotoxicity associated with cumulative oxaliplatin dose[2] Grade 3 PN observed in 12.5% of pts treated with FOLFOX for 6 mos[3] Reduced treatment duration without efficacy loss would benefit pts and lessen resource usage IDEA collaboration undertook pooled analysis to determine if adjuvant oxaliplatin-based tx for 3 mos noninferior to 6 mos in pts with stage III CC[4] CAPOX, capecitabine and oxaliplatin; CC, colon cancer; FOLFOX, leucovorin, fluorouracil, oxaliplatin; PN, peripheral neuropathy; tx, therapy. 1. André T, et al. Curr Colorectal Cancer Rep. 2013;9:261-269. 2. Park SB, et al. CA Cancer J Clin. 2013;63:419-437. 3. André T, et al. J Clin Oncol. 2009;27:3109-3116. 4. Shi Q, et al. ASCO 2017. Abstract LBA1. Slide credit: clinicaloptions.com

IDEA: Trials, Treatment Prospectively pooled analysis of data from 6 concurrent randomized phase III trials in pts with stage III CC (mITT population: N ≥ 12,834) Pts randomized 1:1 to 3 vs 6 mos tx with oxaliplatin-based tx (investigator’s choice of FOLFOX or CAPOX) Trial Stage III CC Pts, N Treatment Country Median F/u, Mos Pts on CAPOX, % TOSCA 2402 CAPOX or FOLFOX4 Italy 62 35 SCOT 3983 CAPOX or mFOLFOX6 Australia, Denmark, New Zealand, Spain, Sweden, UK 37 67 IDEA France 2010 France 51 10 C80702 2440 mFOLFOX6 Canada, US HORG 708 Greece 48 58 ACHIEVE 1291 Japan 75 CAPOX, capecitabine and oxaliplatin; CC, colon cancer; f/u, follow-up; FOLFOX, leucovorin, fluorouracil, oxaliplatin; mFOLFOX, modified FOLFOX; tx, therapy. Slide credit: clinicaloptions.com Shi Q, et al. ASCO 2017. Abstract LBA1.

IDEA: Statistical Plan Primary endpoint: DFS in mITT population* DFS: time from randomization to earliest date of relapse, secondary colorectal primary tumor, or death Preplanned subgroup analyses by regimen, risk groups Statistical analyses DFS HR for 3 vs 6 mos (2-sided 95% CI) estimated with Cox model stratified by trial Predefined noninferiority margin for HR < 1.12 (12% increase in relative risk) Requires 3390 DFS events for 90% power with 1-sided α = 0.025 Predefined noninferiority margin for 3-yr DFS rate difference (3 vs 6 mos): -2.7% Additional endpoints: treatment compliance, safety CAPOX, capecitabine and oxaliplatin; DFS, disease-free survival; FOLFOX, leucovorin, fluorouracil, oxaliplatin; mITT, modified intent to treat. *Received ≥ 1 dose of study drug. Slide credit: clinicaloptions.com Shi Q, et al. ASCO 2017. Abstract LBA1.

IDEA: Pt Characteristics by Tx Duration, Regimen FOLFOX CAPOX 3 Mos (n = 3870) 6 Mos (n = 3893) (n = 2554) (n = 2517) Median age, yrs 64 65 ECOG PS 0/1,* % 77/22 82/18 81/19 T stage, % T1-2 T3 T4 13 68 19 14 67 63 24 12 25 N stage, % N1 N2 72 28 73 27 71 29 Reached final planned cycle, % 90 86 CAPOX, capecitabine and oxaliplatin; ECOG, Eastern Cooperative Oncology Group; FOLFOX, leucovorin, fluorouracil, oxaliplatin; PS, performance status; tx, therapy; yr, year. *1% of FOLFOX-treated pts had ECOG PS 2. Slide credit: clinicaloptions.com Shi Q, et al. ASCO 2017. Abstract LBA1.

IDEA: DFS in mITT Population, Risk Subgroups Noninferiority of oxaliplatin-based tx for 3 vs 6 mos not proven DFS HR: 1.07 (95% CI: 1.00-1.15) Difference in 3-yr DFS rates: -0.9% (95% CI: -2.4% to 0.6%) 3-yr DFS rate difference of 20% between low risk (T1-3, N1) vs high risk (T4 or N2) subgroups Risk Group HR Favors 3 mos Favors 6 mos Interaction P Value DFS, disease-free survival; mITT, modified intent to treat; mos, months; tx, therapy. T1-3, N1 T4 or N2 1.01 1.12 .11 0.5 1 1.12 1.5 HR Slide credit: clinicaloptions.com Shi Q, et al. ASCO 2017. Abstract LBA1. Reproduced with permission.

IDEA: DFS by Risk Subgroups and Regimen Risk Group Regimen Favors 3 mos Favors 6 mos HR (95% CI) FOLFOX CAPOX Not proven Noninferior Inferior 1.10 (0.96-1.26) 0.85 (0.71-1.01) 1.20 (1.07-1.35) 1.02 (0.89-1.17) T1-3, N1 T4 or N2 CAPOX, capecitabine and oxaliplatin; DFS, disease-free survival; FOLFOX, leucovorin, fluorouracil, oxaliplatin. HR 1.0 1.12 Noninferiority margin Slide credit: clinicaloptions.com Shi Q, et al. ASCO 2017. Abstract LBA1. Reproduced with permission.

IDEA: Safety AE, % FOLFOX CAPOX 3 Mos 6 Mos P Value* Any event† Grade 2 Grade 3/4 32 38 57 < .0001 41 24 48 37 Neurotoxicity Grade ¾ 14 3 16 12 36 9 Diarrhea 11 5 13 7 10 .0117 AE, adverse event; CAPOX, capecitabine and oxaliplatin; FOLFOX, leucovorin,, oxaliplatin. *For Chi-squared test for trend. †19 grade 5 events reported. Slide credit: clinicaloptions.com Shi Q, et al. ASCO 2017. Abstract LBA1.

IDEA: Investigator Conclusions DFS noninferiority of adjuvant oxaliplatin-based tx for 3 vs 6 mos not established in pts with stage III CC Effect of tx duration on DFS varied by pt risk group and regimen Trial differences in outcomes potentially due to variability in proportion of pts treated with CAPOX Investigators suggest further study needed to determine whether differences between regimens due to schedule, delivery methods Shorter tx associated with greater treatment compliance, much less grade ≥ 2 neuropathy Investigators recommend risk-vs-benefit approach when selecting duration of adjuvant oxaliplatin-based tx Low-risk pts (T1-3, N1): 3 mos High-risk pts (T4, N2, or other high-risk variables): 3-6 mos depending on tolerability, pt preferences, recurrence risk, regimen (FOLFOX vs CAPOX) CAPOX, capecitabine and oxaliplatin; CC, colon cancer; DFS, disease-free survival; FOLFOX, leucovorin, fluorouracil, oxaliplatin; tx, therapy. Slide credit: clinicaloptions.com Shi Q, et al. ASCO 2017. Abstract LBA1.

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