O3-11-1 - Phase II study of pazopanib as second-line treatment after sunitinib in patients with metastatic renal cell carcinoma

Abstract

Background: The multicentre, single arm, phase 2 study was aimed to assess the efficacy and safety of pazopanib as second line treatment after failure of sunitinib in patients with metastatic renal cell carcinoma (mRCC) and explore biomarkers for pazopanib response. Methods: Patients received pazopanib 800 mg per day. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), overall survival (OS) and safety. Serum protein levels of delta like ligand (DLL4), Notch1, hypoxia inducible factor factor 1A (HIF1A), HIF2A, vascular endothelial growth factor A (VEGFA) and platelet derived growth factor receptor B (PDGFRB) were measured using enzyme linked immunosorbent assay (ELISA). Results: 86 patients with clear cell mRCC were enrolled from December 2009 to March 2012 from three centres in Southern China. Of 85 evaluable patients, the median PFS was 5.6 months (95% confidence interval (CI), 4.1 to 6.7 months) by independent review. No complete response (CR) was observed in all patients. 13 patients achieved partial responses (PR) (ORR 15.3%; 95% CI, 11.2 to 23.9%). Median OS was 18.1 months (95% CI, 13.2 to 19.8 months). The most common adverse events (AEs) were mild to moderate and clinically manageable, including hypertension (37.6%), diarrhea (36.5%), increased AST (51.8%), and anaemia (60%). AEs resulted in dose reduction in 24.7% of patients. Multivariable analysis showed that higher baseline levels of DLL4 and VEGFA and lower baseline level of HIF2A were associated with shorter PFS; only lower baseline level of HIF2A was correlated with shorter OS. The lower expression level of DLL4 after pazopanib treatment was associated with higher response rate probability. Conclusion: Pazopanib was clinically active and well tolerated as second-line treatment after sunitinib in mRCC patients. DLL4, VEGFA and HIF2A may be potential biomarkers of clinical efficacy in this setting (NCT:02324803).