What is the best cytotoxic backbone for biologicals? 14th WCGIC ESMO Barcelona June 27th-30th 2012 Metastatic Colorectal Cnacre What is the best cytotoxic backbone for biologicals? JY DOUILLARD MD PhD Professor of Medical Oncology Integrated Centers of Oncology ICO Nantes France

Disclosures AMGEN: participation in Steering committees, Advisory Boards, Symposia, compensated MERCKSERONO: participation in Steering committees, Advisory Boards, Symposia, compensated Reseach Funding ROCHE: participation in Steering committees, Advisory Boards, Symposia, compensated

Incremental Improvements in Overall Survival in the Last Decade Saltz, NEJM 2000 5-FU bolus 19.5 17.4 14.8 14.1 12.6 Douillard, Lancet 2000 5-FU infusion Saltz, NEJM 2000 IFL Douillard, Lancet 2000 FOLFIRI Goldberg, JCO 2004 FOLFOX Tournigand, JCO 2004 FOLFOX followed by FOLFIRI 20.6 Hurwitz, NEJM 2004 IFL + bevacizumab 21.3 20.3 Saltz JCO 2008 FOLFOX + bevacizumab 22.8 FOLFOX + cetuximab Bokemeyer, Ann Onc 2011 22.8 No therapy has improved PFS or OS combined with 1st line FOLFOX and 2nd line FOLFIRI in a phase 3 trial Douillard, JCO 2009 FOLFOX + panitumumab 23.9 VanCutsem, NEJM 2009 FOLFIRI + cetuximab 23.5 5 10 15 20 25 OS (months) Amgen Corporate Template 3

Chemotherapy for Colorectal cancer The majority of situations includes a Fluoropyrimidine 5 Fluoro-Uracil IV Bolus (Nordic regimen, Mayo Clinic, Roswell Park…) Infusional 5FU (LV5FU2, TTD, AIO…) Oral Fluoropyrimidines: Capecitabine (Xeloda®), Tegafur/Uracil (UFT®) Either as single agent Or in combination Xelox, Capox, Xeliri, Capiri Tegafox, Tegafiri Most of the studies and meta-analysis have concluded that oral fluoropyrimidine were non-inferior to IV 5FU

What is the best cytotoxic backbone for biologicals? Combination with Bevacizumab: Folfox, Xelox and Folfiri, Xeliri

Overview of Bevacizumab-based chemotherapy PFS CT CT+Bev HR Kabbinavar 5FULV 5.6 8.8 0.63 p<0.001 Saltz NO10966 Folfox/Xelox 8 9.4 0.83 =0.002 Hurwitz IFL 6.2 10.6 0.54 p<0.001 TREE oxali/5FU 7.1 9.5 - Hechts PACE control arm Oxali 11.4 BIC-C Folfiri 7.6 11.2 BRITE 10 BEAT 10.8 Adding Bevacizumab to chemotherapy constantly improves PFS (Relative improvement range: 17-46%)

Overview of Bevacizumab-based chemotherapy OS CT CT+Bev HR Kabbinavar 5FULV 14.6 17.9 0.74 ns Saltz NO10966 Folfox/Xelox 19.9 21.3 0.89 ns Hurwitz IFL 15.6 20.3 0.66 P<0.001 TREE oxali/5FU 18.2 23.7 - Hechts PACE control arm Oxali 24.5 BIC-C Folfiri 23.1 28 BRITE 25.1 BEAT 22.7 Adding Bevacizumab to chemotherapy inconstantly improves survival (Relative range improvement 11-34%)

NO 16966: PFS according to chemotherapy backbone 1.0 0.8 0.6 0.4 0.2 0 5 10 15 20 25 Months 1.0 0.8 0.6 0.4 0.2 0 5 10 15 20 25 Months 23% risk reduction 11% risk reduction PFS estimate 7.4 9.3 8.6 9.4 XELOX+placebo XELOX+bevacizumab FOLFOX+placebo FOLFOX+bevacizumab FOLFOX subgroup HR = 0.89 [97.5% CI 0.73–1.08] (ITT) p = 0.1871 XELOX subgroup HR = 0.77 [97.5% CI 0.63–0.94] (ITT) p = 0.0026

TREE 1-2: Efficacy %ORR 52 46 39 41 27 20 TTP 8.7 9.9m 6.9 8.3m +13% +20% +75% TTP 8.7 9.9m 6.9 8.3m 5.9 10.3m OS 19.2 26.1m 17.9 20.4m 17.2 24.6m +36% +14% +43% 52 46 39 41 27 20 Avastin significantly improved overall response rates when added to each regimen (p=0.011, pooled logical regression analysis). Bolus 5-FU/LV (bFOL-Avastin) appears to be less active than infusional 5-FU/LV (FOLFOX-Avastin) (p<0.029), XELOX-Avastin was equally effective compared to FOLFOX-Avastin. 1. Hochster HS et al. Proc 2005 GI Cancers Symposium 2005;204 (Abst 241). mFOLFOX mFOLFOX bFOL bFOL XELOX XELOX + Avastin + Avastin + Avastin Hochster H S et al. JCO 2008;26:3523-3529

MEXICO study: FOLFIRI-Bev vs XELIRI-Bev PFS and OS bevacizumab + XELIRI (n=72) PFS and OS bevacizumab + FOLFIRI (n=73) Ducreux M. et al ASCO 2009

BICC-C study n=430 mIFL mIFL+ Bev FOLFIRI FOLFIRI + B Resp rate 43,3 % 53,3 % 47,2% 63,2 % PFS (months) 5,9 8,3 +40% 7.6 11,2 +47% MS (months) 17,6 19,2 +9% 23.1 28 +21% 1 y . survival 65 % 61 % 75% 87 % Fuchs, C. S. et al. J Clin Oncol; 25:4779-4786 2007

Chemotherapy backbone in combination with Bevacizumab In combination with Oxaliplatin-based chemotherapy: Improvement from Bevacizumab has a larger order of magnitude with Xelox vs. Folfox and Infusional 5FU vs. Bolus. In combination with Irinotecan-based chemotherapy: No direct comparative data with Folfiri or Xeliri Similar magnitude of improvement with bolus or infusional 5FU

Chemotherapy backbone in combination with anti-EGFR antibodies Anti-EGFR antibodies are restricted to Kras Wild-type patients Various trials have been reported: With infusional 5FU regimen FOLFOX and FOLFIRI including Cetuximab and Panitumimab With Capecitabine containing regimen (COIN A and B, AIO 0104) With bolus 5FU regimen (NORDIC VII) With UFT-Oxaliplatin (UFOX)

Kras status and 1st line CT CRYSTAL OPUS PRIME wt Kras Folfiri Folfiri cetux Folfox Folfox Cetux Folfox Pani RR % 43 57 p=0.0001 34 57 0.002 48 57* PFS m 8.4 9.9 HR 0.70* 7.2 8.3 HR 0.56* 8.6 10 HR 0.80* OS m 20 23.5 HR 0.80* 18.5 22.8 HR 0.85** 19.7 23.9 HR 0.88** mt Kras RR% 36 31 52 34 0.02 40 41 7.7 7.4 HR 1.17** 5.5 HR 1.72* 9.2 7.4 HR 1.27* 16.7 16.2 HR 1.03** 17.5 13.4 HR 1.29** 19.2 15.5HR 1.17** * Significant p value ** Non significant p value (updated ECCO/ESMO 2009)

Anti-EGFR antibodies with infusional 5FU regimen in Wild-type Kras mCRC Constant improvement on: Response rate PFS Survival From the addition of anti-EGFR antibodies Cetuximab and Panitumumab to Folfox and Folfiri in 1st and 2nd line

Anti-EGFR antibodies with Capecitabine-containing regimen in Wild-type Kras mCRC COIN trial (UK): mFolfox or Xelox AIO 0104 (Germany): Capiri-Capox Cetuximab Capecitabine-Cetuximab in elderly patients Folfox-Cetuximab vs. UFOX Cetuximab

COIN trial design 5FU or capecitabine oxaliplatin 5FU or capecitabine Arm A N=815 5FU or capecitabine oxaliplatin CONTINUOUS CT until progression, toxicity or patient choice 5FU or capecitabine Arm B N=815 Randomisation oxaliplatin Second-line therapy cetuximab CONTINUOUS CT until progression, toxicity or patient choice Arm C N=815 5FU or cap 5FU or cap 5FU or cap oxaliplatin oxaliplatin oxaliplatin INTERMITTENT CT: Treat for 12 weeks then stop and monitor; restart on progression for a further 12 weeks Maughan T WCGIC Barcelona 2010

COIN trial population XELOX: 64% mFOLFOX6: 36% Total of 2445pts in 3 arms: XELOX: 64% mFOLFOX6: 36% 1316 tested for Kras/Braf 43% Kras mutant 8% Braf mutant 4% Nras mutant Maughan TS The Lancet Oncology on line June 4th 2011 DOI: 10.1016/S0140-7636(11)60613-2

What is the cause of the Xelox effect? Dose intensity? COIN Dose intensity was reduced in arm B (p < 0.001) DI in Arm A is higher for XELOX than for OxMdG (p 0.03) Capecitabine dose reduction slightly increased DI for XELOX + C p < 0.03 A v B p < 0.001

Anti-EGFR antibodies with bolus 5FU-containing regimen in Wild-type Kras mCRC The Nordic VII trial

NORDIC VII study design 571 patients randomised May 2005 - October 2007 5-FU / FA Second line chemo- therapy Irinotecan based Arm A Oxaliplatin Continuous FLOX until progression or toxicity 5-FU / FA Arm B Oxaliplatin Cetuximab Continuous FLOX and cetuximab until progression or toxicity 5-FU / FA 5-FU / FA 5-FU / FA Arm C Oxaliplatin Oxaliplatin Cetuximab Intermittent FLOX and continuous cetuximab. FLOX 16 w, then stop, reintroduce FLOX at progression etc… Nordic FLOX: 2 weekly 5-FU i.v. bolus 500mg/m2 and FA 60 mg/m2 day 1-2, oxaliplatin 85mg/m2 day 1 Cetuximab: 400mg/m2 day 1, then 250 mg/m2 weekly Randomisation: 1:1:1 Stratification: study centre Tveit ESMO 2010

NORDIC VII:Progression free survival, KRAS populations KRAS wild type KRAS mutant Arm A – median: 8.7 Arm B – median: 7.9 HR=1.07 (0.79-1.45), p=0.66 Arm A – median: 7.8 Arm B – median: 9.2 HR=0.71 (0.50-1.03), p=0.07 Arm A: 97 70 29 9 6 Arm B: 97 65 34 9 0 58 41 12 6 3 72 55 26 11 2 Number of patients at risk Number of patients at risk

Median Difference (mo) Benefits of Anti-EGFR MoAb in Combination infusional CT 1st Line KRAS Wild-type Population n HR (95% CI) Progression Free Survival Median Difference (mo) OPUS4 - FOLFOX ± cetuximab 179 0.57 (0.38-0.86) 1.1 CRYSTAL2 - FOLFIRI ± cetuximab 348 0.68 (0.50-0.94) 1.2 COIN3 -m FOLFOX ± cetuximab 243 0.72 (0.53-0.98) NR 200502031 - FOLFOX ± panitumumab 656 0.80 (0.66-0.97) 1.6 Overall Survival CRYSTAL2 - FOLFIRI ± cetuximab 0.84 (0.64-1.11) 3.9 COIN3 -m FOLFOX ± cetuximab 0.93 (0.69-1.25) NR OPUS4 - FOLFOX ± cetuximab 0.86 (0.60-1.22) 4.3 200502031 - FOLFOX ± panitumumab 0.83 (0.67-1.02) 4.2 * ITT population 0.10 1.00 2.00 Favors targeted agent Hazard Ratio Favors chemotherapy alone 1. Douillard JY, et al. J Clin Onc 2010;27: 4697-4705, 2. Van Cutsem E, et al. N Engl J Med 2009; 360:1408-17, 3. Maughan T, et al. EJC 2009;7 (suppl) :a6LBA, 4. Bokemeyer C, et al. Ann Onc 2011; doi:10.1093/annonc/mdq632 , 24

Anti-EGFR antibodies: impact on PFS in combined with oxaliplatin-based CT HR (95% CI) Oxaliplatin + infusional fluorouracil 0.57 (0.380.86) 179 OPUS1 - FOLFOX ± cetuximab* 0.80 (0.670.95) 656 PRIME2 - FOLFOX ± panitumumab* 0.77 (0.591.01) 244 COIN3 - mFOLFOX# ± cetuximab* Other oxaliplatin-based chemotherapy 1.02 (0.861.26) 485 COIN3 - XELOX  cetuximab* 1.07 (0.791.45) 194 NORDIC VII4 - FLOX  cetuximab* 0.10 1.00 2.00 Favours targeted agent Hazard Ratio Favours chemotherapy alone Informal comparison as these are not head-to-head clinical trials; *KRAS wt population; #OxMdG, Oxaliplatin + Modified de Gramont 1. Bokemeyer C, et al. Ann Oncol 2011; 22:1535-46; 2. Douillard JY, et al. J Clin Oncol 2011; 29(Suppl):3510; 3. Maughan TS, et al. Lancet 2011; 377:2103-14; 4. Tveit K, et al. Ann Oncol 2010; 21(S8): LBA 20.

AIO CRC study group: KRK-0104 Study design first line treatment for mCRC n=185 primary endpoint: response rate (ORR) secondary endpoints progression free survival (PFS) disease control rate (DCR) toxicity (NCI CTC) grade 3/4 Capecitabine Cetuximab + Irinotecan 1 R n=185 1 Capecitabine Cetuximab + Oxaliplatin Moosmann N et al. JCO 2011;29:1050-1058 26 149 patients evaluable regarding response 78 patients arm A 71 patients arm B

Overall survival (A, B) and progression-free survival (C, D) for patients with KRAS wild-type (wt) and mutant in the capecitabine and irinotecan (CAPIRI) plus cetuximab and the capecitabine and oxaliplatin (CAPOX) plus cetuximab treatment arms. Overall survival (A, B) and progression-free survival (C, D) for patients with KRAS wild-type (wt) and mutant in the capecitabine and irinotecan (CAPIRI) plus cetuximab and the capecitabine and oxaliplatin (CAPOX) plus cetuximab treatment arms. Moosmann N et al. JCO 2011;29:1050-1058

FUTURE Study design R n=302 Unresectable mCRC (ITT) FOLFOX4 + cetuximab n=150 Cetuximab 400 mg/m2 day 1 then 250 mg/m2 weekly + oxaliplatin 85 mg/m2 d1, d15 + FA 200 mg/m2 + 5-FU 400 mg/m2 IV bolus then 600 mg/m2 infusion over 22 h, d1, d2, d15, d16 Unresectable mCRC R n=302 (ITT) UFOX + cetuximab n=152 Cetuximab 400 mg/m2 day 1 then 250 mg/m2 weekly + oxaliplatin 85mg/m2 d1, d15 + Orally, days 1–21 UFT: tegafur 250 mg/m2/day, uracil 560 mg/m2/day; 3 divided doses* + FA 90 mg/day; 3 divided doses Stratification: Köhne’s criteria1 Study terminated early when significance of tumor KRAS status became apparent Douillard JY et al WCGIC 2012 Abst O-0017

FUTURE study: PFS (KRAS wt) FOLFOX4 + cetuximab n=56 UFOX + cetuximab n=40 Median, months 95% CI 9.2 7.4–9.5 6.8 5.6–8.2 Hazard ratio* 0.72 0.44–1.18 p-value (log-rank)* 0.1853 Clinical cut-off: 30 June 2009 1.0 0.9 0.8 0.7 0.6 Probability of PFS 0.5 FOLFOX4 + cetuximab UFOX + cetuximab 0.4 0.3 0.2 0.1 3 6 9 12 15 18 21 Months Douillard JY et al WCGIC 2012 Abst O-0017 *Stratifed according to randomization strata cet, cetuximab

TTD Group (Spain) Capecitabine + Cetuximab in 1st-line mCRC Elderly > 70y. old Capectabine 1250 mg/m² BID + Cetuximab 400mg/m² loading Then 250 mg/m² weekly n=27 Capectabine 1000 mg/m² BID + Cetuximab 400mg/m² loading Then 250 mg/m² weekly n=39 Metastatic CRC (n=66) This was a first-line, single-arm phase 2 study prospectively evaluating the relationship between KRAS status and response to combination therapy with panitumumab and FOLFIRI. Eligible patients received panitumumab (6 mg/kg; intravenous infusion [IV]) on day 1 of a 14-day cycle with the initial dose administered over 60 minutes ± 15 minutes prior to chemotherapy. If the first dose was well tolerated subsequent infusions were given over 30 minutes ± 10 minutes prior to chemotherapy. No panitumumab-specific pre-medication was given before administration. Treatment was to be given until progression or unacceptable toxicity. Study objectives also included the evaluation of patient reported outcomes, healthcare resource utilisation and any integument and eye toxicity management scheme. Secondary endpoints also included disease control rate, duration of response, time to response, time to progression, duration of stable disease, and time to treatment failure All analyses were descriptive Kras status evaluated retrospectively in 58 pts Sastre J et al. The Oncologist 2012;17:339-345

Capecitabine + Cetuximab in Elderly PFS and OS according to KRAS status. Progression-free survival (PFS) time according to KRAS status by the Kaplan–Meier method. Sastre J et al. The Oncologist 2012;17:339-345 ©2012 by AlphaMed Press

Anti-EGFR antibodies: impact on PFS in combined with oxaliplatin-based CT HR (95% CI) Oxaliplatin + infusional fluorouracil 0.57 (0.380.86) 179 OPUS1 - FOLFOX ± cetuximab 0.80 (0.670.95) 656 PRIME2 - FOLFOX ± panitumumab 0.77 (0.591.01) 244 COIN3 - mFOLFOX# ± cetuximab Other oxaliplatin-based chemotherapy 1.02 (0.861.26) 485 COIN3 - XELOX  cetuximab 1.07 (0.791.45) 194 NORDIC VII4 - FLOX  cetuximab FUTURE5 FOLFOX CTX vs. UFOX-CTX * 96 0.72 (0.44-1.18) 0.10 1.00 2.00 Favours targeted agent *Favors FOLFOX Hazard Ratio Favours chemotherapy alone 1. Bokemeyer C, et al. Ann Oncol 2011; 22:1535-46; 2. Douillard JY, et al. J Clin Oncol 2011; 29(Suppl):3510; 3. Maughan TS, et al. Lancet 2011; 377:2103-14; 4. Tveit K, et al. Ann Oncol 2010; 21(S8): LBA 20.; 5 Douillard JY et al WCGIC 2012 Abst O-0017

Chemotherapy backbone in combination with anti EGFR antibodies Cetuximab and Panitumumab Anti EGFR antibodies have activity when combined with chemotherapy in Wild-type mCRC Constant benefit has been demonstrated with both Cetuximab and Panitumumab in 1st and 2nd lines with infusional 5FU/LV based regimen (Folfox and Folfiri) in Kras Wild-type Use of anti-EGFR antibodies have constantly failed to improve outcome in combination with oral fluoropyrimidine Capecitabine in Wild-type Kras, similar outcome was reported independent of Kras status. In combination with bolus 5FU/LV, no benefit was obtained in Kras Wild-type and more surprisingly a beneficial trend was seen in Kras mutant!

Chemotherapy backbone in combination with anti EGFR antibodies Cetuximab and Panitumumab Based on present data, Cetuximab and Panitumumab should only be combined to infusional 5FU regimen-containing chemotherapy in Kras Wild-type Bolus 5FU/LV and Capecitabine-based regimen in combination with Oxaliplatin or Irinotecan ( FLOX, Xelox, Capox, Xeliri, Capiri) should not be used. Bevacizumab and Anti-EGFR should not be combined together with chemotherapy.