AG-013736, a multi-target tyrosine kinase receptor inhibitor, demonstrates anti-tumor activity in a Phase 2 study of cytokine-refractory, metastatic renal cell cancer (RCC)

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Abstract
4509 Background: Clear cell renal carcinoma (RCC) is characterized by inactivation of the von Hippel-Lindau tumor suppressor gene, which leads to overexpression of hypoxia-regulated genes including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). AG-013736 is an oral small molecule with potent inhibitory effects against the VEGF receptors 1 and 2 and PDGF-β receptor. A phase 2 trial was conducted to assess the safety and efficacy of AG-013736 in cytokine-refractory RCC. Methods: Patients (pts) with metastatic RCC were treated with repeat 4-week cycles of AG-013736 at 5 mg twice daily. Eligibility included measurable disease, ECOG performance status (PS) of 0 or 1 and failure of one prior cytokine-based therapy. A Simon 2 stage minimax design was used (α=0.05; β=0.2; null response rate (RR)=5%; alternative RR=15%). Results: The median age of 52 enrolled pts was 58.5 (35–85) years, 40 (77%) were men, 49 (94%) had prior nephrectomy and 31 (60%) had PS 0. Best response as assessed by RECIST criteria was PR in 21 pts. (40%) (95% confidence interval: 27.0–54.9%). With a median follow up of 1 year (235–387 days), 13 pts (25%) have progressed, 3 (6%) have discontinued for adverse events (AEs) and 36 (69%) remain on study with response or stable disease. Median time to progression has not been reached, and only 1 patient with PR has relapsed (after 232 days of therapy). Drug-related hypertension (htn), controlled by standard therapy, was observed in 17 pts (33%), and 1 pt was discontinued for worsening htn. Other related AEs were mostly grade 1/2 events including fatigue (29%), nausea (29%), diarrhea (27%), hoarseness (19%), anorexia (17%) and weight loss (15%). Grade 3/4 AEs related to AG-013736 in >1 pt. include htn (12%), aggravated htn (6%), diarrhea (6%), fatigue (6%), blister (4%) and limb pain (4%). There were no cases of neutropenia or thrombocytopenia above grade 1. Conclusions: AG-013736 has a substantial objective response rate in cytokine-refractory, metastatic RCC. Therapy was well tolerated with manageable toxicity. Additional investigation of AG-013736 in multiple solid tumor settings is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer

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