A prespecified analysis of trial subgroups demonstrated that improvement of PFS was impartial of age, performance status, gender, and MSKCC risk group

A prespecified analysis of trial subgroups demonstrated that improvement of PFS was impartial of age, performance status, gender, and MSKCC risk group. six new brokers have been approved in the US for the treatment of advanced RCC. Three are multi-targeted tyrosine kinase inhibitors (TKI) including sunitinib, sorafenib, and pazopanib, two target the mammalian target of rapamycin (temsirolimus and everolimus), and one is a humanized monoclonal antibody (bevacizumab in combination with interferon-). CC2D1B The current review focuses on the TAPI-1 newest TKI available to treat patients with metastatic RCC, pazopanib. The development of this agent both preclinically and clinically is usually reviewed. The efficacy and safety data from the pivotal TAPI-1 clinical trials are discussed, and the potential role of pazopanib in the treatment of patients with metastatic RCC in comparison to other treatment alternatives is usually critically appraised. This agent has a favorable overall risk benefit, and the available data demonstrate efficacy in patients with metastatic RCC who are either treatment-na?ve or cytokine refractory. It therefore represents another alternative for treatment of metastatic RCC patients. 0.0000001). This difference was more pronounced in treatment-na?ve patients (11.1 months vs 2.8 months, HR: 0.40, 0.0000001) than in the cytokine refractory group (7.4 months vs 4.2 months, HR: 0.54, 0.001). A prespecified analysis of trial subgroups exhibited that improvement of PFS was impartial of age, performance status, gender, and MSKCC risk group. The data for the various MSKCC risk groups are not yet available. ORR was higher in all patients receiving pazopanib compared with the control group (30% vs 3%). In treatment-na?ve subjects, the ORR was 32% vs 4% for the placebo group. The median response duration was 59 weeks. Selected efficacy data reported in various first-line Phase II/III trials of VEGF/VEGFR inhibitors in metastatic RCC patients (excluding the temsirolimus trial) are summarized in Table 2 (PFS), and Table 3 (OS). The ORR in treatment- na?ve patients varies between 5.2% and 47% depending upon the trial, agent utilized, and type of analysis (independent vs investigator). The most active agent appears to be sunitinib, with an ORR of 37% (47% investigator assessment).15,34 The ORR observed with pazopanib appears similar (32% vs 37%). Responses appear to be durable with all brokers, with median response durations between 11.0 months and 14.0 months. Table 2 Progression free survival in frontline metastatic renal cell cancer randomized trials value 0.001 0.0001 0.0001 0.00010.5040.532 Open in a separate window Abbreviation: INF-, interferon-alpha. Table 3 Overall survival in randomized trials: frontline metastatic renal cell cancer patients value0.0510.12910.069NA0.224Hazard ratio (95% CI)0.821 (0.673, 1.001)0.91 (0.76, 1.10)0.86 (0.73, 1.01)NA0.91 (0.71, 1.16) Open in a separate window Abbreviations: CI, confidence interval; INF-, interferon-alpha; mos, months. An interim survival analysis in the pazopanib Phase III trial initially reported a median OS of 21.1 months for pazopanib vs 18.7 months for the placebo patient group (HR: 0.73, one-sided = 0.02).17 Final OS data are available, and revealed a median OS of 22.9 months for the pazopanib vs 20.5 months in the placebo cohort (HR: 0.91, 95% CI: 0.71C 1.16, stratified log rank = 0.224).29 A high rate of secondary therapy in placebo patients compared with those randomized to pazopanib was reported (66% vs 30%), with 54% of the placebo group ultimately receiving pazopanib.29 In an inverse probability censoring weighted analysis which adjusts for the activity of pazopanib vs placebo, pazopanib therapy was associated with a 50% reduction in the risk of death. Direct comparisons between the various trial results are not possible TAPI-1 in view of the different trial designs and patient populations treated. Since the trials were conducted using comparable endpoints and evaluation methods, the PFS data from these studies is usually illustrated in Physique 3. The effect of pazopanib on PFS appears comparable to that of the other anti-angiogenic brokers in either treatment-na?ve or cytokine pretreated subjects. Open in a separate window Physique 3 Comparison of progression free survival data from recent phase II and II randomized clinical trials utilizing a variety of targeted brokers in treatment-na?ve or cytokine refractory patients with metastatic renal cell carcinoma. Notes: apatient number; bhazard ratio (95% confidence interval). The pazopanib data have been compared37 to the Phase III trial results with.This may be a reflection of the crossover study design. These benefits should be examined in the context of possible pazopanib associated toxicity. from the pivotal clinical trials are discussed, and the potential role of pazopanib in the treatment of patients with metastatic RCC in comparison to other treatment alternatives is usually critically appraised. This agent has a favorable overall risk benefit, and the available data demonstrate efficacy in patients with metastatic RCC who are either treatment-na?ve or cytokine refractory. It therefore represents another alternative for treatment of metastatic RCC patients. 0.0000001). This difference was more pronounced in treatment-na?ve patients (11.1 months vs 2.8 months, HR: 0.40, 0.0000001) than in the cytokine refractory group (7.4 months vs 4.2 months, HR: 0.54, 0.001). A prespecified analysis of trial subgroups exhibited that improvement of PFS was impartial of age, performance status, gender, and MSKCC risk group. The data for the various MSKCC risk groups TAPI-1 are not yet available. ORR was higher TAPI-1 in all patients receiving pazopanib compared with the control group (30% vs 3%). In treatment-na?ve subjects, the ORR was 32% vs 4% for the placebo group. The median response duration was 59 weeks. Selected efficacy data reported in various first-line Phase II/III trials of VEGF/VEGFR inhibitors in metastatic RCC patients (excluding the temsirolimus trial) are summarized in Table 2 (PFS), and Table 3 (OS). The ORR in treatment- na?ve patients varies between 5.2% and 47% depending upon the trial, agent utilized, and type of analysis (independent vs investigator). The most active agent appears to be sunitinib, with an ORR of 37% (47% investigator assessment).15,34 The ORR observed with pazopanib appears similar (32% vs 37%). Responses appear to be durable with all brokers, with median response durations between 11.0 months and 14.0 months. Table 2 Progression free survival in frontline metastatic renal cell cancer randomized trials value 0.001 0.0001 0.0001 0.00010.5040.532 Open in a separate window Abbreviation: INF-, interferon-alpha. Table 3 Overall survival in randomized trials: frontline metastatic renal cell cancer patients value0.0510.12910.069NA0.224Hazard ratio (95% CI)0.821 (0.673, 1.001)0.91 (0.76, 1.10)0.86 (0.73, 1.01)NA0.91 (0.71, 1.16) Open in a separate window Abbreviations: CI, confidence interval; INF-, interferon-alpha; mos, months. An interim survival analysis in the pazopanib Phase III trial initially reported a median OS of 21.1 months for pazopanib vs 18.7 months for the placebo patient group (HR: 0.73, one-sided = 0.02).17 Final OS data are available, and revealed a median OS of 22.9 months for the pazopanib vs 20.5 months in the placebo cohort (HR: 0.91, 95% CI: 0.71C 1.16, stratified log rank = 0.224).29 A high rate of secondary therapy in placebo patients compared with those randomized to pazopanib was reported (66% vs 30%), with 54% of the placebo group ultimately receiving pazopanib.29 In an inverse probability censoring weighted analysis which adjusts for the activity of pazopanib vs placebo, pazopanib therapy was associated with a 50% reduction in the risk of death. Direct comparisons between the various trial results are not possible in view of the different trial designs and patient populations treated. Since the trials were conducted using comparable endpoints and evaluation methods, the PFS data from these studies is usually illustrated in Physique 3. The effect of pazopanib on PFS appears comparable to that of the other anti-angiogenic brokers in either treatment-na?ve or cytokine pretreated subjects. Open in a separate window Figure.