Correlation of PD-L1 tumor expression and treatment outcomes in patients with renal cell carcinoma receiving sunitinib or pazopanib : results from COMPARZ, a randomized controlled trial

Purpose: The interaction of programmed death-1 ligand (PDL1) with its receptor (PD-1) on T cells inactivates antitumor immune responses. PD-L1 expression has been associated with poor outcomes in renal cell carcinoma (RCC) but has not been investigated in advanced RCC patients receiving VEGF-targeted therapy. Experimental Design: Formalin-fixed paraffin-embedded specimens were collected at baseline from patients in the COMPARZ trial. Tumor cell PD-L1 expression by IHC was evaluated using Hscore (HS). Dual PD-L1/CD68 staining was used to differentiate PD-L1 tumor expression from tumor-associated macrophages. Intratumor CD8-positive T cells were quantified morphometrically. Associations between biomarkers and survival were investigated using the log-rank test. Results: HS data were available from 453 of 1,110 patients. Sixty-four percent of patients had negative PD-L1 expression (HS = 0). Patients with HS > 55 (n = 59, 13%) had significantly shorter overall survival (OS) than those with HS ≤ 55 in both pazopanib and sunitinib arms (median 15.1 vs. 35.6 and 15.3 vs. 27.8 months, respectively, P = 0.03). In both arms, median OS was shortest in patients with HS > 55 and intratumor CD8- positive T-cell counts > 300 (9.6 and 11.9 months with pazopanib and sunitinib, respectively). Median OS in patients with HS ≤ 55 and CD8-positive T-cell counts ≤ 300 was 36.8 and 28.0 months with pazopanib and sunitinib, respectively. Progression-free survival results were similar to OS results. Conclusions: Increased tumor cell PD-L1, or PD-L1 plus tumor CD8-positive T-cell counts, were associated with shorter survival in patients with metastatic RCC receiving VEGF-targeted agents. These findings may have implications for future design of randomized clinical trials in advanced RCC

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

Pazopanib efficacy in renal cell carcinoma: evidence for predictive genetic markers in angiogenesis-related and exposure-related genes.

PURPOSE: Pazopanib, an oral angiogenesis inhibitor, is approved for the treatment of advanced renal cell carcinoma (RCC). Response to pazopanib monotherapy varies between patients, and no validated biomarkers predictive of treatment outcome have been identified. We tested the hypothesis that this variability is partially dependent on germline genetic variants that may affect pazopanib exposure or angiogenesis pathways. PATIENTS AND METHODS: Twenty-seven functional polymorphisms within 13 genes were evaluated in 397 patients with RCC. Genetic association with progression-free survival (PFS) and objective response rate (RR) was analyzed using the Cox proportional hazards model and proportional odds model, respectively. RESULTS: Three polymorphisms in IL8 and HIF1A and five polymorphisms in HIF1A, NR1I2, and VEGFA showed nominally significant association (P ≤ .05) with PFS and RR, respectively. Compared with the wild-type AA genotype (median PFS, 48 weeks), the IL8 2767TT variant genotype showed inferior PFS (27 weeks, P = .009). The HIF1A 1790AG genotype was associated with inferior PFS and reduced RR, compared with the wild-type GG genotype (median PFS, 20 v 44 weeks; P = .03; RR, 30% v 43%, P = .02). Reductions in RR were detected for the NR1I2 -25385TT genotype, compared with the wild-type CC genotype (37% v 50%, P = .03), and for the VEGFA -1498CC genotype compared with the TT genotypes (33% v 51%). CONCLUSION: Germline variants in angiogenesis- and exposure-related genes may predict treatment response to pazopanib monotherapy in patients with RCC. If validated, these markers may explain why certain patients fail antiangiogenesis therapy and they may support the use of alternative strategies to circumvent this issue

Pazopanib versus sunitinib in metastatic renal-cell carcinoma

BACKGROUND Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy. METHODS We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life. RESULTS Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22), meeting the predefined noninferiority margin (upper bound of the 95% confidence interval, &lt;1.25). Overall survival was similar (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs. 55%), the hand-foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60%, vs. 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P&lt;0.05 for all 11 comparisons). CONCLUSIONS Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000323349300009&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Medicine, General &amp; InternalSCI(E)297ARTICLE8722-73136