Background. Imatinib mesylate, a potent inhibitor of the KIT and PDGFR tyrosine kinases, is highly effective in the treatment of advanced gastrointestinal stromal tumors (GISTs). However, most imatinib-treated tumors eventually become resistant, accounting foramedianprogression-freesurvivalof19–23months.Expression of vascular endothelial growth factor (VEGF) correlates with poor prognosis in GIST; bevacizumab, a monoclonal antibody against VEGF, is effective in a variety of solid tumors. We postulated combination therapy with imatinib plus bevacizumab would benefit patients with advanced GIST, particularly those reliant on VEGFA-dependent angiogenesis. Methods. PatientswithmetastaticorsurgicallyunresectableGIST were eligible for this phase III open-label clinical trial, S0502. At registration, patients were randomly assigned to either imatinib 400mg(standard)or 800mg(patientswith exon 9 KITmutations), or imatinib plus bevacizumab, 7.5 mg/kg i.v. every 3 weeks. Patients were treated to progression, symptomatic deterioration, unacceptable toxicity, treatment delay greater than 4 weeks, or patient choice towithdraw fromthe study.The primary objective was to determine whether the addition of bevacizumab to imatinib would improve progression-free survival (PFS) in first-line treatment of incurable GIST. Results. S0502 opened on April 15, 2008. As of fall 2009, only 12 patients from at least 178 eligible SWOG centers plus those participating through Cancer Trials Support Unit had been entered in the study. Despite an aggressive promotion scheme involving the other cooperative groups and a major GIST patient advocacy group, accrual remained slow. The trial was closed on October 1, 2009, having accrued only 2% of the 572 patients planned. No scientific conclusionswere forthcoming because of the small number of patients entered in the study. Two patients of the 6 in the combination arm reported grade 3 toxicities, 1 with proteinuria and 1 with fatigue, upper gastrointestinal hemorrhage, and anemia. Conclusion. No conclusions may be drawn from this trial and, thus, the combination of imatinib plus bevacizumab cannot be recommended for use.
ASJC Scopus subject areas
- Cancer Research