91IN - Successful Targeting of VEGFR in Soft Tissue Sarcomas

Abstract

ABSTRACT Successful targeting of VEGFR in soft tissue sarcomas Increasing evidence suggests that angiogenesis plays an important role in the biology of the heterogeneous group of soft tissue sarcomas (STS). During the last years clinical studies have shown the importance of targeting angiogenesis in STS. Most attention has been paid to pazopanib, a tyrosine kinase inhibitor, known for its activity in renal cell cancer. Pazopanib targets multiple kinases, including vascular endothelial growth factors (VEGFR1-3), and platelet derived growth factors. In a previous phase 2 study in relapsed or metastatic STS (EORTC study 62043) the progression free rate at 12 weeks was promising in the strata of leiomyosarcoma, synovial sarcoma, and other types of STS, but was disappointing in liposarcoma patients. In the subsequent phase 3 study which consisted of 372 metastatic STS patients, pazopanib was compared with placebo in a 2:1 fashion in patients with progressive non-adipocytic STS, who had had anthracyclines and all locally available systemic treatment options. The results of this so-called PALETTE trial (EORTC study 62072), which allowed no crossover, showed a statistically significant improvement in PFS of 3 months: 4.6 months with pazopanib compared to 1.6 month with placebo. The final overall survival did not show a significant improvement, being 12.5 months with pazopanib and 10.7 months with placebo. Pazopanib was generally well tolerated. Most common adverse events were fatigue, diarrhea, nausea, weight loss and hypertension. The effect of pazopanib was observed in all subgroups of STS, which suggests a universal important role of VEGFR, but whether this is the driving force in the pathogenesis of all STS is unknown. Based on the positive results of the PALETTE study pazopanib has recently been approved by FDA and EMA for the treatment of patients with advanced STS who have received prior chemotherapy. GIST and liposarcoma were not part of this registration. Apart from VEGFR also VEGF has been the target of a couple of clinical studies in STS, either as single agent or as combination therapy. With the success of pazopanib in STS the pathogenic role of the VEGF-VEGFR pathway in STS becomes even more of interest than has been before and the challenge will be to further explore the success of targeting this pathway in future clinical studies. Disclosure The author has declared no conflicts of interest.