An understanding of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways has greatly changed the way metastatic renal cell carcinoma (RCC) is treated. Based on available phase III randomized trials, anti-VEGF agents such as sunitinib, sorafenib, bevacizumab-based therapy, and mTOR-targeted agents such as temsirolimus and everolimus have been used in the treatment armamentarium for this disease. Now that agents directed against these pathways have largely replaced immunotherapy as the standard of care, new questions have emerged and are the subject of ongoing clinical trials. The development of new targeted therapies including axitinib, pazopanib, cediranib, volociximab, tivozanib (AV-951), BAY 73-4506, and c-met inhibitors such as GSK1363089 and ARQ197 may potentially expand the list of treatment options. Sequential and combination targeted therapies are currently under investigation in advanced disease as are adjuvant and neo-adjuvant approaches around nephrectomy.
adjuvant; combination therapy; mammalian target of rapamycin; neo-adjuvant; nonclear cell histologies; renal cell carcinoma; vascular endothelial growth factor
With an explosion of available treatments for metastatic renal cell carcinoma (mRCC) in recent years, it is important to recognize that approved targeted therapies fall broadly into only two mechanistic categories. The first category, vascular endothelial growth factor (VEGF)-directed therapies, includes sunitinib, pazopanib, sorafenib and bevacizumab. The second category includes inhibitors of the mammalian target of rapamycin (mTOR), namely everolimus and temsirolimus. A pivotal trial of ever-olimus supports use of the agent in patients with mRCC refractory to VEGF- tyrosine kinase inhibitors (TKI) therapy, while pivotal data for temsirolimus supports use in poor-prognosis patients as first-line therapy. Multiple reviews exist to delineate the laboratory and clinical development of mTOR inhibitors. This paper will outline the future applications of these therapies. It will explore ongoing trials evaluating combinations of mTOR inhibitors with other targeted therapies, along with sequencing strategies and biomarker discovery efforts. The application of mTOR inhibitors in unique populations is also described.
mTOR; Everolimus; Temsirolimus; Deferolimus; INTORACT; TORAVA; BeST; Biomarkers; Clinical trials
The landscape of treatment for advanced/metastatic renal cell carcinoma (mRCC) has advanced significantly in the last decade and continues to evolve with the approval of new drugs targeting the vascular endothelial growth factor (VEGF) and its receptors and mammalian target of rapamycin (mTOR). Currently available oral VEGF tyrosine kinase inhibitors (TKIs) approved for treatment of mRCC include sorafenib, sunitinib, pazopanib, and axitinib. This review focuses on pazopanib, a multikinase VEGF TKI indicated for patients with treatment-naïve and cytokine-refractory mRCC. This article describes the preclinical and clinical evolution of pazopanib, with an emphasis on its development and role in mRCC. Pivotal trials are discussed that demonstrate the efficacy and safety of pazopanib and its important role in the treatment of patients with mRCC in comparison to other available treatment options. The clinical path of pazopanib continues to develop further, with several ongoing studies exploring its role in neoadjuvant and adjuvant RCC. Furthermore, its potential role in sequential and combination studies with other VEGFR and non-VEGFR targeted agents is discussed. Overall, pazopanib is a unique VEGF TKI, with a different and more favorable safety profile compared with other members of the VEGF TKI family and represents an attractive alternative for patients with mRCC.
kidney cancer; pazopanib; renal cell carcinoma; targeted therapy; tyrosine kinase inhibitors; vascular endothelial growth factor
There are now a variety of therapies approved for the treatment of metastatic renal cell carcinoma (RCC). These include the immunotherapeutics, alfa-interferon, and interleukin-2, and agents that target the vascular endothelial growth factor receptor (VEGFR) via its tyrosine kinase, such as sorafenib, sunitinib, and pazopanib, or the mammalian target of rapamycin (mTOR), such as temsirolimus and everolimus. Bevacizumab, a monoclonal antibody directed against the ligand, VEGF, has shown activity against RCC as a single agent in patients who had failed prior cytokine therapy and as first line therapy in combination with interferon. The activity of bevacizumab in patients who had received and failed prior therapy has not been described. We report our experience in 4 patients with metastatic RCC who had failed prior cytokine, TKI, and mTOR inhibitors who were treated with bevacizumab as single agent therapy. These heavily pretreated patients sustained very prolonged periods of stable disease (median of 12 months) with very little toxicity and excellent quality of life. The activity of this agent in patients who had failed prior therapies directed against the VEGFR and mTOR suggests that therapy targeting the ligand, VEGF, is still a viable approach in these patients and deserves further study.
With the increasing understanding of the biology of the disease and the development of targeted therapy, there has been a paradigm shift in the treatment of clear cell metastatic renal cell carcinoma (mRCC). Traditionally patients with metastatic RCC have been treated with immunotherapy which has limited efficacy. The multikinase inhibitors sunitinib, sorafenib and pazopanib, the VEGF antibody bevacizumab in combination with interferon and the mTOR inhibitor temsirolimus have all been shown to prolong progression-free survival in phase III studies. Here we review another mTOR inhibitor, everolimus (Afinitor®; Novartis, USA) which was approved in March 2009 by the US FDA for treatment of targeted-therapy refractory metastatic renal cell cancer. The phase III study of everolimus (the RECORD study) was terminated early after a significant difference in efficacy was noted in the treatment arm with everolimus (progression-free survival of 4.0 months in patients on the treatment arm vs 1.9 months in the placebo arm). The most common adverse events were stomatitis, pneumonitis, fatigue and infections. We review Phase I–III data with a particular emphasis on safety data and patient focused outcomes.
metastatic renal cell carcinoma; targeted therapy; mTOR; everolimus
The treatment of metastatic renal cell carcinoma (mRCC) has recently evolved from being predominantly cytokine-based treatment to the use of targeted agents, which include sorafenib, sunitinib, bevacizumab (plus interferon alpha [IFN-α]), temsirolimus, everolimus, pazopanib, and most recently, axitinib. Improved understanding of the molecular pathways implicated in the pathogenesis of RCC has led to the development of specific targeted therapies for treating the disease. In Korea, it has been 5 years since targeted therapy became available for mRCC. Thus, we now have broader and better therapeutic options at hand, leading to a significantly improved prognosis for patients with mRCC. However, the treatment of mRCC remains a challenge and a major health problem. Many questions remain on the efficacy of combination treatments and on the best methods for achieving complete remission. Additional studies are needed to optimize the use of these agents by identifying those patients who would most benefit and by elucidating the best means of delivering these agents, either in combination or as sequential single agents. Furthermore, numerous ongoing research activities aim at improving the benefits of the new compounds in the metastatic situation or their application in the early phase of the disease. This review introduces what is currently known regarding the fundamental biology that underlies clear cell RCC, summarizes the clinical evidence supporting the benefits of targeted agents in mRCC treatment, discusses survival endpoints used in pivotal clinical trials, and outlines future research directions.
Molecular targeted therapy; mTOR protein; Renal cell carcinoma; Vascular endothelial growth factor A
Chemotherapy and immunotherapy failed to deliver decisive results in the systemic treatment of metastatic
renal cell carcinoma. Agents representing the current standards operate on members of the RAS signal transduction
pathway. Sunitinib (targeting vascular endothelial growth factor), temsirolimus (an inhibitor of the mammalian target of
rapamycin - mTOR) and pazopanib (a multi-targeted receptor tyrosine kinase inhibitor) are used in the first line of
recurrent disease. A combination of bevacizumab (inhibition of angiogenesis) plus interferon α is also first-line therapy.
Second line options include everolimus (another mTOR inhibitor) as well as tyrosine kinase inhibitors for patients who
previously received cytokine. We review the results of clinical investigations focusing on survival benefit for these agents.
Additionally, trials focusing on new agents, including the kinase inhibitors axitinib, tivozanib, dovitinib and cediranib and
monoclonal antibodies including velociximab are also discussed. In addition to published outcomes we also include
follow-up and interim results of ongoing clinical trials. In summary, we give a comprehensive overview of current
advances in the systemic treatment of metastatic renal cell carcinoma.
Biomarkers; everolimus; renal cell cancer; sunitinib; temsirolimus; tyrosine kinase inhibitors.
The agents currently approved for use in metastatic renal cell carcinoma (mRCC) can be divided broadly into two categories: (1) vascular endothelial growth factor receptor (VEGFR)-directed therapies or (2) inhibitors of the mammalian target of rapamycin (mTOR). The latter category includes everolimus and temsirolimus, both approved for distinct indications in mRCC. Everolimus gained its approval on the basis of phase III data showing a benefit in progression-free survival relative to placebo in patients previously treated with sunitinib and/or sorafenib. In contrast, temsirolimus was approved on the basis of a phase III trial in treatment-naïve patients with poor-risk mRCC, demonstrating an improvement in overall survival relative to interferon-alfa. While these pivotal trials have created unique positions for everolimus and temsirolimus in current clinical algorithms, the role of mTOR inhibitors in mRCC is being steadily revised and expanded through ongoing trials testing novel sequences and combinations. The clinical development of mTOR inhibitors is outlined herein.
metastatic renal cell carcinoma; mRCC; mTOR inhibitors
Renal cell carcinoma (RCC) accounts for approximately 3% of all cancers and is refractory to cytotoxic chemotherapy – immunotherapy has until recently been the standard of care for advanced disease. Randomised trials reported in the last 5 years have demonstrated that a number of agents including the monoclonal antibody, bevacizumab, and the kinase inhibitors – sorafenib sunitinib, temsirolimus and everolimus – are active in advanced RCC. Bevacizumab is directed against the vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, whilst sorafenib and sunitinib inhibit a number of targets including the VEGF and platelet-derived growth factor (PDGFR) receptor tyrosine kinases. Temsirolimus and everolimus inhibit the intracellular mammalian target of rapamycin (mTOR) kinase. Sunitinib and temsirolimus have demonstrated efficacy in comparison with immunotherapy in the first-line setting in patients with favourable and poor prognosis advanced disease respectively. In the second-line setting, everolimus has shown benefit over placebo in patients who progress following treatment with a VEGF receptor tyrosine kinase inhibitor and sorafenib has demonstrated efficacy in comparison with placebo in patients with immunotherapy-refractory disease. We review here recent clinical trial data and discuss future developments in the systemic treatment of RCC including combination and sequential therapy, adjuvant therapy, the role of biomarkers and the prospects for the development of rational mechanism-directed therapy in this disease.
renal cell carcinoma; bevacizumab; sorafenib; sunitinib; temsirolimus; everolimus
Vascular endothelial growth factor (VEGF) plays a crucial role in tumor angiogenesis. VEGF expression in metastatic renal cell carcinoma (mRCC) is mostly regulated by hypoxia, predominantly via the hypoxia-induced factor (HIF)/Von Hippel-Lindau (VHL) pathway. Advances in our knowledge of VEGF role in tumor angiogenesis, growth, and progression have permitted development of new approaches for the treatment of mRCC, including several agents targeting VEGF and VEGF receptors: tyrosine kinase pathway, serine/threonine kinases, α5β1-integrin, deacetylase, CD70, mammalian target of rapamycin (mTOR), AKT, and phosphatidylinositol 3′-kinase (PI3K). Starting from sorafenib and sunitinib, several targeted therapies have been approved for mRCC treatment, with a long list of agents in course of evaluation, such as tivozanib, cediranib, and VEGF-Trap. Here we illustrate the main steps of tumor angiogenesis process, defining the pertinent therapeutic targets and the efficacy and toxicity profiles of these new promising agents.
Metastatic renal cell carcinoma is uncommon (only 3% of cancers worldwide) but of poor prognosis. Renal cell carcinoma has traditionally been treated with cytokines (interferon-α or interleukin-2). More recently, a more clear understanding of the molecular and cellular mechanisms of the disease, involving the VEGF receptor and mTOR, has led to the discovery of novel therapies. Therapeutic options in patients with advanced RCC include the VEGF receptor inhibitors Sunitinib and Sorafenib, the anti-VEGF monoclonal antibody Bevacizumab and the mTORC1 inhibitors Temsirolimus and Everolimus. In 2009, Everolimus was FDA-approved for the treatment of patients with advanced clear cell RCC which had progressed within 6 months of stopping treatment with Sunitinib or sorafenib, or both drugs. Everolimus resulted in a 70% reduction in the risk of disease recurrence or death. The purpose of this review is to update on the current knowledge of the role of Everolimus in metastatic renal cell carcinoma.
everolimus; renal cell cancer; mTOR
Simultaneous inhibition of the vascular epithelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway may improve treatment response in advanced renal cell carcinoma (RCC). Everolimus, an oral mTOR inhibitor, and sunitinib, an oral tyrosine kinase inhibitor (TKI) targeting VEGF are standard agents in the management of metastatic RCC.
Sequential cohorts of 3 to 6 patients with advanced RCC received dose escalated combinations of sunitinib (37.5 or 50 mg daily, 4 weeks on / 2 weeks off) with everolimus (2.5–5 mg daily or 20–30 mg weekly). Dose-limiting toxicities (DLTs) were assessed in the first 6-week cycle to determine MTD. Pharmacokinetic profiles were obtained.
20 patients (13 clear cell and 7 non-clear cell RCC) were enrolled in 5 cohorts. Daily everolimus was not tolerated when combined with sunitinib; the first 2 patients on the 2nd cohort suffered DLTs. With weekly everolimus, the MTD was 30 mg everolimus on days 7, 14, 21, and 28, plus 37.5 mg sunitinib on days 1–28 of a 42-day cycle; however, chronic treatment was associated with grade 3 and 4 toxicities. A schedule of 20 mg everolimus weekly/37.5 mg sunitinib was tolerated as chronic therapy. Five patients (25%) had confirmed partial responses, 3 had non-clear cell RCC. No unexpected accumulation of everolimus, sunitinib, or N-desethyl sunitinib was observed.
The combination everolimus and sunitinib is associated with significant acute and chronic toxicities and is only tolerated at attenuated doses. Responses were observed in non-clear cell and clear cell RCC.
renal cell carcinoma; everolimus; sunitinib; targeted therapy; combination drug therapy
Metastatic clear cell renal cell cancer has traditionally been treated with cytokines (interferon or interleukin-2). Improved understanding of biology has engendered novel targeted therapeutic agents that have altered the natural history of this disease. The vascular endothelial growth factor and its related receptor and the mTOR signal transduction pathway have particularly been exploited. Sunitinib malate, sorafenib tosylate, temsirolimus, and bevacizumab have improved clinical outcomes in randomized trials. Other multitargeted tyrosine kinase inhibitors (lapatinib, axitinib, pazopanib) and antiangiogenic agents (VEGF Trap, lenalidomide) have also demonstrated activity in early studies. Combinations of these agents are being evaluated. The future of the therapy of renal cancer appears promising owing to the efficacy of these novel agents.
The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine protein kinase positioned at a central point in a variety of cellular signaling cascades. The established involvement of mTOR activity in the cellular processes that contribute to the development and progression of cancer has identified mTOR as a major link in tumorigenesis. Consequently, inhibitors of mTOR, including temsirolimus, everolimus, and ridaforolimus (formerly deforolimus) have been developed and assessed for their safety and efficacy in patients with cancer. Temsirolimus is an intravenously administered agent approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of advanced renal cell carcinoma (RCC). Everolimus is an oral agent that has recently obtained US FDA and EMEA approval for the treatment of advanced RCC after failure of treatment with sunitinib or sorafenib. Ridaforolimus is not yet approved for any indication. The use of mTOR inhibitors, either alone or in combination with other anticancer agents, has the potential to provide anticancer activity in numerous tumor types. Cancer types in which these agents are under evaluation include neuroendocrine tumors, breast cancer, leukemia, lymphoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, sarcoma, endometrial cancer, and non-small-cell lung cancer. The results of ongoing clinical trials with mTOR inhibitors, as single agents and in combination regimens, will better define their activity in cancer.
Metastatic renal cell carcinoma (RCC) poses one of the great therapeutic challenges in oncology. RCC is predominantly refractory to treatment with traditional cytotoxic chemotherapies, and until recently management options were limited to immunotherapy or palliative care. However, in the past few years we have experienced a sea change in the treatment of advanced RCC with the introduction of targeted therapies that derive their efficacy at least in part through alterations in tumor angiogenesis. The tyrosine kinase inhibitors sunitinib, pazopanib, and sorafenib, the monoclonal antibody bevacizumab (in combination with interferon-α), and the rapamycin analogs, temsirolimus and everolimus, are now approved agents in the United States for the treatment of metastatic RCC. Efforts to expand upon these successes include developing novel antiangiogenic agents, optimizing concomitant and sequential regimens, identifying predictors of response to specific treatments, and further dissecting the underlying molecular pathogenesis of RCC to reveal novel therapeutic targets.
carcinoma; renal cell; therapeutics
Renal cell carcinoma (RCC) is one of the most lethal genitourinary malignancies. Recently, there has been a paradigm shift in the management of advanced RCC. New targeted therapies including vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors have been developed which have shown promising results in a patient population who otherwise had very few options for treatment. The first mTOR inhibitor, temsirolimus, an intravenous prodrug, has shown improved overall survival in poor prognosis patients. More recently, an oral mTOR inhibitor, everolimus (RAD 001), has been developed which has been shown to delay disease progression in patients with metastatic RCC who have progressed on other targeted therapies. Although a survival advantage in phase III trials is seen with everolimus, associated systemic toxicities, while generally well tolerated, are not insignificant. These include mucositis, hyperglycemia, hyperlipidemia, and pneumonitis. Despite the side effects, emerging evidence points to everolimus as the optimal second-line treatment for patients with advanced renal cell carcinoma.
metastatic renal cell carcinoma; everolimus; mTOR inhibitors; VEGF inhibitors
A better understanding of the aetiopathogenetic molecular targets in renal cell carcinoma (RCC) and the subsequent advent of targeted therapeutic agents have greatly improved the management and prognosis of RCC and patient survival. However, optimising therapeutic outcomes through appropriate sequential or combination therapy remains a challenge. Our 45-year-old male patient presented with metastatic renal cell carcinoma (mRCC); we effectively managed his aggressive, progressive disease across six lines of treatment, including sequential monotherapy and combination therapy, with targeted agents like sunitinib, everolimus, sorafenib, temsirolimus, and bevacizumab, resulting in a >48-month survival. Appropriate therapy with agents that have non-overlapping target profiles minimised treatment-related toxicities, enabling our patient to tolerate therapy at full doses. This case represents a good example of a significant clinical benefit of targeted therapy beyond the fourth line in mRCC. The survival and prognosis of mRCC patients may thus be significantly improved with the suitable use of newer targeted agents.
metastatic renal cell carcinoma; everolimus; sequential therapy
Over the last 6 years, the treatment of metastatic renal cell carcinoma (mRCC) has undergone dramatic changes. A better understanding of the pathogenesis and tumor biology of sporadic renal cell carcinoma has led to the approval of 6 drug regimens: 3 oral multi-targeted tyrosine-kinase inhibitors (sorafenib, sunitinib, and pazopanib), 2 inhibitors of the mammalian target of rapamycin (temsirolimus and everolimus), and 1 monoclonal antibody against the vascular endothelial growth factor (bevacizumab). Pazopanib, a multi-targeted tyrosine kinase inhibitor that targets VEGFR-1, -2, and-3; PDGFR-α and PDGFR-β, and c-Kit, was approved for the treatment of mRCC in October 2009, several years after the other drugs in its class. The efficacy and safety of pazopanib in Phase I, II, and III trials will be examined and its role in mRCC treatment will be described. Future studies that may clarify pazopanib’s role in mRCC will be discussed. Based on pazopanib’s demonstrated efficacy in treatment-naïve and cytokine-refractory patients, along with a seemingly favorable toxicity profile compared with other multi-targeted tyrosine-kinase inhibitors, pazopanib may have a unique niche in the armamentarium of treatment options for mRCC. Results from ongoing studies are awaited to confirm pazopanib’s favorable efficacy-toxicity ratio, especially in comparison with the previous first-line standard-of-care, sunitinib.
pazopanib; GW786034; VEGFR; TKI; renal cell carcinoma
Multiple molecularly targeted agents (MTAs) have been approved for the management of metastatic renal cell carcinoma(mRCC). Sunitinib and M-TOR inhibitors (temsirolimus, everolimus) are primarily metabolized in the liver, while the metabolism of bevacizumab is unclear. There are limited data on the toxicity profile and efficacy of these agents in patients with renal impairment(RI). This is clinically relevant especially since about one third of mRCC patients have renal dysfunction.
The primary objective was to assess the safety and efficacy of targeted agents in mRCC patients with RI. Medical records of patients with mRCC at Wayne State University started on sunitinib, temsirolimus, everolimus or bevacizumab were reviewed. Patients with a calculated creatinine clearance(CrCl) of ≤60ml/min were deemed to have RI. Data on safety and efficacy of MTA therapy were collected and analyzed with respect to renal function.
RI was observed in 33% of our mRCC patients. The incidence of toxicities, responses, time to progression(TTP), and overall survival(OS) were not significantly different in patients with RI compared to patients with normal renal function. Patients with RI had larger median increases in blood pressure with sunitinib and bevacizumab, increased incidence of thyroid dysfunction with sunitinib, and increased incidence of rash and dose interruptions with m-TOR inhibitors, than did patients with normal renal function.
RI was commonly observed in our mRCC patients. MTAs are well tolerated and efficacy appears to be maintained in patients with RI. Vigilant monitoring of hypertension would be recommended for pts receiving sunitinib and bevacizumab.
renal dysfunction; kidney cancer; sunitinib; temsirolimus; bevacizumab; everolimus
The therapeutic options in metastatic renal cell carcinoma have been recently expanded by the discovery of the VHL gene, the mutation of which is associated with development of clear cell carcinoma, and overexpression of the angiogenesis pathway, resulting in a very vascular tumor. This breakthrough in science led to the development of a variety of small molecules inhibiting the VEGF-dependent angiogenic pathway, such as sunitinib and sorafenib. These agents prolong overall and progression-free survival, respectively. The result was the development of robust front-line therapies which ultimately fail and are associated with disease progression. In this setting, there existed an unmet need for developing second-line therapies for patients with refractory metastatic renal cell carcinoma (MRCC). Everolimus (RAD 001) is an oral inhibitor of the mammalian target of rapamycin (mTOR) pathway. The double-blind, randomized, placebo-controlled phase III trial of everolimus (RECORD-1) conducted in MRCC patients after progression on sunitinib or sorafenib, or both, demonstrated a progression-free survival benefit favoring the study drug (4.9 months vs 1.9 months, HR 0.33, 95% CI 0.25 to 0.43, P ≤ 0 0.001). Everolimus thus established itself as a standard of care in the second-line setting for patients with MRCC who have failed treatment with VEGF receptor inhibitors.
mTOR inhibitor; mammalian target of rapamycin inhibitor; signal transduction inhibitor; renal cell carcinoma; targeted therapy
Targeted therapies have introduced a paradigm shift in the management of metastatic renal cell carcinoma. Currently, four molecules (sunitinib, pazopanib, bevacizumab plus interferon, temsirolimus) are considered in first-line therapy, and three other molecules for second, or subsequent lines of therapy (everolimus, axitinib, sorafenib). In addition, other molecules and sequencing schemes are being tested in ongoing phase II/III studies. We conducted a systematic review using PubMed and several other databases up to December 2011 of prospective and retrospective studies on treatment management of metastatic renal cell carcinoma using targeted therapies, with a special focus on use of sequential treatment. Based on phase III data, the optimal sequencing scheme for patients with clear cell or even non-clear cell histological subtype appears to consist of sunitinib, followed by axitinib, followed by everolimus. Subsequent treatment options rely on lower evidence studies and could consist of fourth-line sorafenib or sunitinib rechallenge. Such therapies would qualify as last recourse options. In another context, temsirolimus may be used in patients who fulfill the Memorial Sloan-Kettering Cancer Center poor risk criteria or who have poor performance status. We conclude that in the current setting, sequential therapy represents the cornerstone of effective management of metastatic renal cell carcinoma.
metastatic renal cell carcinoma; sequential therapy; targeted therapies
This article reviews the clinical evidence supporting the benefits of targeted agents in the treatment of metastatic renal cell carcinoma, discusses survival endpoints used in their pivotal clinical trials, and outlines future research directions.
Although systemic therapy for patients with metastatic renal cell carcinoma (mRCC) was once limited to the cytokines interleukin-2 and interferon (IFN)-α, in recent years several targeted therapies have become available for first- and second-line use. These include sorafenib, sunitinib, bevacizumab (plus IFN-α), temsirolimus, everolimus, and, most recently, pazopanib. This expanded list of treatment options arose from molecular biological research that revealed aberrant signal transduction activities in RCC, enabling the identification of specific molecular targets for therapy. Molecular-targeted therapies have better efficacy and tolerability than cytokine therapy, and many are administered orally. The superior outcomes achieved with molecular-targeted agents are prompting investigators to reconsider overall survival as a primary endpoint in clinical trials, given the inherent complications of a required long duration of follow-up, a required large population, and confounding caused by crossover trial designs or effects of subsequent therapy after progression on the agent of interest. In mRCC trials, progression-free survival has become a popular primary endpoint and has served as the basis of approval for several targeted therapies. In addition to the identification of new agents, current research is focused on the evaluation of combination therapy with targeted agents. As more information regarding mechanisms of disease and drug resistance becomes available, new targets, new targeted agents, and new combinations will be studied with the goal of providing maximal efficacy with minimal toxicity. This article reviews the clinical evidence supporting the benefits of targeted agents in mRCC treatment, discusses survival endpoints used in their pivotal clinical trials, and outlines future research directions.
Angiogenesis inhibitor; Combination drug therapy; Mammalian target of rapamycin; Renal cell carcinoma; Vascular endothelial growth factor
In China, there are currently no approved therapies for the treatment of metastatic renal cell carcinoma (mRCC) following progression with vascular endothelial growth factor (VEGF)-targeted agents. In the phase 3 RECORD-1 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus afforded clinical benefit with good tolerability in Western patients with mRCC whose disease had progressed despite VEGF receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. This phase 1b study was designed to further evaluate the safety and efficacy of everolimus in VEGFr-TKI-refractory Chinese patients with mRCC.
An open-label, multicenter phase 1b study enrolled Chinese patients with mRCC who were intolerant to, or progressed on, previous VEGFr-TKI therapy (N = 64). Patients received everolimus 10 mg daily until objective tumor progression (according to RECIST, version 1.0), unacceptable toxicity, death, or study discontinuation for any other reason. The final data analysis cut-off date was November 30, 2011.
A total of 64 patients were included in the study. Median age was 52 years (range, 19–75 years) and 69% of patients were male. Median duration of everolimus therapy was 4.1 months (range, 0.0-16.1 months). Expected known class-effect toxicities related to mTOR inhibitor therapy were observed, including anemia (64%), hypertriglyceridemia (55%), mouth ulceration (53%), hyperglycemia (52%), hypercholesterolemia (50%), and pulmonary events (31%). Common grade 3/4 adverse events were anemia (20%), hyperglycemia (13%), increased gamma-glutamyltransferase (11%), hyponatremia (8%), dyspnea (8%), hypertriglyceridemia (6%), and lymphopenia (6%). Median PFS was 6.9 months (95% CI, 3.7-12.5 months) and the overall tumor response rate was 5% (95% CI, 1-13%). The majority of patients (61%) had stable disease as their best overall tumor response.
Safety and efficacy results were comparable to those of the RECORD-1 trial. Everolimus is generally well tolerated and provides clinical benefit to Chinese patients with anti-VEGF-refractory mRCC.
Asian; Everolimus; mTOR inhibitor; Renal cell cancer; Sunitinib; Sorafenib
Sunitinib is an oral receptor tyrosine kinase inhibitor with potent antiangiogenic and antitumor activity that is approved for the treatment of advanced renal cell carcinoma (RCC), malignant gastrointestinal stromal tumors and pancreatic neuroendocrine tumors. Well-known side effects of sunitinib include hypertension, fatigue, thyroid dysfunction, cardiotoxicity, gastrointestinal toxicity and skin toxicity. In this study, we report the case of a 61-year-old male with papillary metastatic RCC who responded to sunitinib but developed generalized tonic-clonic seizures during the third cycle. Magnetic resonance imaging (MRI) was compatible with reversible posterior leukoencephalopathy syndrome (RPLS). After the administration of anti-epileptic drugs and the withdrawal of sunitinib there was rapid clinical improvement. Notably, radiological characteristics of RPLS persisted during second-line therapy with the mammalian target of rapamycin (mTOR) inhibitor everolimus and only resolved when everolimus was terminated due to disease progression. Although sunitinib-induced RPLS has been reported previously, our case is the first to additionally suggest that everolimus may sustain and therefore potentially contribute to the occurrence of RPLS.
renal cell cancer; sunitinib; reversible posterior leukoencephalopathy syndrome
The landscape of renal cell carcinoma (RCC) treatment has changed dramatically during recent years. Bevacizumab/interferon, sunitinib, sorafenib, temsirolimus, everolimus, and pazopanib have been proven effective in metastatic RCC. Axitinib is a novel tyrosine kinase inhibitor, which inhibits the vascular endothelial growth factor receptor (VEGFR) at subnanomolar level. Based on this extraordinary VEGFR inhibition, axitinib is considered a next-generation agent. The recent AXIS trial reported on axitinib’s efficacy in second line treatment of RCC, which led to its recent approval in the USA. This review focuses on the clinical efficacy of axitinib in RCC patients.
tyrosine kinase inhibitor; axitinib; tivozanib; renal cell carcinoma; VEGF