mFOLFOX-bevacizumab or XELOX-bevacizumab then bevacizumab alone or with erlotinib in 1st line treatment of patients with metastatic colorectal cancer : Interim safety analysis of DREAM study. C. Tournigand1, B. Samson2, W. Scheithauer3, C. Louvet1, T. Andre4, G. Lledo5, J. Latreille2, F. Viret6, B. Chibaudel7, A. de Gramont1; 1Hopital Saint Antoine, Paris, France; 2Hopital Charles Lemoyne, Greenfield Park, QC, Canada; 3University of Vienna, Vienna, Austria; 4Hopital Pitié-Salpetrière, Paris, France; 5Hopital Privé Jean Mermoz, Lyon, France; 6Institut Paoli Calmette, Marseille, France; 7Gercor, Paris, France

ABSTRACT Background : Anti-VEGF or EGFR inhibitors demonstrated clinical activity in combination with chemotherapy (CT) in mCRC. The DREAM trial compares, after an induction CT of 6 cy of FOLFOX-Bev or XELOX-Bev, a maintenance with Bev +/- Erlotinib. We report here a pre-planned safety analysis of induction (I) and maintenance (M) phase for the first 200 patients. Methods : Patients (pts) with untreated mCRC were randomly assigned to 2 arms (I): mFOLFOX+Bev (n=100), or mXELOX+Bev (n=100). mFOLFOX-Bev: LV 400 mg/m², Oxaliplatin (ox) 100 mg/m², B 5 mg/kg d1, 5FU ci 2.4g/m² 46h, q2w, mXELOX-Bev: Ox 100 mg/m² d1, capecitabine 2.5 g/m² d1-7, Bev 5mg/kg, q2w. To date, 117 pts with a disease control after 6 cy have had a 2nd randomisation (M): Bev alone (7.5 mg/kg q3w, n=56) or Bev+Erlotinib 150 mg/d (n=61) until PD. Results : Pts characteristics were: sex: 124M/76F, median age: 62.4 years (26-80), primary tumors: colon 152, rectum 53, synchronous metastases: 150 pts, > 1 metastase site: 115, PS 0/1: 134/66, Alk. Ph.>UNL: 87 pts, and LDH>UNL: 88pts. For I, 92 pts in mFOLFOX-Bev and 93 in XELOX-Bev were evaluable for toxicity (tox). Tox (%) for mFOLFOX-Bev/XELOX-Bev were: any toxicity grade (gr) 3 or 4: 21/30; neutropenia gr 3 6/1, gr 4 0/2; febrile neutropenia gr 3 1/1, gr 4 0/1; thrombopenia gr 3 0/1, gr 4 0/2; anemia gr 2 8/15, gr 3 2/1; nausea gr 2 17/15, gr 3 4/6; vomiting gr 2 10/12, gr 3 2/5; mucositis gr 2 6/6, gr 3 0/4; diarrhea gr 2 8/12, gr 3 5/20, gr 4 0/1; neuropathy gr 2 23/17 gr 3 3/1; HFS gr 2 0/7, gr 3 0/2; hypertension gr 2 2/3, gr 3 1/0; proteinuria gr 2 1/5; SAEs 14/25. For Maintenance, 56 pts in B and 61 pts in Bev+Erlotinib were evaluable. Tox (% Bev/Bev+Erlotinib) were: neutropenia gr 2 0/3; thrombopenia gr 2 2/0; nausea gr 2 2/2, gr 3 2/0; vomiting gr 3 2/0; mucositis gr 2 2/3; diarrhea gr 2 0/6, gr 3 2/6; skin tox gr 1 9/31, gr 2 0/38, gr 3 0/16, gr 4 0/2; proteinuria gr 2 5/5; hypertension gr 1 9/15, gr 2 3/8, gr 3 3/0.  Conclusion : This interim safety analysis demonstrated that induction with mFOLFOX-Bev or XELOX-Bev as well as maintenance with Bev or Bev + Erlotinib appears to be well-tolerated, without unexpected side effects. The DREAM study is ongoing, with a prolonged induction phase of 6 months (3 mo with ox then 3 mo with fluoropyrimidines-B) before randomisation for maintenance therapy.  

INTRODUCTION OPTIMOX1 and 2 studies validated the "stop and go strategy" or stopping oxaliplatin after 6 cycles in metastatic colorectal cancer. (Tournigand et al. JCO 2006, Maindrault-Goebel, ASCO 2007) Bevacizumab increases PFS in combination with first-line chemotherapy. (Saltz et al., JCO 2008) A modified XELOX regimen (7 days on, 7 days off) demonstrated a good therapeutic ratio (Scheithauer et al., JCO 2003) Erlotinib is an orally active, selective inhibitor of HER1/EGFR tyrosine-kinase. In preclinical models, administration of EGFR inhibitors in combination with antiangiogenic agents has shown additive cytotoxicity. (Ciardello et al. Clinical Cancer Res 2000, 2004)

DREAM study (Phase III) RANDOMI SAT ION RANDOMI SAT ION mFOLFOX7 + bevacizumab x6 cycles bevacizumab + erlotinib until PD PR or SD mXELOX + bevacizumab X6 cycles bevacizumab until PD N=640 INDUCTION MAINTENANCE

Erlotinib 150 mg/day, continuous CHEMOTHERAPY D1 D2 mFolfox7 LV 400 5-FU 2.4 g/m² oxali 100 bev. 5 Every 2 weeks INDUCTION D1 D7 mXELOX Capecitabine 2500 mg/m²/d oxali 100 Every 2 weeks bev. 5 erlotinib bev. 7.5 Every 3 weeks MAINTENANCE Erlotinib 150 mg/day, continuous

Inclusion criteria Histologically proven adenocarcinoma of colon or rectum. Unresectable metastatic disease, i.e. non suitable for complete carcinological surgical resection. No previous chemotherapy and/or immunotherapy for metastatic disease. In case of previous adjuvant chemotherapy, progression-free interval from end of previous adjuvant chemotherapy > 6 months (2 years if oxaliplatin or CPT11 received as adjuvant therapy) Measurable lesion or non measurable lesions Age 18 years - 80 years. WHO (ECOG) performance status 0-2 . Hematological status: Neutrophils  1,5 109/L Platelets  100 109/L Haemoglobin > 9 g/dL (may be transfused to maintain or exceed this level) International Normalized Ratio (INR)  1.5; APPT <1.5 x UNL Adequate renal function, No proteinuria at baseline. Hepatic function: Total bilirubin < 1.5 x upper normal limit (UNL), ALP :< 3 x ULN Neurologic status: no peripheral sensory neuropathy (NCI grade 0).

Patients Characteristics n=200 Sex ratio 124 M / 76 F Median Age 62.4 years (26-80yrs) WHO PS 0 vs 1 134 vs 66 pts Colon vs rectum 152 vs 53 pts Synchronous mets 150 pts >1 metastatic site 115 pts Alk Phosphatase >UNL 87 pts LDH>UNL 88 pts

INDUCTION CHEMOTHERAPY Hematologic toxicity (grade 3-4) FOLFOX-Bevacizumab N=92 % XELOX-Bevacizumab N=93 Neutropenia grade 3 grade 4 6 1 2 Thrombocytopenia Anemia grade 2 8 15 Febrile neutropenia

INDUCTION CHEMOTHERAPY Non-Hematologic toxicity FOLFOX-Bevacizumab N=92 % XELOX-Bevacizumab N=93 Nausea grade 3 grade 2 4 17 6 15 Vomiting 2 10 5 12 Mucositis Diarrhea grade 3-4 8 21 Neuropathy grade 3 grade 2 3 23 1 17 Hand-Foot syndrome 2 7

INDUCTION CHEMOTHERAPY Bevacizumab-related toxicity FOLFOX- Bevacizumab N=92 % XELOX- N=93 HTA grade 3 grade 2 1 2 3 Proteinuria 5

MAINTENANCE : toxicity Bevacizumab N=56 % Bevacizumab – Erlotinib N=61 Nausea grade 3 grade 2 2 Vomiting Mucositis 3 Diarrhea 6 Neutropenia grade 2 3 Thrombocytopenia 2

Bevacizumab – Erlotinib MAINTENANCE toxicity Bevacizumab N=56 % Bevacizumab – Erlotinib N=61 Cutaneous toxicity Grade 1 Grade 2 Grade 3 Grade 4 9 31 38 16 2 HTA Grade 1 Grade 2 Grade 3 9 3 15 8 Proteinuria 5

Conclusion Both mFOLFOX7-bevacizumab and mXELOX-bevacizumab are well tolerated as first-line therapy in metastatic colorectal cancer As expected, the main toxicity of the association of bevacizumab and erlotinib is cutaneous (18% grade 3-4) Considering the recent results of OPTIMOX2, a prolongation of the maintenance phase from 3 months to 6 months before maintenance therapy has been adopted in the study KRAS status will be available for all patients 18% verif Acknowledgement : Roche for financial support of the DREAM study

DREAM study (Phase III) FOLFIRI – bevacizumab 6 months New design REGI STRAT ION RANDOMI SAT ION mFOLFOX7 + bevacizumab X6 cycles mLV5FU2 + bevacizumab 3 months bevacizumab + erlotinib until PD Or1 CR2 or PR SD mXELOX + bevacizumab x6 cycles capecitabine + bevacizumab 3 months bevacizumab until PD Or1 FOLFIRI – bevacizumab 6 months Inclusion criteria : IP 0 – 2 Alk Ph < 5xN 1 investigator’s choice 2without surgery