Pazopanib,a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma

Background: The recent approvals of sunitinib, sorafenib and temsirolimus have revolutionized the management of renal cell carcinoma (RCC). Pazopanib (GW-786034) is a second-generation multitargeted tyrosine kinase inhibitor against VEGFR-1, 2 and 3, platelet-derived growth factor receptor (PDGFR)-α, PDGFR-β and c-kit. Objective: Data supporting the development of pazopanib for RCC are reviewed. Methods: Preclinical and clinical data available for pazopanib are presented. Results: Preclinical evaluation has revealed excellent anti-angiogenic and anti-tumor activity in several mouse models. A Phase II clinical trial of pazopanib in untreated or cytokine/bevacizumab pretreated RCC has demonstrated promising activity accompanied by a favorable toxicity profile. A placebo-controlled Phase III trial is ongoing in untreated or cytokine-treated patients with RCC. Ongoing trials are further evaluating pazopanib in a variety of other malignancies.     

Axitinib for renal cell carcinoma

Background: The approval of sunitinib, sorafenib and temsirolimus has dramatically altered the management of renal cell carcinoma (RCC). Bevacizumab plus IFN may also be added to the therapeutic armamentarium. Axitinib (AG-013736) is an oral and selective tyrosine kinase inhibitor. Objective: Data supporting the development of axitinib for RCC are reviewed. Methods: Preclinical and clinical data available for axitinib for RCC are presented. Results: Axitinib inhibits VEGFR-1, VEGFR-2 and VEGFR-3 with picomolar potencies, and PDGFR-α, PDGFR-β and c-kit with nanomolar potencies. Phase II clinical trials of axitinib in pretreated RCC following sorafenib or cytokine treatment have demonstrated promising activity accompanied by a favorable toxicity profile. Further development of axitinib for RCC is warranted.     

Present and future therapeutic options for locally advanced and metastatic renal cell carcinoma

Introduction: Locally advanced or metastatic renal cell carcinoma (RCC) is notoriously chemo- and radioresistant, leaving immunotherapy as the only treatment option. In recent years, targeted therapies have offered significant increases in progression-free survival (PFS). Despite this, the majority of patients soon develops resistant disease and finally succumbs. The need to implement treatment strategies that improve overall survival while having an acceptable safety profile is imperative.

Areas covered: This review provides information on the efficacy of recently studied treatment strategies for advanced RCC. These include sequential and combination therapy of established drugs as well as data on agents in early clinical development. The Medline and ASCO database were searched for clinical trials on medical therapy of advanced RCC from 2004 until May 2010. Data on targeted therapies, including tyrosine kinase inhibitors, vascular endothelial growth factor inhibitors, mammalian target of rapamycin inhibitors, and antiepidermal growth factor receptor agents are summarized.

Expert opinion: Improvements in response rates and PFS in patients with advanced RCC have been observed with new treatment strategies. The benefit in overall survival is less clear and needs further evaluation. Toxicity represents a concern especially in combination regiments.     

Pazopanib for the treatment of renal cancer

Introduction: Dramatic advances in the care of patients with advanced renal cell carcinoma (RCC) have occurred over the last 10 years. Insights into the molecular pathogenesis of this disease have elucidated the importance of signaling cascades related to angiogenesis in the management of RCC. Pazopanib is a novel, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3; platelet-derived growth factor receptors (PDGFR)-α and -β; and c-kit tyrosine kinases. Pazopanib exhibits distinct pharmacokinetic and toxicity profiles compared with other agents in the class of VEGF signaling pathway inhibitors.

Areas covered: This review discusses the scientific rationale for the development of pazopanib, as well as the preclinical and clinical trials that led to the approval of pazopanib for patients with advanced RCC. The most recent information, including data from the 2010 meeting of the American Society of Clinical Oncology and the design of ongoing Phase III trials, is discussed. Finally, an algorithm utilizing level I evidence for the treatment of patients with this disease is proposed.

Expert opinion: The treatment of metastatic RCC has changed dramatically over the last 5 years. Six novel agents – sunitinib, sorafenib, temsirolimus, everolimus, bevacizumab (used in combination with interferon), and pazopanib (Votrient) – have been approved for the treatment of metastatic RCC. The clinical data to date clearly place pazopanib among the most active of the targeted therapies.     

In vitro effect of IL-2 in combination with pazopanib or sunitinib on lymphocytes function and apoptosis of RCC cells

Objective: Combination of immunotherapy with tyrosine kinase inhibitors (TKIs) has been used with some success for the treatment of metastatic renal cell carcinoma. Herein we evaluate the in vitro effect of high-dose interleukin-2 (HDIL-2) and pazopanib or sunitinib on the lymphocyte function and on induction of apoptosis in renal cell carcinoma (RCC) cell lines.

Methods: Peripheral blood mononuclear cells (PBMCs) isolated from healthy donors or RCC patients were treated with different HDIL-2/TKI combinations. Effects of different combinations on proliferation and cytotoxic activity of PBMCs were evaluated, in addition to their effect on apoptosis of three different RCC cell lines.

Results: While sunitinib did not inhibit the proliferation of various immune cells induced by HDIL-2, pazopanib appeared to inhibit the HDIL-2–induced proliferation of these cells. Interestingly, none of the HDIL-2/TKI combinations appeared to compromise the functional properties of these cells. Additionally, significant proportion of RCC cell lines treated with pazopanib alone underwent apoptosis, while the proportions of apoptotic cells post-HDIL-2 or sunitinib were not different from the background. Furthermore, the combination of HDIL-2/pazopanib did not inhibit the pazopanib-induced RCC apoptosis.

Conclusion: The combination of HDIL-2 with either pazopanib or sunitinib exerts different anticancer mechanisms that could enhance the treatment efficacy.     

Progress and contrasts of the development of tivozanib for therapy of kidney cancer

Introduction: Targets for drug development for the treatment of kidney cancer (renal cell carcinoma; RCC) include vascular endothelial growth factor (VEGF) and its receptors and mammalian target of rapamycin. Currently available oral multitargeted VEGF tyrosine kinase inhibitors (TKIs) that have been approved by the US Food and Drug Administration for advanced RCC, include sunitinib, sorafenib and pazopanib. Off-target TKI inhibition can potentially preclude full-dose combination with other targeted and chemotherapeutic agents. There is a need to develop more potent and selective targeted agents for RCC therapy, which are more effective and have minimal off-target effects.

Areas covered: This drug evaluation review addresses the ongoing development for the treatment of RCC with tivozanib: a potent, selective and long-half-life VEGF TKI. The testing for clinical efficacy alone or in combination with other therapies for RCC and for other tumor types, and the clinical and market relevance of introducing another RCC therapy are discussed.

Expert opinion: Tivozanib is distinguished by its high potency, selectivity, long-half-life and its potential to be effectively combined with other agents in RCC. This may offer more effective, yet well-tolerated treatment options. The relative clinical and market relevance remain to be seen, both for RCC therapy and other tumor types.     

Sunitinib in solid tumors

Background: Until recently, few treatments were available for renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GIST). Several targeted agents inhibiting key pathogenetic pathways have since been developed for RCC (sunitinib, sorafenib, bevacizumab, temsirolimus, everolimus) and GIST (imatinib, sunitinib). Sunitinib is a multi-kinase inhibitor of VEGFR-2, PDGFR (α,β), FLT-3, KIT, CSF-1 and RET. Objective: To summarize the literature regarding the structure, pharmacokinetics, pharmacodynamics, toxicity and current clinical use of sunitinib. Other potential roles for this drug in RCC, GIST and other tumor types will be discussed. Methods: A literature search identified relevant (pre)clinical studies of sunitinib and other relevant agents. Results/conclusions: Sunitinib revolutionized the management of advanced RCC and GIST. With the realization that cross-resistance between targeted agents is incomplete, evolving strategies include sequential treatment, concurrent treatment, and biomarker development. Sunitinib also shows promise in several other tumor types that lack therapeutic options. What remains less clear is its role in tumors that are not heavily dependent on a central pathogenetic pathway, especially if effective cytotoxic therapies exist. Future clinical trials will clarify whether there is a role for sunitinib in these tumors, possibly in combination with cytotoxic agents.     

Systemic therapy for metastatic renal cell carcinoma in treatment naïve patients: a risk-based approach

Importance of the field: Kidney cancer is the ninth most common cancer in the USA, with an annual incidence of approximately 55,000 cases per year. Over 13,000 patients are estimated to die from this disease annually. Cloning of the VHL gene, recognition of the associated abnormalities in sporadic clear-cell carcinoma, and its role as a regulator of the hypoxic response, were important milestones in our understanding of renal-cell carcinoma (RCC) biology and the recognition of the vascular endothelial growth factor (VEGF) dependency of RCC. A variety of clinical features, including histologic features, prognostic factors, and patient history of comorbid illness, provide the framework in which the results of recent clinical trials and regulatory approvals of these agents are utilized to develop treatment recommendations for the largest metastatic patient RCC group, the therapy naïve individual.

Areas covered in this review: The rationale for use of VEGF-targeted therapy in advanced RCC patients and the recently developed treatment options for these individuals are reviewed. Regulatory approval of sorafenib for the treatment of metastatic RCC (mRCC), was followed by the approval of sunitinib, temsirolimus, bevacizumab plus interferon (IFNα), everolimus, and – most recently – pazopanib. These licences were granted from late 2005 through late 2009, a very short span of 4 years. In treatment-naïve mRCC patients, sunitinib, sorafenib, pazopanib, bevacizumab + IFNα, and temsirolimus were approved by the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMEA). The clinical trials and data supporting these approvals are reviewed.

What will the reader gain: This review examines these developments and provides the reader an overview and understanding of available current systemic therapy options for treatment-naïve mRCC patients.

Take home message: As multiple treatment options are now available for treatment-naïve mRCC patients, an understanding of how to utilize this group of agents is required. The use of various clinical features allows a rational approach to therapy selection. These features include prior treatment status, histologic subtype, and prognostic group. Further refinement of therapy selection is required and will require further biologic information as well as comparative randomized trials.     

Targeted therapy and hand–foot skin reaction in advanced renal cell carcinoma

Importance of the field: Targeted therapy has significantly prolonged the survival of patients with advanced renal cell carcinoma (RCC). As first-line treatment, sunitinib, temsirolimus and bevacizumab plus IFN-α are demonstrated to prolong progression-free survival and/or overall survival. As second-line treatment, sorafenib was active mainly for patients in whom cytokine therapy failed. Recently, second-line treatment with everolimus has been shown to benefit patients progressing through tyrosine kinase inhibitors. Meanwhile, FDA has just approved pazopanib for the treatment of patients with advanced RCC. Various toxicities were associated with these agents. These toxicities were generally well tolerated. However, a high frequency of severe skin and bone marrow toxicities has been reported in Asian countries.

Areas covered in this review: We have reviewed the literature of current targeted therapeutic agents and hand–foot skin reaction (HFSR) in advanced RCC available in MEDLINE and meeting reports of ASCO, ECCO-ESMO and the 2009 Genitourinary Cancers Symposium.

What the reader will gain: Readers will know of the efficacy and safety, including HFSR, of current targeted therapy.

Take home message: Careful monitoring and appropriate management of the toxicities, especially HFSR, are needed.     

Renal cell carcinomas in trichloroethene(TRI) exposed persons are associated with somatic mutations in the von Hippel-Lindau (VHL) tumour suppressor gene

Renal cell carcinomas (RCC) develop as a consequence of somatic mutations of the von Hippel-Lindau (VHL) tumour suppressor gene. Recent epidemiological studies show that high and prolonged occupational exposures to trichloroethene (TRI) are associated with an increased incidence of RCC. Tumour tissues from 23 RCC patients with occupational histories of very high TRI exposure were analysed for somatic mutations within the VHL gene. DNA was isolated from microdissected tumour cells, amplified by polymerase chain reaction (PCR), and analysed in single strand conformation polymorphism (SSCP) and sequencing. RCC tissues of all 23 TRI exposed persons analysed thus far showed aberrations of the VHL gene, with 30% having aberrations in exon 1, 44% in exon 2, and 26% in exon 3. By comparison to much lower reported VHL mutation frequencies of 33–55% in TRI-unexposed RCC patients, these results indicate a specifically high mutation frequency at the VHL gene in TRI-exposed RCC patients; four of these aberrations have thus far been confirmed as VHL mutations by sequence analysis. This finding indicates the VHL gene being a susceptible and specific target in TRI induced renal carcinogenesis. Furthermore, the frequent involvement of exon 2 identifies potential `hot spots' for this carcinogen. In addition to the available epidemiological studies the results are now further proof for human renal carcinogenicity induced by high occupational exposures to TRI. Received: 15 November 1996 / Accepted: 20 December 1996     

Safety and tolerability of pazopanib in the treatment of renal cell carcinoma

Introduction: Renal cell carcinoma (RCC) is still a challenging disease. Over the last 6 years, the use of novel targeted therapies interfering with vascularization and inhibition of other downstream pathways has revolutionized the therapy of this disease, leading to an improvement of patient outcomes. In particular, dysregulation of the vascular endothelial growth factor (VEGF) pathway and VEGF protein overexpression have proved important, as they result in increased tumor angiogenesis and RCC growth and development.

Areas covered: This review briefly discusses the mechanisms of action and clinical applications of pazopanib. It mainly outlines the safety and tolerability of pazopanib for locally advanced/metastatic RCC. Phase III pazopanib safety data are also indirectly compared with other standard, antiangiogenic receptor tyrosine kinase inhibitors currently used in the management of RCC.

Expert opinion: Pazopanib is a new drug available in the oncology portfolio to treat patients with predominantly clear-cell RCC. The toxicity profile of pazopanib is comparable, but in some ways distinct, from other antiangiogenic drugs used in the treatment of RCC. Long-term data about late side effects of this treatment are awaited.     

Targeting the c-MET signaling pathway for cancer therapy

Background: In many human cancers, c-MET is activated via receptor overexpression, amplification, mutation and/or a ligand-dependent autocrine/paracrine loop. These biochemical and genetic abnormalities have been correlated with poor clinical outcomes and drug resistance in cancer patients. Preclinical studies suggest that targeting aberrant c-MET signaling could be an attractive therapy in cancer, but this notion has only recently been tested in the clinic. Objectives: To describe the biological aspects of the c-MET signaling pathway and to discuss recent progress and possible future trends in the development of agents that target the c-MET pathway, with an emphasis on small-molecule c-MET kinase inhibitors. Method: A review of relevant publications, including published articles in literature, reports at scientific meetings, and information available through the Internet. Results/conclusion: The dysregulated c-MET pathway represents a promising target for cancer drug development. The agents that target the c-MET pathway have demonstrated impressive evidence of early clinical activity and may have a significant therapeutic potential.     

Janus kinase inhibitors for the treatment of myeloproliferative neoplasms

Introduction: Disordered signaling through the JAK/STAT pathway is a hallmark of myeloproliferative neoplasms (MPNs). Targeted therapies that inhibit and regulate this pathway are reasonable strategies for disease management. Only one JAK1/JAK2 inhibitor has gained FDA approval for treatment of myelofibrosis. Despite significant reductions in splenomegaly and disease-associated symptoms, additional agents are necessary to manage disease in those that do not respond.

Areas covered: A review of the currently available literature and meeting abstracts for JAK inhibitors in myeloproliferative neoplasms identified studies aimed at improving outcomes and establishing alternative therapies in MPNs. Development of specific JAK inhibitors and ongoing trials involving ruxolitinib, CYT387, SAR302503, CEP701, SB 1518, XL-019, LY2784544, BMS-911453, NS-018, AZD1480 and INCB039110 are reviewed.

Expert opinion: The identification of JAK2V617F mutation and its link to MPNs has revolutionized treatment options. Resultant research in targeting the JAK/STAT pathway led to the approval of ruxolitinib, a JAK1/JAK2 inhibitor with activity in MPNs. While ruxolitinib produces durable reductions in splenomegaly and improvement of symptoms, and prolongs survival, there is room for new and more specific agents to be developed. Minimizing toxicity and avoiding drug resistance are challenges that lie ahead. Combining agents with different mechanisms seems to be a rational strategy.     

Tivozanib for the treatment of renal cell carcinoma

Introduction: Renal cell carcinoma (RCC) represents a heterogeneous group of cancers with distinct histological features, molecular alterations, prognosis, and response to therapy. Target agents directed against vascular endothelial growth factor and its receptor and mammalian target of rapamycin (mTOR) inhibitors have completely changed the landscape of RCC. However, the rate of complete response is still low, thus supporting the research of novel therapeutic agents.

Area covered: The authors describe the chemical features of tivozanib, its pharmacodynamic and pharmacokinetic properties, and the results obtained in human phase I–III clinical trials. Tivozanib received its first global approval in EU, Iceland, and Norway on 28 August 2017 for the first-line treatment of adult patients with advanced RCC and for adult patients who are VEGFR and mTOR inhibitor-naive following disease progression after one prior treatment with cytokines.

Expert opinion: The US Food and Drug Administration did not approve tivozanib due to the lack of a significant advantage in terms of survival compared to sorafenib. To date, the role of tivozanib in the pharmaceutical landscape of mRCC appears to be very limited. However, ongoing trials on the association between tivozanib and immunotherapy may represent a promising strategy to be assessed in future clinical trials.     

mTOR-blocking agents in advanced renal cancer: an emerging therapeutic option

Background: The mammalian target of rapamycin (mTOR) pathway inhibition has emerged as one of the main directions for the development of new targeted agents in renal cell carcinoma (RCC). A prominent member in its class of medications, temsirolimus has already been shown to improve overall survival in advanced kidney cancer, when compared with the previous standard, IFN-α. Objective: The aim of this study was to review the most relevant preclinical and clinical data on the mTOR inhibitors, both in clinical use or in current development. Methods: The authors give a comprehensive review of the existing English literature on the role of the mTOR pathway in renal tumorigenesis, as well as a detailed safety and efficacy analysis of older and newer rapamycin analogs. Results/conclusions: Rapamycin derivatives temsirolimus and everolimus have significant clinical activity in patients with advanced-stage RCC. Both parenteral and oral formulations of mTOR inhibitors have shown clinical efficacy and are currently being developed. Combinations of mTOR inhibitors with VEGF/VEGFR-blocking agents are also being studied, in an attempt to further enhance the antineoplastic effect.     

Targeting RhoA/ROCK pathway in pulmonary arterial hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a rare disease with a complex pathogenesis. It is often associated with an increased vascular resistance, whilst in the more advanced stages there is a remodelling of the vascular walls. PAH has an intricate involvement of various signaling pathways, including the ras homolog family member A (RhoA)–Rho kinase (ROCK) axis. Currently, available therapies are not always able to significantly slow PAH progression. Therefore, newer approaches are needed.

Areas covered: In this review, areas covered include the role of the RhoA/ROCK in PAH pathogenesis and the plausibility of its therapeutic targeting. Furthermore, various inhibitory compounds are discussed, including Fasudil and SB-772077-B.

Expert opinion: Currently, specific RhoA/ROCK inhibition is the most promising therapeutic approach for PAH. Research has shown that it suppresses both the components of this axis and the upstream upregulating mediators. An inhaled RhoA/ROCK inhibitor may be a successful future therapy; however, further clinical trials are needed to support this approach.     

System-based drug discovery within the human kinome

Introduction: For well over a decade, significant effort has been devoted to the search for inhibitors of the human protein kinase family. This is increasingly translating into success in the clinic, with five new kinase inhibitor drugs approved since 2011. However, despite encouraging signs in other areas, success has been largely restricted to oncology.

Areas covered: This article reviews the prospects for kinase inhibitor drug discovery in oncology and other therapeutic areas. Major topics include the application of kinome profiling and lessons learned from kinase system-based research. With these fields nearing maturity, the validation of kinases as targets or their classification as liabilities is becoming increasingly pertinent. Other topics include a discussion of the properties required of good small molecule kinase probes.

Expert opinion: The tractability of protein kinases to small molecule discovery through system-based research is excellent, and adequate selectivity can often be achieved. With advances in screening methodology now enabling compound profiling across most of the kinome, researchers involved in drug discovery must decide what inhibition profiles are desirable. However, this assessment must be made on the basis of incomplete understanding of the disease biology of most kinases, and as a result there is a significant risk that drugs entering clinical trials will lack efficacy. Because of this, as well as greater effort to determine which kinases are therapeutically relevant for particular diseases, opportunities for quality pre-candidate compounds developed for specific indications to find alternative uses should be maximised by early screening through panels of phenotypic assays.