Efficacy and safety of bevacizumab combined with capecitabine in progressive, metastatic well-differentiated digestive endocrine tumors (BETTER study).

Abstract

4071 Background: Neuroendocrine digestive tumors are highly vascularized neoplasms known to express the vascular endothelial growth factor (VEGF). We assessed the activity of bevacizumab (Bv), a monoclonal antibody directed against VEGF combined with capecitabine (CAP). Methods: In this multicenter, open-label, non-randomized, two-group phase II trial, one group assessed Bv (7.5 mg/m² on d1/3 weeks) combined with CAP (1,000 mg/m2 twice daily, orally d1-14, resumed on day 22). Eligible patients (pts) had progressive, metastatic well-differentiateddigestive tract endocrine tumors (WHO 2000 classification), ECOG-PS ≤2, Ki 67 index < 15%, no prior systemic chemotherapy and acceptable organ functions. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival, response rate, safety and quality of life. Pts were treated for a minimum of 6 months and study duration was 24 months. Results: From Jun 2007 to Oct 2009, 49 pts were enrolled, 26 (53.1%) were men; median age 60.3 years (41.2-82.3); ECOG-PS was 0/1 in 46 (93.9%) pts. Primary tumor site was: small intestine 40 (81.6%) pts, caecum 3 (6.1%), rectum 4 (8.2%) and stomach 2 (4.1%). Ki-67 proliferative index was 0-2% in 17 (35.4%) pts, 3-4% in 14 (29.2%), 5-9% in 13 (27.1%), 10-14% in 4 (8.3%) Metastatic sites were liver: 46 (93.9%) pts, lymph nodes: 24 (49.0%), peritoneum 23 (46.9%). Median treatment duration was 13.8 months; median number of cycles was 19. At 24 months, median PFS was 23.4 months [95%CI: 13.2; not reached] based on 26 events. PFS rate at 18 months was 55%. Tumor control rate was 87.8% (n=43) including partial response in 9 (18.4%) pts and stable disease in 34 (69.4%) pts. Survival rate at 24 months was 85%, median overall survival was not reached, 8 patients died. CTC grade 3/4 Adverse Events (AEs) occurred in 41 (83.7%) pts, mainly digestive 14 (28.6%) pts. Main G3/4 Bv targeted AE was hypertension in 15 (30.6%) pts. Conclusions: In this chemotherapy resistant tumor, the combination of capecitabine and bevacizumab, assessed in a phase II study, shows such encouraging results that this combination may become a reference in the medical treatment of ileal NET.