6061 Stable early onset colorectal cancer: are we in front of a different group in colorectal cancer?

Abstract

Pazopanib (Votrient, GSK) is an indazolylpyrimidine second-generation adenosine triphosphate–competitive inhibitor of human vascular endothelial growth factor receptors (VEGFRs), pleteled derived growth factor receptors (PDGFRs), and KIT in the range of IC50 10–84 nM. Lower activity was detected against FGFR1, FGFR3, and CSF1R, followed by FGFR4, AURKA, RAF, MLK1, PTKS, and TAOK3 kinases, shown at about 10-fold and over the concentration inhibiting VEGFR2, against which the molecule was optimized. The Food and Drug Administration (FDA) granted approval in 2009 for the treatment of patients with advanced renal cell carcinoma (RCC). In 2012, the indication was extended to patients with advanced soft tissue sarcoma (STS) who had received prior chemotherapy. In 2010, the European Medicines Agency (EMA) granted conditional approval of pazopanib as first-line treatment monotherapy, or following cytokine therapy for advanced RCC. The initial safety profile of pazopanib in monotherapy was based on 977 oncologic patients, including 586 with RCC; a detailed profile was depicted in 435 RCC patients (290 exposed to 800 mg/d), which was characterized by diarrhea, hypertension, hair depigmentation, nausea, anorexia, and vomiting. The corresponding profile in STS included fatigue, diarrhea, nausea, weight loss, hypertension, decreased appetite, hair depigmentation, vomiting, tumor pain, dysgeusia, cephalea, musculoskeletal pain, myalgia, gastrointestinal pain, and dyspnea. Events of major relevance were hepatotoxicity, for which a black box warning was issued since first approval, cardiotoxicity signs, hemorrhage, arterial/venous thromboembolic event, thrombotic microangiopathy, gastrointestinal perforation/fistula, infection, impaired wound healing, and proteinuria. In the limited pediatric experience, the safety profile appears similar to adult STS patients, with the exception of growth plate abnormalities in the pediatric profile, a rare but relevant adverse event.