MOSAIC study: Actualization of Overall Survival (OS) with 10 years follow up and evaluation of BRAF by GERCOR and MOSAIC investigators

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1 MOSAIC study: Actualization of Overall Survival (OS) with 10 years follow up and evaluation of BRAF by GERCOR and MOSAIC investigators Thierry André, Armand de Gramont, Benoist Chibaudel, Annemilaï Raballand, Aurelie Scriva, Tamas Hickish, Josep Tabernero, Jean Luc Van Laethem, Maria Banzi, Eduard Maartense, Adi Shani, Goran U Carlsson, Werner Scheithauer, Demetris Papamichael, Marcus Möhler, Stefania Landolfi, Pieter Demetter, Sarah Dumont; Jean-Francois Fléjou, Aimery de Gramont. For The Multicenter International Study Of Oxaliplatin/5 Fluorouracil/Leucovorin In The Adjuvant Treatment Of Colon Cancer (MOSAIC) Investigators For correspondance: thierry.andre@sat.aphp.fr

2 Abstract Background: The MOSAIC study (André T, N Engl J Med, 2004) has demonstrated in stage II/III resected colon cancer (CC) a benefit of oxaliplatin added to adjuvant 5FU and LV (LV5FU) in 3-year disease-free survival (DFS) and in OS. FOLFOX4 has also shown a benefit in dmmr CC pts (Fléjou JF, J Clin Oncol 31: 2013;suppl; abstr 3524). We report here 1) the result of MOSAIC after 10 year follow-up and 2) the results in the BRAF population. Methods: Of the 2246 pts included in MOSAIC study (whole population), the actualization of survival was done with 10 yrs Follow up. Formalin-fixed, paraffin-embedded (FFPE) tissue blocks or slides were available in 903 patients for the research of the BRAF V600E mutation (BRAF population) using a preamplification method followed by Amplification Refractory Mutation System (ARMS ) technology. Positive mutants were confirmed by pyrosequencing. Fifteen variables were evaluated in uni- and multivariate analysis as prognostic factors for DFS in the BRAF population. Results: 1) 10yr-OS rates were 67.1% and 71.7% (HR OS 0.85, P=0.043) in the LV5FU2 and the LV5FU2/ox (FOLFOX4) arms, respectively (median follow-up of 9.5 yrs). In stage III pts, HR for OS were 0.80 (P=0.015), respectively. 2) A total of 94 (10.4%) pts were BRAF mutated. Survivals according to BRAF mutational status are presented in Table 1. In multivariate analysis (n=903), mutated BRAF was not prognostic for DFS (p=0.82) while dmmr was prognostic in both, uni and multivariate analyses. Table 1. 3yr-DFS and 5yr- and 10yr-OS rates according to BRAF mutational status Stage II and III 3-year DFS, % (SE) BRAF mutated (n=94) FOLFOX4 (n=50) 80.0 (5.7) LV5FU2 (n=44) 63.6 (7.2) 5-year OS, % (SE) 80.0 (5.7) 70.5 (6.9) 10-yr OS, % (SE) 75.8 (6.1) 65.7 (7.2) HR (95% CI) P-value BRAF wild type (n=809) FOLFOX4 (n=413) LV5FU2 (n=396) 0.50 ( ) (2.0) 76.1 (2.1) 0.66 ( ) (1.9) 70.3 (2.3) 80.0 (2.0) 68.4 (2.4) HR (95% CI) P-value 0.90 ( ) ( ) Conclusions: As 10 years follow up, benefit of oxaliplatin as adjuvant therapy for stage II/III CC is confirmed for DFS and OS. Patients with tumor with BRAF mutation seem to benefit of FOLFOX.

3 Background The MOSAIC study has demonstrated in stage II/III resected colon cancer (CC) a benefit of oxaliplatin added to adjuvant 5FU and LV (LV5FU) in 3-year and 5-year disease-free survival (1,2) and in OS (2) with a median follow up of 6 year. FOLFOX4 has also shown a benefit in dmmr Colon Cancer patients (3) Stage Endpoint LV5FU2 FOLFOX HR [95% CI] N=51 N=44 II-III 3-yr RFS, % (sd) 80,2 (5.6) 90.9 (4.3) yr DFS, % (sd) 78.4 (5.8) 88.6 (4,8) yr OS, % (sd) 82.3 (5.3) 90.9 (4.3) We report here 1) the result of MOSAIC after 10 year follow-up and 2) the results in the BRAF population. (1) André T, N Engl J Med, 2004 (2) André T, J Clin Oncol 2009 (3) Fléjou JF, J Clin Oncol 31: 2013;suppl; abstr 3524

4 Methods Of the 2246 pts included in MOSAIC study (whole population), actualization of survival was done at 10-yr follow up. Formalin-fixed, paraffin-embedded (FFPE) tissue blocks or slides were available in 903 patients for BRAF V600E mutation testing (BRAF population) using a preamplification method followed by Amplification Refractory Mutation System (ARMS ) technology. Positive mutants were confirmed by pyrosequencing. Fifteen variables were evaluated in uni- and multivariate analysis of prognostic factors for DFS in the BRAF population.

5 Flow Chart: Patient distribution according to MMR and BRAF status

6 MOSAIC - Overall Survival at 10 yr follow up Whole population: Stage II and III (N=2 246) 100 FOLFOX4 LV5FU Absolute difference 2,1% 4,3% 4,6% 8,1% Hazard ratio 0,85 95% CI 0,73 to 0,99 P = 0, Number at risk Yeras Group: FOLFOX Group: LV5FU

7 MOSAIC - Overall Survival at 10 yr follow up Stage III (N=1347) 100 REGIMEN FOLFOX4 LV5FU Absolute difference 4,3% 8,1% Hazard ratio 0,80 95% CI 0,66 to 0,96 P = 0, Number at risk Yeras Group: FOLFOX Group: LV5FU

8 MOSAIC - Overall Survival at 10 yr follow up Stage IIIC (N=1347) 100 FOLFOX4 LV5FU Hazard ratio 0,8 95% CI 0,66 to 0,96 P = 0, Absolute difference 12,1% 13,2% 20 Hazard ratio 0,70 95% CI 0,53 to 0,92 P = 0, Number at risk Years Group: FOLFOX Group: LV5FU

9 BRAF population (N=903) Prognostic value of BRAF mutational status (BRAF wild-type vs. BRAF mutant) Relapse-free interval (RFI) RFI Events/Patients Stage II Stage III All stages Mut : 6/31 WT : 59/293 Mut : 22/63 WT : 186/516 Mut :28 /94 WT : 245/809 5yr-RFI Mut : 83.9 (6.6) WT : 83.7 (2.2) Mut : 67.7 (5.9) WT : 66.1 (2.1) Mut : 73.1 (4.6) WT : 72.5 (1.6) HR (95%CI) P-value HR 1.06 ( ) P=0.896 HR 0.95 ( ) P=0.804 HR 0.97 ( ) P=0.863 BRAF is not pronostic factor in MOSAIC

10 MOSAIC with 10 year Follow up: Univariate and multivariate analysis for DFS Population with available Braf and MMR status (N=903) Univariate analysis Multivariate analysis Variables N Events HR (95% CI) P-value HR P-value Age < > BMI < > CEA Grade Well Poor LNE No 758 Yes 133 Obstruction No 730 Yes 173 Perforation No 833 Yes 70 ECOG PS Sex Male 482 Female 421 Site Stage II 324 III 579 T T T N N0 325 N1 376 N2 202 MMR BRAF dmmr pmmr WT Mutant ( ) ( ) < ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) < < ( ) < ( ) ( ) 0.818

11 BRAF population (N=903) 3yr-DFS and 5yr- and 10yr-OS rates according to BRAF mutational status Stage II and III 3-year DFS, % (SE) BRAF mutated (n=94) FOLFOX4 (n=50) 80.0 (5.7) LV5FU2 (n=44) 63.6 (7.2) 5-year OS, % (SE) 80.0 (5.7) 70.5 (6.9) 10-yr OS, % (SE) 75.8 (6.1) 65.7 (7.2) HR (95% CI) P-value BRAF wild type (n=809) FOLFOX4 (n=413) LV5FU2 (n=396) 0.50 ( ) (2.0) 76.1 (2.1) 0.66 ( ) (1.9) 70.3 (2.3) 80.0 (2.0) 68.4 (2.4) HR (95% CI) P-value 0.90 ( ) ( ) 0.599

12 Conclusions With 10 years follow up, benefit of oxaliplatin as adjuvant therapy for stage II/III CC is confirmed for DFS and OS. Delta (absolute OS difference) has increased from 2.2% to 4.6% Delta (absolute OS difference) is increasing according to stage, up to 13.2% in stage IIIC dmmr is a pronostic factor in but not BRAF Patients with dmmr status benefit of FOLFOX (HR 0,48 for DFS at 5 yr and 0,42 for OS at 5 yr). Patients with BRAF mutation benefit of FOLFOX (HR 0,50 for DFS at 3 yr and 0,66 for OS at 10 yr). Differences are not significant but the number of patients in these subgroups is small. A pooled analysis of MOSAIC and NSABP C07 is ongoing to confirm the benefit of oxaliplatin in dmmr and BRAF mutated populations.