Uni- & Multivariate Analysis Sponsored by GERCOR (

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MOSAIC Stage ll+lll FOLFOX4 LV5FU2 Randomize. DFS DFS (months) Hazard ratio: 0.77 [0.65 – 0.92] p < 0.01 FOLFOX (n=1123) 77.9% LV5FU2 (n=1123) 72.8% FOLFOX.

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Uni- & Multivariate Analysis Sponsored by GERCOR (www.canceronet.com) Effect of adding oxaliplatin to adjuvant 5-fluorouracil/leucovorin (5FU/LV) in patients with defective mismatch repair (dMMR) colon cancer stage II & III included in the MOSAIC study. Jean-François Flejou, Thierry André, Benoist Chibaudel, Aurelie Scriva, Tamas Hickish, Josep Tabernero, Jean-Luc Van Laethem, Maria Banzi, Eduard Maartense, Adi Shani, Göran Carlsson, Werner Scheithauer, Demetris Papamichael, Markus Moehler, Stefania Landolfi, Pieter Demetter, Alex Duval, Mark Lee, Soudhir Colote, Aimery de Gramont Background MMR availability dMMR population Uni- & Multivariate Analysis Adding oxaliplatin to adjuvant 5FU and leucovorin improved 3-year Disease- Free Survival (DFS) and Overall Survival (OS) after resection of stage II and III colon cancer in the MOSAIC study. 1, 2 Prognosis of patients with stage II and III colon cancer is better in patients with dMMR (dMMR) tumors than in patients with proficient MMR (pMMR). Data suggest that 5FU-based chemotherapy is less or ineffective in patients with stage II dMMR tumor. Efficacy of FOLFOX4 in pts with dMMR stage III was suggested in a retrospective study. 3 MMR status is an independent prognostic biomarker of DFS in patients with stage III colon cancer receiving adjuvant FOLFOX chemotherapy. 4 In NSAP C07 and C08, MMR status seems not predictive for oxaliplatin benefit ? Univariate analysis Multivariate analysis N HR 95% CI P value Arm LV5FU2 FOLFOX 491 513 0,84 0,68-1.02 0.083 0.82 0.67-1.00 0.054 Age <70 ≥70 848 156 1.74 1.30-2.31 <0.0001 1.64 1.29-2.10 0.0001 Sex Male Female 541 463 0.74 0.61-091 0.004 0.73 0.60-0.90 0.003 PS 1 803 201 1.41 1.09-1.83 1.28 1.01-1.63 0.041 Stage II III 365 639 1.76 1.43-2.16 0.76 0.50-1.14 0.196 MMR pMMR dMMR 909 95 0.65 0.46-0.91 0.036 0.67 0.45-1.01 0.056 Perforation No Yes 933 71 1.54 1.02-2.34 0.013 1.42 0.98-2.06 0.066 T stage T1-3 T4 805 199 1.18-2.00 0.0002 1.38 1.08-1.77 0.011 N stage N0 N1 N2 366 411 227 1.43 2.46 1.12-1.82 1.86-3.27 1.83 1.44-2.33 . Stage Endpoint MMR NA MMR OK HR [95% CI] P value N=1242 N=1004 II-III RFS, No of events 351 303 1.01 0.86-1.17 0.942 DFS, No of events 385 378 1.08 0.94-1.24 0.284 OS, No of events 322 309 0.97 0.83-1.13 0.740 Stage Endpoint LV5FU2 FOLFOX HR [95% CI] P value N=51 N=44 II-III 3-yr RFS, % (sd) 80.2 (5.6) 90.9 (4.3) 0.49 0.20-1.19 0.134 3-yr DFS, % (sd) 78.4 (5.8) 88.6 (4.8) 0.48 0.22-1.06 0.081 5-yr OS, % (sd) 82.3 (5.3) 0.42 0.18-0.98 0.060 N=29 N=18 III 69.0 (8.6) 83.3 (8.8) 0.55 0.19-1.59 0.302 0.50 0.18-1.39 0.499 72.2 (8.3) 88.9 (7.4) 0.43 0.14-1.31 0.190 N=22 N=26 II 95.2 (4.6) 96.2 (3.8) 0.58 0.10-3.35 0.542 90.9 (6.1) 92.3 (5.2) 0.53 0.15-1.86 0.324 95.5 (4.4) 0.46 0.11-1.86 0.273 MMR NA : MMR status not available; MMR OK : MMR status available In patients with MMR available (N=1004), hazard ratios (HR) for comparing FOLFOX4 (N=513) with LV5FU2 (N= 591) were : - 0.79 [0.63-0.99] for 3-Year Relapse Free-Survival (RFS) 0.84 [0.68-1.02] for 3-Year Disease Free Survival (DFS) Methods Of the 2246 pts included in MOSAIC study, formalin-fixed, paraffin-embedded (FFPE) tissue blocks or slides from 1019 pts were obtained. Twenty two samples with insufficient tumor tissue were excluded from this translational study. MMR status was determined by immunohistochemistry (IHC) of the protein products of MLH1, MSH2, PMS2 and MSH6 genes. In 11 pts with inconclusive IHC (negative staining of both tumor and internal control), MMR status was determined by pentaplex PCR with 5 mononucleotide repeats. 6 pMMR population Stage II & III Conclusions RFS DFS OS Stage Endpoint LV5FU2 FOLFOX HR [95% CI] P value N=440 N=469 II-III 3-yr RFS, % (sd) 74,8 (2.1) 78.9 (1.9) 0.81 0.64-1.02 0.076 3-yr DFS, % (sd) 73.9 (2.1) 77.6 (1.9) 0.86 0.70-1.06 0.170 5-yr OS, % (sd) 78.8 (2.0) 80.5 (1.8) 0.91 0.72-1.15 0.434 Findings of these translational analyses in MOSAIC show Hazard Ratio in favor of FOLFOX4 vs LV5FU2 in dMMR colon cancer patients. Low dMMR prevalence in stage II & III colon cancer limits conclusive evidence for oxaliplatin benefit in this population, even in this large study. Analyses of colon cancer MMR status in patients included in the MOSAIC study support the use of FOLFOX4, in patients with dMMR stage III cancer Flow-chart MOSAIC study N=2246 MMR status available, N=1004 MMR status not available N=1242 Tumor block not collected, N=1220 MMR not evaluable, N=22 pMMR, N=909 dMMR, N=95 Stage II & III - DFS Stage III - DFS Stage II - DFS Stage III - DFS References 1 André T et al, N Engl J Med 2004 2 André T et al, J Clin Oncol 2009 3 Zaanan A, Ann Oncol 2010; 4 Zaanan A, Clin Cancer Res 2011 5 Gavin P G et al. Clin Cancer Res 2012 6 Suraweera N et al, Gastroenterology 2002 Sponsored by GERCOR (www.canceronet.com)