Disparity in peripheral and renal B-cell depletion with rituximab in systemic lupus erythematosus: an opportunity for obinutuzumab

ObjectivesTo investigate key factors that may contribute to the variability of rituximab-mediated peripheral and renal B cell depletion (BCD) in SLE.MethodsWe analysed: (i) CD19+ B cell counts in patients with SLE before and 1, 2, 3 and 6 months after treatment with rituximab, comparing them with RA patients; (ii) the presence of B cells in renal biopsies after rituximab therapy; (iii) whether the duration of BCD correlated with patient demographics and B cell expression of CD20 and FcγRIIb; and (iv) the effect of B cell activation factor (BAFF) on the efficiency of rituximab and obinutuzumab at inducing BCD in whole blood assays, in vitro.ResultsIn SLE (n = 71), the duration of BCD was shorter compared with RA (n = 27). B cells were detectable in renal biopsy samples (n = 6) after treatment with rituximab in all patients with poor response while peripheral blood B cells remained low or undetectable in the same patients. There were no significant relationships between peripheral BCD and patient age, disease duration, serum C3 levels or the level of expression of B cell surface proteins CD20 and FcγRIIb. Obinutuzumab was more efficient than rituximab at inducing BCD in whole blood assays, regardless of excess BAFF.ConclusionsBCD in SLE is less efficient than in RA. Renal B cell presence following rituximab treatment was associated with poor outcomes. No significant relationships between any measured B cell related, clinical or laboratory parameters and the efficiency of BCD by rituximab was found. Obinutuzumab was superior to rituximab at inducing BCD

Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial

Purpose Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). Patients and Methods Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2: 1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. Results Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. Conclusion Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC. J Clin Oncol 28: 1061-1068. (C) 2010 by American Society of Clinical Oncology*US DEP HHS, 2009, CANC INC SURV EP ENDRini BI, 2008, J CLIN ONCOL, V26, P5422, DOI 10.1200/JCO.2008.16.9847Hutson T, 2008, ANN ONCOL, V19, P187Motzer RJ, 2008, LANCET, V372, P449, DOI 10.1016/S0140-6736(08)61039-9Coppin C, 2008, EXPERT REV ANTICANC, V8, P907, DOI 10.1586/14737140.8.6.907Karaman MW, 2008, NAT BIOTECHNOL, V26, P127, DOI 10.1038/nbt1358Coppin C, 2008, COCHRANE DB SYST REV, DOI 10.1002/14651858.CD006017.pub2CURADO M, 2008, CANC INCIDENCE 5 CON, V9HUTSON TE, 2008, J CLIN ONCOL, V26, pS261Pickard AS, 2007, HEALTH QUAL LIFE OUT, V5, DOI 10.1186/1477-7525-5-70Escudier B, 2007, LANCET, V370, P2103Negrier S, 2007, CANCER, V110, P2468, DOI 10.1002/cncr.23056Motzer RJ, 2007, J UROLOGY, V178, P1883, DOI 10.1016/j.juro.2007.07.030Hudes G, 2007, NEW ENGL J MED, V356, P2271Nelson EC, 2007, CANCER TREAT REV, V33, P299, DOI 10.1016/j.ctrv.2006.12.005Motzer RJ, 2007, NEW ENGL J MED, V356, P115Escudier B, 2007, NEW ENGL J MED, V356, P125van Spronsen DJ, 2005, ANTI-CANCER DRUG, V16, P709Hurwitz H, 2005, J CLIN ONCOL, V23, p195SRabin R, 2001, ANN MED, V33, P337Therasse P, 2000, J NATL CANCER I, V92, P205Motzer RJ, 1999, J CLIN ONCOL, V17, P2530DIAZ JI, 1999, CANC CONTROL, V6, P571Osoba D, 1998, J CLIN ONCOL, V16, P139AARONSON NK, 1993, J NATL CANCER I, V85, P365*NAT CANC I CANC T, COMM TERM CRIT ADV E20