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. Tournigand 1 , B. Samson 2 , W. Scheithauer 3 , C. Louvet 1 , T. Andre 4 , G. Lledo 5 , J. Latreille 2 , F. Viret 6 , B. Chibaudel 7 , A. de Gramont 1 ; 1 Hopital Saint Antoine, Paris, France; 2 Hopital Charles Lemoyne, Greenfield Park, QC, Canada; 3 University of Vienna, Vienna, Austria; 4 Hopital Pitié-Salpetrière, Paris, France; 5 Hopital Privé Jean Mermoz, Lyon, France; 6 Institut Paoli Calmette, Marseille, France; 7 Gercor, Paris, France
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MFOLFOX-bevacizumab or XELOX- bevacizumab then bevacizumab alone or with erlotinib in 1st line treatment of patients with metastatic colorectal cancer.
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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.
INTRODUCTIONOPTIMOX1 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)
Inclusion criteriaHistologically 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).
Acknowledgement : Roche for financial support of the DREAM study
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