Development of Conventional Chemotherapy in mcrc BSC vs. Chemo, Biochemical modulation, Oral fluoropyrimidines, Developmentof combination chemotherapy

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1 ESMO Preceptorship Colorectal Cancer Colorectal ESMO Cancer Preceptorship Valencia May Program 20-21st 2016 Prague May 22-23rd 2014 Development of Conventional Chemotherapy in mcrc BSC vs. Chemo, Biochemical modulation, Oral fluoropyrimidines, Developmentof combination chemotherapy J.Y. DOUILLARD MD PhD Chief Medical Officer ESMO Emeritus Professor of Medical Oncology University of Nantes France

2 Disclosure JY Douillard Compensated participations in: Advisory Boards and Symposia: Amgen Bayer Boehringer Ingelheim Merckserono Roche/Genentech Sanofi Takeda Research Funding Merckserono

3 Chemotherapy vs. "Best supportive care" # Pat Response TTP Survival BSC 12 0% 2.3 mo 5 mo BSC + CTx 24 33% 6.0 mo 11 mo p<0.001 p=0.006 LQ -FLIC BSC CTx Months Scheithauer et al. BMJ 306, 1993

4 Immediate vs. delayed CTx in metastatic CRC Treatment NPat Time without Survival Symptoms Progression (median) Immediate mo 8 mo 14 mo Delayed 90 2 mo 3 mo 9 mo p-value <.001 <.001 <.002 Glimelius et al. JCO 1992

5 Points to be discussed Biochemical modulation, infusional 5-FU Oral fluoropyrimidines Combination treatment (irinotecan, oxaliplatin)

6 Fluoropyrimidine Metabolic Pathway Catabolism 85% Anabolism RNA FUH 2 DPD FU FUrd FUMP FUDP FUTP FUPA FUdR FBAL dump 5, 10 CH 3 THF FdUMP FdUDP FdUTP TS dtmp DHF DNA

7 modified according to Hyrniuk and Wils 5-FU dose intensity and response 40 Bolus Infusional FU dose intensity mg / m 2 / week

8 Results from Meta-Analyses Treatment Trials N Pat FU FU/FA FU FU/MTX FU Bolus FU CI FU+/-FA FU+/FA+IFN FU/FA FU/IFN ORR (CR/PR) p-value 11% 23% < % 19% < % 22% < % 24% n.s. 23% 18% 0.04 med OS (Months) p-value 11,0 11,5 0,57 9,1 10, ,3 12, ,4 11,5 n.s. 11,7 11,3 n.s.

9 5-FU Prodrugs S1: Tegafur [1] CDHP [0.4] Oxo [1] 5 deoxy-5-fluorouridine Capecitabine 5 deoxy-5-fluorocytidinpentoxycarbomyl 5 deoxy-5-fluorocytidine Cytidindeaminase Carboxylesterase UFT: Tegafur [1] Uracil [4] C-5 Oxidation C-2 Hydrolysis Cytochrom P450 Pyrimidin Phosphorylase FUra FdUMP OXO FUMP CDHP: EU: Oxo: 5-chloro-2,4-dihydoxypyridine Ethynyluracil Oxonic acid DPD EU CDHP FUH 2

10 Oral Fluorpyrimidines vs. Mayo-Clinic regimen (mo) N Pat CR/PR PFS (mo) Survival Cape % Mayo % Cape % Mayo % UFT/LV % Mayo 190 9% UFT/LV % Mayo % Van Cutsem JCO 2001, Hoff JCO 2001; Douillard JCO , Carmichael JCO 2002

11 TAS 102 The latest drug added for mcrc TAS-102 is an orally administered combination of a thymidine-based nucleic acid analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride Trifluridine is the active cytotoxic component of TAS-102; Tipiracil hydrochloride is a potent inhibitor of thymidine phosphorylase

12 Randomised trials have shown: Contribution of Oxaliplatin and Irinotecan

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17 Irinotecan+5FU/LV Survival (Study V303) Probability mo* CPT-11/5-FU/LV (N=198) 5-FU/LV (N=187) 17.4 mo* p< Months JY Douillard The Lancet 2000 * Medians Log-rank test

18 : Overall Survival 5-FU 24h /LV (AIO) +/- Irinotecan (Secondary Endpoint) Median 95% CI AIO + IRI 20.1 [ ] AIO 16.9 [ ] p= log-rank p= Wilcoxon 20% of pts (months) O N Number of patients at risk : HDFU/FA HDFU/FA/CPT11

19 FOCUS- trial Pts receiving all 3 drugs 2100 Pts. not suitable for neoadjuv. therapy 1. line 2. line 3. line A 5-FU/FA Irinotecan OxCape B1 5-FU/FA FOLFIRI OxCape B2 5-FU/FA FOLFOX IriCape C1 FOLFIRI OxCape C2 FOLFOX IriCape 16% 19% 33% Seymour, Lancet 2007

20 FOCUS- trial Seymour, Lancet 2007

21 Focus trial

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25 Efficacy of Oxaliplatin Plus Capecitabine or Infusional Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer: A Pooled Analysis ofrandomized Trials Arkenau et al. JCO 2009

26 Efficacy of Oxaliplatin Plus Capecitabine or Infusional Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer: A Pooled Analysis of Randomized Trials Arkenau et al. JCO 2009

27 Efficacy of Oxaliplatin Plus Capecitabine or Infusional Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer: A Pooled Analysis ofrandomized Trials Arkenau et al. JCO 2009

28 Survival according to availability of lines of treatment Mediane Überlebenszeit (Monate) 22 IROX 21 FOLFOX type 20 FOLFIRI type IFL P= Grothey et al. J Clin Oncol 2004; 22; % Patienten mit FU, Oxaliplation und Irinotecan

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30 Oxaliplatin in adjuvant pretreated patients Factor N HR p FOLFOXIRI + Bev FOLFIRI + Bev SWJOG4407GS Subgroup analysis for PFS FOLFIRI / Bev vs. FOLFOX / Bev Category Subgroup mfolfox6 +Bev N FOLFIRI+Bev MST (m) mfolfox6 FOLFIRI+Bev HR p value +Bev Overall ECOG PS Adjuvant Chemotherapy yes no *Except for 3 patients of multiple sites 0,100 1,000 10,000 Favors FOLFIRI+Bev Favors mfolfox6+bev Falcone et al. ASCO 2013, Yamazaki et al. ASCO 2014

31 5-Year Survival Rate for Stage IV CRC Remains Only 6% Adapted from E Van Cutsem FU/LV bolus FU/LV infusion IFL LVFU2/irinotecan FOLFOX IFL + bevacizumab FOLFOX/FOLFIRI XELOX/FOLFOX + bevacizumab FOLFOX + cetuximab FOLFIRI + cetuximab FOLFOX + panitumumab FOLFIRI + bevacizumab FOLFOX + panitumumab FOLFIRI + cetuximab FOLFOXIRI + bevacizumab FOLFIRI + cetuximab FOLFOX/FOLFIRI + cetuximab or bevacizumab 22.8* Overall Survival (months) *KRAS wild type tumors; **Extended RAS wild type population. Note: Informal comparison as these are not head-to-head clinical trials. 1. Saltz. N Engl J Med. 2000; 2. Douilliard. Lancet. 2000; 3. Goldberg. J Clin Oncol. 2004; 4. Hurwitz. N Engl J Med. 2004; 5. Saltz. J Clin Oncol. 2008; 6. Falcone. J Clin Oncol. 2007; 7. Bokemeyer. Ann Oncol. 2011; 8. Van Cutsem. J Clin Oncol. 2011; 9. Douilliard. ASCO Abstract 3510; 10. Heinemann. ASCO Abstract LBA3506; 11. Stintzing and Heinemann. ESMO Abstract LBA17; 12. Falcone. ASCO Abstract 3505; 13. Douillard JY, et al. New Engl J Med. 2013;369(11): ;14. Van Cutsem et al. Ann Oncology ESMO GI 2014 A. 15. Venook P, et al. ASCO Abstract LBA3; Plenary presentation.

32 Survival with multidiciplinary approach % --- BSC FU % 48% --- FOLFIRI/FOLFOX6 --- FOLFOX6/FOLFIRI --- resectabel --- primary non-resectabel 40 52% 30% 20 33% Long term survival with chemotherapy and resection 23% Colon Cancer Collaborative Group, BMJ 2000 / Tournigand, JCO 2004 / Adam, Ann Surg 2004