RESUMEN
BACKGROUND: In a phase 3, randomized, open-label trial (Pazopanib versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma, COMPARZ; NCT00720941), pazopanib was found to be noninferior to sunitinib in terms of progression-free survival in patients with metastatic renal cell carcinoma with no prior therapy. Overall treatment differences were evaluated in a post hoc analysis with a quality-adjusted time without symptoms or toxicity (Q-TWiST) methodology. METHODS: Each patient's overall survival was partitioned into 3 mutually exclusive health states: time with grade 3 or 4 toxicity (TOX), time without symptoms of disease or grade 3/4 toxicity of treatment, and time after tumor progression or relapse (REL). The time spent in each state was weighted by a health-state utility associated with that state and summed to calculate the Q-TWiST. A threshold utility analysis was used, and utilities were applied across the range of 0 (similar to death) to 1 (perfect health). RESULTS: A total of 1110 patients were enrolled (557 on pazopanib and 553 on sunitinib). The mean TOX was 31 days (95% confidence interval, 13-48 days) longer for sunitinib versus pazopanib. In the threshold utility analysis, the difference in the Q-TWiST ranged from -11 days (utility for TOX, 1; utility for REL, 0) to 43 days (utility for TOX, 0; utility for REL, 1) in favor of pazopanib across most utility combinations. Differences were significant in less than half of the utility combinations examined, and this typically occurred when the utility for TOX was lower than the utility for REL. CONCLUSIONS: Patients randomized to pazopanib had a slightly longer Q-TWiST in comparison with sunitinib patients, and this was primarily due to the reduced length of TOX.
Asunto(s)
Inhibidores de la Angiogénesis/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Pirimidinas/efectos adversos , Pirroles/efectos adversos , Calidad de Vida , Sulfonamidas/efectos adversos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Carcinoma de Células Renales/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Indazoles , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Sunitinib , Adulto JovenRESUMEN
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, <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<0.05 for all 11 comparisons). CONCLUSIONS: Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib. (Funded by GlaxoSmithKline Pharmaceuticals; COMPARZ ClinicalTrials.gov number, NCT00720941.).
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Inhibidores de la Angiogénesis/efectos adversos , Carcinoma de Células Renales/secundario , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Humanos , Indazoles , Indoles/efectos adversos , Estimación de Kaplan-Meier , Neoplasias Renales/patología , Masculino , Pirimidinas/efectos adversos , Pirroles/efectos adversos , Calidad de Vida , Sulfonamidas/efectos adversos , SunitinibRESUMEN
OBJECTIVES: Evaluation of the safety and efficacy of pazopanib, a multikinase angiogenesis inhibitor, in a single-arm, open-label, extension study (VEG107769/NCT00387764) for placebo-treated patients with advanced renal cell carcinoma (RCC) from a randomized, double-blind, placebo-controlled phase III study (VEG105192/NCT00334282). METHODS: Patients received pazopanib 800 mg/day. The primary endpoint was the safety and tolerability of pazopanib treatment. Secondary endpoints included response rate per Response Evaluation Criteria in Solid Tumors, progression-free survival (PFS), and overall survival (OS). RESULTS: Seventy-nine placebo-treated patients from VEG105192/NCT00334282 who experienced disease progression and one pazopanib-treated patient (an exemption) were enrolled. Forty-one patients (51%) were treatment-naive; 39 (49%) were cytokine-pretreated. Median exposure to pazopanib was 9.7 months. All patients had discontinued pazopanib at the time of analysis. The most common reason for discontinuation was disease progression (61%). The most common adverse events were hypertension (45%), diarrhea (45%), hair color changes (44%), anorexia (30%), and nausea (25%). The response rate was 37.5% [95% confidence interval (CI): 26.9-48.1]; median PFS was 9.2 months (95% CI: 7.3-12.0); median OS was 23.5 months (95% CI: 16.3-28.0). CONCLUSIONS: Efficacy and safety profiles for pazopanib in this extension study of patients with RCC previously treated with placebo were very similar to those observed for pazopanib-treated patients in the pivotal phase III study.
Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Anorexia/inducido químicamente , Carcinoma de Células Renales/patología , Diarrea/inducido químicamente , Supervivencia sin Enfermedad , Femenino , Color del Cabello/efectos de los fármacos , Humanos , Hipertensión/inducido químicamente , Indazoles , Estimación de Kaplan-Meier , Neoplasias Renales/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Estadificación de Neoplasias , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la Enfermedad , Resultado del TratamientoAsunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Sulfonamidas/uso terapéutico , Carcinoma de Células Renales/mortalidad , Supervivencia sin Enfermedad , Estudios de Seguimiento , Humanos , Indazoles , Estimación de Kaplan-Meier , Neoplasias Renales/mortalidad , SunitinibAsunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Sulfonamidas/uso terapéutico , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Pazopanib was noninferior to sunitinib in progression-free survival in a phase III, open-label, randomized clinical trial comparing the efficacy and safety of the 2 drugs for treatment of patients with advanced renal cell carcinoma (RCC). A secondary analysis of this trial conducted on patient-reported health care resource utilization (HCRU) endpoints revealed significantly fewer monthly telephone consultations and emergency department visits among patients treated with pazopanib over the first 6 months of treatment. OBJECTIVES: To (a) compare total costs of HCRU and adverse events (AEs) in patients with advanced RCC receiving first-line pazopanib or sunitinib from the phase III clinical trial and (b) perform a post hoc economic analysis that applied direct medical care and pharmacy unit costs, obtained from the Truven Health MarketScan Databases, to HCRU and AE rates. METHODS: Total HCRU costs included components for provider contacts, diagnostics, hospitalizations, procedures, and study/nonstudy drugs. Patients were stratified by the presence or absence of an AE in order to estimate costs attributable to AEs. Costs were adjusted to 2013 U.S. dollars. The highest 1% of cost outliers were equally excluded from each group. Univariate (t-test and Kaplan-Meier sample average [KMSA]) and multivariate (using treatment group and region as covariates) analyses were performed. RESULTS: A total of 906 patients (pazopanib, n = 454; sunitinib, n = 452) reported HCRU; higher rates were observed for sunitinib. In unadjusted cost analyses, the mean total costs for pazopanib-treated patients were 8.0% lower than those treated with sunitinib ($80,464 vs. $86,886; P = 0.20). The difference in KMSA-estimated costs was significantly higher for sunitinib versus pazopanib ($156,128 vs. $143,585; P = 0.003). Adjusted cost differences between arms consistently suggested higher costs for sunitinib. Among patients who experienced greater than or equal to 1 AE, costs were $8,118 higher for pazopanib-treated patients and $14,343 for sunitinib-treated patients. CONCLUSIONS: The findings suggest that health care costs were lower among patients with advanced RCC treated first-line with pazopanib versus sunitinib.
Asunto(s)
Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/economía , Costos de la Atención en Salud , Indoles/economía , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/economía , Pirimidinas/economía , Pirroles/economía , Sulfonamidas/economía , Femenino , Servicios de Salud/estadística & datos numéricos , Humanos , Indazoles , Indoles/efectos adversos , Indoles/uso terapéutico , Masculino , Persona de Mediana Edad , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Pirroles/efectos adversos , Pirroles/uso terapéutico , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéutico , Sunitinib , Estados UnidosRESUMEN
PURPOSE: The interaction of programmed death-1 ligand (PD-L1) 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 H-score (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.