Tivozanib in the treatment of renal cell carcinoma

Mehmet Hepgur, Sarmad Sadeghi, Tanya B Dorff, David I Quinn Division of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, USA Abstract: Renal cell carcinoma (RCC) is an aggressive malignancy compared to other urological malignancies and has been associated with poor responses to conventional cytotoxic chemotherapy. Interferon-a and interleukin-2 were previously utilized in a limited number of patients with good performance status due to toxicity and safety issues. Over the last decade, through advances in the understanding of the biology and pathology of RCC, the important role of vascular endothelial growth factor (VEGF) in RCC has been identified. Data from randomized trials have led to the approval of first-generation tyrosine kinase inhibitors (TKIs) sorafenib, sunitinib, and pazopanib; however, these agents inhibit a wide variety of kinase targets and are associated with a range of adverse effects. More recently, a new generation TKI, axitinib, has been approved by the US Food and Drug Administration. Tivozanib is a novel TKI, which is a potent inhibitor of VEGF-1, VEGF-2, VEGF-3, c-kit, and PDGR kinases, with a more restricted target spectrum. Phase II and III studies have demonstrated significant activity and a favorable safety profile as an initial targeted treatment for advanced RCC. This review examines the emerging data with tivozanib for the treatment of advanced RCC. Preclinical investigations as well as Phase I, II, and III data are examined; data on the comparative benefits of tivozanib are reviewed. Finally, we discuss the future potential of tivozanib in combination, biomarkers associated with tivozanib response, and acquisition of resistance and nonkidney cancer indications. Keywords: targeted therapy, renal cell cancer, tyrosine kinase inhibitor, tivozani

Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression

Immune system defects are at the center of aging and a range of diseases. Here, we show that prolonged fasting reduces circulating IGF-1 levels and PKA activity in various cell populations, leading to signal transduction changes in long-term hematopoietic stem cells (LT-HSCs) and niche cells that promote stress resistance, self-renewal, and lineage-balanced regeneration. Multiple cycles of fasting abated the immunosuppression and mortality caused by chemotherapy and reversed age-dependent myeloid-bias in mice, in agreement with preliminary data on the protection of lymphocytes from chemotoxicity in fasting patients. The proregenerative effects of fasting on stem cells were recapitulated by deficiencies in either IGF-1 or PKA and blunted by exogenous IGF-1. These findings link the reduced levels of IGF-1 caused by fasting to PKA signaling and establish their crucial role in regulating hematopoietic stem cell protection, self-renewal, and regeneration

Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial.

Background A subset of patients with metastatic renal-cell carcinoma show indolent growth of metastases. Because of the toxicity and non-curative nature of systemic therapy, some of these patients could benefit from initial active surveillance. We aimed to characterise the time to initiation of systemic therapy in patients with metastatic renal-cell carcinoma under active surveillance.Methods In this prospective phase 2 trial, we enrolled patients with treatment-naive, asymptomatic, metastatic renal-cell carcinoma from five hospitals in the USA, Spain, and the UK. Patients were radiographically assessed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months thereafter. Patients continued on observation until initiation of systemic therapy for metastatic renal-cell carcinoma; a decision that was made at the discretion of the treating physician and patient. The primary endpoint of the study was time to initiation of systemic therapy in the per-protocol population. The follow-up of patients is ongoing.Findings Between Aug 21, 2008, and June 7, 2013, we enrolled 52 patients. Median follow-up of patients in the study was 38·1 months (IQR 29·4-48·9). In the 48 patients included in analysis, median time on surveillance from registration on study until initiation of systemic therapy was 14·9 months (95% CI 10·6-25·0). Multivariate analysis showed that higher numbers of International Metastatic Database Consortium (IMDC) adverse risk factors (p=0·0403) and higher numbers of metastatic disease sites (p=0·0414) were associated with a shorter surveillance period. 22 (46%) patients died during the study period, all from metastatic renal-cell carcinoma.Interpretation A subset of patients with metastatic renal-cell carcinoma can safely undergo surveillance before starting systemic therapy. Additional investigation is required to further define the benefits and risks of this approach.Funding None

Effect of Visceral Disease Site on Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer Treated With Enzalutamide in the PREVAIL Trial.

Background The Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy (PREVAIL) trial was unique as it included patients with visceral disease. This analysis was designed to describe outcomes for the subgroup of men from PREVAIL with specific sites of visceral disease to help clinicians understand how these patients responded to enzalutamide prior to chemotherapy.Patients and methods Prespecified analyses examined the coprimary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) only. All other efficacy analyses were post hoc. The visceral subgroup was divided into liver or lung subsets. Patients with both liver and lung metastases were included in the liver subset.Results Of the 1717 patients in PREVAIL, 204 (12%) had visceral metastases at screening (liver only or liver/lung metastases, n = 74; lung only metastases, n = 130). In patients with liver metastases, enzalutamide was associated with an improvement in rPFS (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.22-0.90) but not OS (HR, 1.04; 95% CI, 0.57-1.87). In patients with lung metastases only, the HR for rPFS (0.14; 95% CI, 0.06-0.36) and the HR for OS (0.59; 95% CI, 0.33-1.06) favored enzalutamide over placebo. Patients with liver metastases had worse outcomes than those with lung metastases, regardless of treatment. Enzalutamide was well tolerated in patients with visceral disease.Conclusions Enzalutamide is an active first-line treatment option for men with asymptomatic or mildly symptomatic chemotherapy-naive metastatic castration-resistant prostate cancer and visceral disease. Patients with lung-only disease fared better than patients with liver disease, regardless of treatment

Clinical use of cabozantinib in the treatment of advanced kidney cancer: efficacy, safety, and patient selection

Steven S Yu, David I Quinn, Tanya B Dorff Division of Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA Abstract: Clear cell (cc) renal cell carcinoma (RCC) is the most common type of cancer found in the kidney accounting for ~90% of all kidney cancers. In 2012, there were ~337,000 new cases of RCC diagnosed worldwide with an estimated 143,000 deaths, with the highest incidence and mortality in Western countries. Despite improvements in cancer control achieved with VEGF- and mTOR-targeted therapy for RCC, progression remains virtually universal and additional therapies are needed. The pivotal results of the METEOR trial led to cabozantinib’s designation as a breakthrough drug by the US Food and Drug Administration and its approval for treatment of advanced RCC in 2016. Subsequent data from the CABOSUN trial, where caboxantinib is compared with sunitinib, will provide information on the relative activity of cabozantinib as first-line therapy for ccRCC. We review the development of cabozantinib in advanced RCC and its role in the treatment landscape for advanced RCC. Keywords: cabozantinib, renal cell carcinoma, kidney cancer, clear cell carcinoma, tyrosine kinase inhibito