title: Phase II study of pazopanib as second-line treatment after sunitinib in patients with metastatic renal cell carcinoma: a Southern China Urology Cancer Consortium Trial.
abstract: This multicentre, single arm, phase II 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. Patients received pazopanib 800mgperday. The primary end-point was progression-free survival (PFS). Secondary end-points included objective response rate (ORR), overall survival (OS) and safety. Serum proteins (Delta-like ligand (DLL4), Notch1, hypoxia inducible factor-1α (HIF-1α), HIF-2α, vascular endothelial growth factor A (VEGFA) and platelet-derived growth factor receptor β (PDGFRB)) levels were measured using enzyme-linked immunosorbent assay (ELISA). 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 5.6months (95% confidence interval (CI), 4.1-6.7months) by independent review. No complete response (CR) was observed in all patients. 13 (15.3%; 95% confidence interval [CI], 11.2-23.9%) patients achieved partial responses (PR) (ORR 15.3%). Median OS was 18.1months (95% CI, 13.2-19.8months). The most common adverse events (AEs) were mild to moderate and clinically manageable, including hypertension (37.6%), diarrhoea (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 HIF-2α were associated with shorter PFS; only lower baseline level of HIF-2α was correlated with shorter OS. The lower expression level of DLL4 after pazopanib treatment was associated with higher response rate probability. In conclusion, pazopanib was clinically active and well tolerated as second-line treatment after sunitinib in mRCC patients. Baseline levels of serum DLL4, VEGFA and HIF-2α may have potential utility as biomarkers of clinical efficacy in this setting (chiCTR-TRC-13004016).
authors.affiliation: Laboratory of translational research, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. Electronic address: mianxie@gird.cn.
authors.forename: Mian
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Urology, Guangdong General Hospital, Guangzhou, China.
authors.forename: Chao Sheng
authors.initials: CS
authors.lastname: He
authors.affiliation: Department of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Jin Kun
authors.initials: JK
authors.lastname: Huang
authors.affiliation: Department of Urology, Traditional Chinese Medical Hospital of Guangdong Province, Guangzhou, China.
authors.forename: Qi Zhan
authors.initials: QZ
authors.lastname: Lin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D051792:Basic Helix-Loop-Helix Proteins / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood; D002135:Calcium-Binding Proteins; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D002681:China; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007191:Indazoles; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D012307:Risk Factors; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D000077210:Sunitinib; D013997:Time Factors; D017211:Treatment Failure; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D007191:Indazoles; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C424126:DLL4 protein, human; C467484:VEGFA protein, human; C516667:pazopanib
keywords: Delta-like ligand 4; Hypoxia-inducible factor; Metastatic renal cell carcinoma; Pazopanib; Phase II