Marc R. Matrana

Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with pazopanib after disease progression with other targeted therapies

AIM The multi-tyrosine kinase inhibitor pazopanib prolongs progression-free survival (PFS) versus placebo in treatment-naive and cytokine-refractory metastatic clear-cell renal cell carcinoma (ccRCC). Outcomes and safety data with pazopanib after targeted therapy (TT) are limited. METHODS We retrospectively evaluated records of consecutive patients with metastatic ccRCC who had progressive disease (PD) after TT and received pazopanib from November 2009 through November 2011. Tumour response was assessed by a blinded radiologist using Response Evaluation Criteria In Solid Tumours (RECIST). PFS and overall survival (OS) were estimated by Kaplan-Meier methods. RESULTS Ninety-three patients were identified. Median number of prior TTs was 2 (range, 1-5). There were 68 events (PD or death). Among 85 evaluable patients, 13 (15%) had a partial response. Median PFS was 6.5 months (95% CI: 4.5-9.7); median OS was 18.1 months (95% CI: 10.26-NA). Common adverse events (AEs) included fatigue (44%), elevated transaminases (35%), diarrhoea (30%), hypothyroidism (18%), nausea/vomiting (17%), anorexia (14%) and hypertension exacerbation (14%); 91% of AEs were grade 1/2. Eleven patients (12%) discontinued therapy due to AEs. There were no treatment-related deaths. CONCLUDING STATEMENT Pazopanib demonstrated efficacy in patients with metastatic ccRCC after PD with other TTs. Toxicity overall was mild/moderate and manageable.

BAP1, PBRM1 and SETD2 in clear-cell renal cell carcinoma: molecular diagnostics and possible targets for personalized therapies

Several novel recurrent mutations of histone modifying and chromatin remodeling genes have been identified in renal cell carcinoma. These mutations cause loss of function of several genes located in close proximity to VHL and include PBRM1, BAP1 and SETD2. PBRM1 encodes for BAF180, a component of the SWI/SNF chromatin remodeling complex, and is inactivated in, on average, 36% of clear cell renal cell carcinoma (ccRCC). Mutations of BAP1 encode for the histone deubiquitinase BRCA1 associated protein-1, and are present in 10% of ccRCCs. They are largely mutually exclusive with PBRM1 mutations. Mutations to SETD2, a histone methyltransferase, occur in 10% of ccRCC. BAP1- or SETD2-mutated ccRCCs have been associated with poor overall survival, while PBRM1 mutations seem to identify a favorable group of ccRCC tumors. This review describes the roles of PBRM1, BAP1 and SETD2 in the development and progression of ccRCC and their potential for future personalized approaches.

Systemic therapy for metastatic non-clear-cell renal cell carcinoma: recent progress and future directions.

Insights into the biology of clear-cell renal cell carcinoma (CCRCC) have identified multiple pathways associated with the pathogenesis and progression of this cancer. This progress has led to the development of multiple agents targeting these pathways, including the tyrosine kinase inhibitors sorafenib, sunitinib, and pazopanib, the monoclonal antibody bevacizumab, and the mTOR inhibitors temsirolimus and everolimus. With the exception of temsirolimus, phase 3 trials tested these agents in patients with clear-cell histology; therefore, their efficacy in non-CCRCC is unclear. To date, there is no established effective therapy for patients with advanced non-CCRCC. This article focuses on treatment options for metastatic non-CCRCC.

Outcomes of Patients With Metastatic Renal Cell Carcinoma and End-Stage Renal Disease Receiving Dialysis and Targeted Therapies: A Single Institution Experience

INTRODUCTION Limited data are available regarding patients with renal cell carcinoma and ESRD treated with TTs. The objective of this study was to explore the tolerability and safety of TT in patients with mRCC and ESRD. PATIENTS AND METHODS We retrospectively identified patients with mRCC and ESRD treated at the University of Texas M.D. Anderson Cancer Center from 2002 to 2012. Patient characteristics including demographic, histology, treatment, and adverse events are reported. Duration of treatment (TOT) was determined from date of drug initiation to discontinuation. Overall survival (OS) was determined from initiation of TT to death. Statistics are descriptive. RESULTS Fourteen patients were identified. Ten patients had clear-cell histology and 4 had papillary histology. The median number of TTs per patient was 3 (range, 1-4) with median TOT of 28 months for all TTs. Eighty-eight percent of all toxicities were Grade 1 to 2; no Grade 4 toxicities were noted. Treatment discontinuations included 3 patients treated with sorafenib due to hand-foot syndrome, intolerable fatigue, and squamous cell skin cancer development; 2 patients treated with pazopanib due to intolerable fatigue and increased transaminase levels; and 1 patient treated with everolimus due to pneumonitis. Eight patients died from progressive disease. Median OS from initiation of TT was 28.5 months and 35 months from time of diagnosis. CONCLUSION Toxicities were mild to moderate and consistent with those reported in previous studies. TTs appear to be safe, well tolerated and produce antitumor response in patients with mRCC and ESRD receiving dialysis.

Emerging Targeted Therapies in Metastatic Renal Cell Carcinoma

Insights into renal cell carcinoma (RCC) biology have greatly expanded the treatment armamentarium for metastatic RCC (mRCC). Since 2005, six targeted agents have been approved by the US Food and Drug Administration (FDA) for the management of mRCC, and many new targeted therapies are in development. A number of novel VEGF Inhibitors/Multi-Tyrosine Kinase Inhibitors are currently in various stages of development. New targeted agents with novel mechanisms of action are also being studied, including Histone Deacetylase Inhibitors, Angiopoietin/TIE-2 inhibitors, Carbonic anhydrase IX inhibitors, vaccines, and others. In addition to combining currently available immunologic therapies with emerging agents, researchers are also developing novel immunologic therapies to treat mRCC, including those that block Cytotoxic T-Lymphocyte Antigen 4 (CTLA4). Several trials evaluating combinations and sequential therapy of targeted agents have been published, and several others are underway. Trials of special mRCC populations, including poor-risk disease, non-clear cell RCC (NCC-RCC), and papillary type RCC are further refining the use of targeted treatments. As new targeted agents emerge and therapies with novel mechanisms of action are developed, the treatments options available for metastatic RCC are expected to increase. New therapies will likely have fewer detrimental side effects and better efficacy, leading to better quality of life for patients.

Emerging Immunotargets in Metastatic Renal Cell Carcinoma

Renal cell carcinoma (RCC) is one of the most immunoresponsive human cancers. High-dose IL-2 and Interferon-α were once the principle therapies for metastatic RCC, however they had harsh-tolerance profiles and limited response rates. In the last decade, targeted therapies have supplanted cytokine therapy due to higher response rates and more favorable toxicity profiles. Emerging immunotherapies targeting the PD-1 receptor and PD-L1 ligand have shown promising results. Likewise, other novel targeted immunotherapies are currently under evaluation. The safety profiles and response rates of new generation immunotherapies are encouraging and justify the progression of clinical trials. However, longer follow-up data are needed to confirm these promising results. In addition, it is still unclear if an optimal sequence or combinations of new immunotherapies paired with current targeted therapies will emerge.

Emerging Immunotargets in Bladder Cancer

Bladder cancer treatment, namely systemic therapy, was dominated in the last three decades due to the absence of newer therapeutic options other than chemotherapy regimens. Chemotherapy, by itself, both in first and second-line seems to have achieved the modest plateau of its possibilities at the cost of non-negligible toxicity. Targeted therapies, which changed the therapy of many different tumors, seem rather ineffective in bladder cancer. More recently, a new generation of Immunotherapy based regimens represent the most promising avenue for the future systemic treatment of bladder cancer. Checkpoint inhibition, namely PD1/PD-L1 pathway inhibition, showed impressive results in many other tumor types and are expected to become a major player in the treatment of bladder cancer. Other immunotherapy strategies such as fusion proteins represent distant, although promising, options. A brief overview of the current status of bladder cancer immunotherapy is presented.

Outcomes of unselected patients with metastatic clear-cell renal cell carcinoma treated with first-line pazopanib therapy followed by vascular endothelial growth factor receptor tyrosine kinase inhibitors or mammalian target of rapamycin inhibitors: a single institution experience

To explore the efficacy and safety of pazopanib in a ‘real‐world’ setting in unselected patients, as data regarding unselected patients with metastatic clear‐cell renal cell carcinoma (ccRCC) treated with first‐line pazopanib are limited.

Prognosis of patients with metastatic renal cell carcinoma and pancreatic metastases.

To identify the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) with pancreatic metastases (PM) treated with either pazopanib or sunitinib and assess whether PM is an independent prognostic variable in the current therapeutic environment.

Outcomes of Patients With Metastatic Non-Clear-Cell Renal Cell Carcinoma Treated With Pazopanib.

Micro‐Abstract Outcomes data in patients with metastatic non–clear‐cell renal cell carcinoma (RCC) treated with pazopanib are limited. We identified 29 patients with non–clear‐cell metastatic RCC who received pazopanib (9 in the front‐line setting, and 20 in the salvage setting). Median overall survival was 31 months (95% confidence interval [CI], 9.2‐NA [not available]) in the front‐line group compared with 13.6 months (95% CI, 6.4‐NA) in the salvage group. Background: Pazopanib is associated with increased progression‐free survival (PFS) in clear‐cell renal cell carcinoma (RCC) and has become a standard of care in this disease. The drug is used in metastatic non–clear‐cell RCC, but data on outcomes in this setting are limited. Patients and Methods: We conducted a retrospective data analysis of records of consecutive metastatic non–clear‐cell RCC patients who received pazopanib in front‐line and salvage settings between November 2009 and November 2012. Tumor response rate was assessed by a blinded radiologist using Response Evaluation Criteria in Solid Tumors version 1.1. PFS and overall survival (OS) times were estimated using Kaplan–Meier methods. Results: Twenty‐nine patients were identified with non–clear‐cell metastatic RCC, 9 received pazopanib in the front‐line setting, 20 in the salvage setting after progression of disease with other targeted therapies. Seven patients (24%) had papillary RCC, 4 (14%) had chromophobe, 5 (17%) had unclassified histopathology, and 13 (45%) had other subtypes including collecting duct, translocation Xp11.2, and various subtypes with sarcomatoid differentiation. All patients discontinued pazopanib before analysis. Median PFS was 8.1 months (95% CI, 5.7‐NA [not available]) in the front‐line group, and 4 months (95% CI, 2.1‐9.9) in the salvage group. Median OS was 31 months (95% CI, 9.2‐NA) in the front‐line group, and 13.6 months (95% CI, 6.4‐NA) in the salvage group. Conclusion: Pazopanib showed efficacy in patients with metastatic non–clear‐cell RCC in the front‐line and salvage settings. Toxicity was mild to moderate and manageable. Further studies are needed to evaluate pazopanibs role in non–clear‐cell RCC in terms of efficacy and safety.