Drug insight: advances in renal cell carcinoma and the role of targeted therapies

In metastatic renal cell carcinoma (RCC) immunotherapy results in a small but important improvement in overall survival, but a need exists to develop more-effective systemic therapies. Recent developments in our understanding of the molecular biology of RCC have identified several pathways associated with the development of the disease. A number of strategies designed specifically to target these pathways have resulted. Initial studies have shown marked clinical benefits of so-called 'targeted therapies'. Sunitinib, sorafenib and axitinib are kinase inhibitors that inhibit the VEGF, platelet-derived growth factor and c-kit receptor tyrosine kinases. Bevacizumab is a monoclonal antibody that is directed against VEGF. Temsirolimus inhibits the mammalian target of rapamycin. These agents have all shown considerable activity with manageable toxicity in phase II and III studies in both previously treated and untreated patients. In phase III studies, sorafenib and bevacizumab have been associated with prolonged progression-free survival compared with placebo. Phase III data have shown improvements in progression-free and overall survival with sunitinib and temsirolimus, respectively, compared with interferon alfa. Additional studies are needed to determine the optimum utilization of these agents at the appropriate stage of disease and in the best combinations for maximal clinical benefit.     

Adjuvante postoperative Therapie beim Nierenzellkarzinom

Nephrectomy provides curative treatment of local renal cell carcinoma. Unfortunately 30% of patients experience recurrence and metastases with 7 year overall survival rates below 10%. In these patients adjuvant therapy would be indicated. The risk stratification is imperative for proper patient selection in adjuvant settings. Ideally high-risk patients can be identified and efficient therapy can be offered to those who would benefit most from adjuvant therapy. Hormonal and immunotherapy has been administered in this setting with high toxicity and no improvement in progression-free survival. In contrast adjuvant therapy with autologous tumor cell vaccine (Reniale®) demonstrated an improvement of progression-free survival and overall survival with moderate side effects. Targeted small molecule inhibitors such as sunitinib, sorafenib, temsirolimus and everolimus have demonstrated great potential for advanced or disseminated renal cell carcinoma. The adjuvant use of these agents seems to be promising. Sorafenib and sunitinib are currently under clinical investigation in several phase III trials. Another phase III trial investigating the adjuvant use of the monoclonal antibody G250 for clear cell renal carcinoma is being carried out. First results of the studies are expected to be available in 2012.     

Improving outcomes in patients with advanced renal cell carcinoma

The emergence of targeted therapies for advanced renal cell carcinoma has been a dramatic turning point in improving outcomes for the majority of patients with this disease. In study populations comprising primarily good- and intermediate-risk patients with clear cell renal cell carcinoma and prior nephrectomy, prolonged progression-free survival was demonstrated for three angiogenesis-targeted agents: sunitinib (compared with interferon [IFN]), bevacizumab plus IFN (vs IFN alone) and sorafenib (vs placebo in cytokine-refractory patients). As a first-line treatment for patients with multiple poor-risk factors, temsirolimus, which inhibits mTOR, has improved not only progression-free survival compared with IFN but, more importantly, overall survival. Further studies are needed to determine whether combinations and/or sequencing of these targeted agents can further improve outcomes.     

Improving outcomes in patients with advanced renal cell carcinoma

The emergence of targeted therapies for advanced renal cell carcinoma has been a dramatic turning point in improving outcomes for the majority of patients with this disease. In study populations comprising primarily good- and intermediate-risk patients with clear cell renal cell carcinoma and prior nephrectomy, prolonged progression-free survival was demonstrated for three angiogenesis-targeted agents: sunitinib (compared with interferon [IFN]), bevacizumab plus IFN (vs IFN alone) and sorafenib (vs placebo in cytokine-refractory patients). As a first-line treatment for patients with multiple poor-risk factors, temsirolimus, which inhibits mTOR, has improved not only progression-free survival compared with IFN but, more importantly, overall survival. Further studies are needed to determine whether combinations and/or sequencing of these targeted agents can further improve outcomes.     

Targeted therapies in metastatic renal cell carcinoma: the light at the end of the tunnel

The year 2006 will mark a turning point in the daily management of patients with metastatic renal cell carcinoma. The impact of immunotherapy with interferon-alpha or interleukin-2 has been shown to be restricted to a minority of patients. The growing understanding of molecular mechanisms involved in the pathogenesis of the disease, especially clear-cell carcinoma, has led to the development of multiple targeted therapies with significant clinical benefits. Two compounds that predominantly inhibit the tyrosine kinase activity of the vascular endothelial growth factor receptor have been shown to improve the progression-free survival of patients in first- (sunitinib versus interferon-alpha) or second-line (sorafenib versus placebo) treatment. Temsirolimus, an agent that inhibits the serine-threonine kinase activity of the mammalian target of rapamycin, offers better overall survival than interferon in patients with poor-risk characteristics. Further studies are needed to determine the optimal combinations of these agents in metastatic disease and to assess their impact in the adjuvant setting.     

What Role Do Combinations of Interferon and Targeted Agents Play in the First-Line Therapy of Metastatic Renal Cell Carcinoma?

Interferons (IFNs) are a class of cytokines with pleotropic actions that regulate a variety of cellular activities. Clinical trials with recombinant IFNs (IFN-α2a and IFN-α2b) have demonstrated clinical activity in patients with advanced renal cell carcinoma (RCC). Their efficacy is characterized by a low overall tumor regression rate of < 15%, progression-free survival of 4-5 months, and overall median survival of 10-18 months. This cytokine became the standard of care for patients with metastatic RCC and was then used as the comparator arm in a series of phase II and III clinical trials that have defined a new treatment paradigm for patients with advanced RCC. This paradigm uses the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib, the mammalian target of rapamycin (mTOR) inhibitor temsirolimus, and the vascular endothelial growth factor monoclonal antibody bevacizumab. These 3 categories of agents were then investigated in combination with IFN-α in a series of preclinical and clinical studies. The collective data from these reports suggest the combination of IFN-α and bevacizumab is active and has a role in RCC therapy, whereas combinations with the TKIs or mTOR inhibitors have limited efficacy and/or excessive toxicity. The clinical and preclinical studies leading to these conclusions are reviewed herein.     

4th International Symposium on Leukemia and Lymphoma – Molecular Pharmacology and New Treatment Modalitie

Renal cell carcinomas (RCCs) represent one of the ten leading cancer entities with an increasing incidence especially in the western world. Unfortunately, about 25% of the patients develop metastatic RCC (mRCC) associated with a most unfavorable prognosis. In the recent years, various new agents targeting VEGF or VEGF receptor (VEGFR) or the mTOR pathway have been approved for the treatment of mRCC with significant prolongation of progression-free survival and, in part, of overall survival (OS). Targeting the mTOR kinase is an interesting option for mRCC. Temsirolimus, one of the available mTOR inhibitors, has been approved as a single agent in poor-risk mRCC patients based on the pivotal Phase III trial showing a significant superiority in OS versus IFN-α or temsirolimus + IFN-α, which has been verified by a pivotal Phase III trial. The benefit has been shown for clear cell carcinoma and papillary RCC as well. For poor prognosis patients, temsirolimus improves median survival by 3.6 months. In second-line treatment compared with sorafenib following first-line treatment with sunitinib temsirolimus showed a relative progression-free survival benefit for patients with nonclear cell RCC with temsirolimus. The median OS for the temsirolimus group was 12.27 and 16.64 months for the sorafenib group. In 2007, the US FDA granted approval for temsirolimus for the treatment of advanced RCC.     

Bevacizumab in combination with IFN-α in metastatic renal cell carcinoma: the AVOREN trial

Metastatic renal cell carcinoma (mRCC) is tumor resistant to all cytotoxic agents. During the last decade, effective targeted therapies emerged including sunitinib, pazopanib and the combination of bevacizumab with IFN-α. The use of bevacizumab plus IFN-α combination in mRCC is supported by the AVOREN trial. Although the primary end point of the AVOREN trial was overall survival, progression-free survival was used to evaluate efficacy and served as the basis of regulatory submission owing to the advent of targeted agents that probably resulted in the prolongation of overall survival in both experimental and control arms. The doubling of median progression-free survival in the AVOREN trials (from 5.4 to 10.2 months) is remarkably similar compared with the results of Phase III trials with sunitinib and pazopanib. Bevacizumab plus IFN-α is the only combined regimen currently used in mRCC and serves as a comparator in the trials combining bevacizumab with other agents.     

Targeting angiogenesis in metastatic breast cancer

Angiogenesis has become an important target in the treatment of several solid tumors, including breast cancer. As monotherapy, antiangiogenic agents have demonstrated limited activity in metastatic breast cancer (MBC); therefore, they have generally been developed for use in combination with chemotherapies. Thus far, the experience with antiangiogenic agents for MBC has been mixed. The results from one study assessing addition of the monoclonal antibody bevacizumab to paclitaxel led to approval of bevacizumab for MBC. However, the modest improvement of progression-free survival rates in subsequent MBC studies has led to reappraisal of bevacizumab. Phase III studies have not produced evidence supporting use of the multikinase inhibitor sunitinib alone or in combination with MBC chemotherapy. Experience with sorafenib in a phase IIb program indicates potential when used in select combinations, particularly with capecitabine; however, phase III confirmatory data are needed. Although antiangiogenic therapies combined with chemotherapy have increased progression-free survival rates for patients with MBC, increases in overall survival times have not been observed. Some studies have tried to combine antiangiogenic agents such as bevacizumab and sunitinib or sorafenib, but that approach has been limited because of toxicity concerns. Sequential use of antiangiogenic agents with differing mechanisms of action may be an effective approach. Despite setbacks, angiogenesis will likely remain an important target of treatment for selected patients with MBC.     

Targeting von Hippel-Lindau pathway in renal cell carcinoma.

Inheritance of a defective copy of the von Hippel-Lindau (VHL) gene leads to the most common cause of inherited renal cell carcinoma (RCC). In addition, most patients with sporadic RCC have aberrant VHL. In the absence of VHL, hypoxia-inducible factor alpha accumulates, leading to production of several growth factors, including vascular endothelial growth factor and platelet-derived growth factor. We review here the biology of RCC and how a combination of proximal and distal block of VHL/hypoxia-inducible factor alpha pathway by novel targeted agents, including sunitinib, sorafenib, bevacizumab, everolimus, and temsirolimus, has led to significant improvements in progression-free survival.     

Targeted therapies for metastatic renal cell carcinoma: an overview of toxicity and dosing strategies

The targeted therapies sunitinib, sorafenib, temsirolimus, and bevacizumab (when used in combination with interferon-alpha2a) have dramatically improved outcomes for patients with advanced renal cell carcinoma (RCC). Clinical application of these novel agents outside the trial setting, however, may present some challenges for treating individual patients with unique needs. In some patients, dose modifications may be considered for potential drug interactions and for management of severe cases of hematologic or nonhematologic toxicities. The more common grade 3 or 4 side effects with sunitinib and sorafenib include hypertension, fatigue, hand-foot syndrome, elevated lipase, lymphopenia, and neutropenia. Congestive heart failure is a less common but serious side effect that warrants treatment discontinuation. Temsirolimus exhibits a different side-effect profile, with the more common grade 3 or 4 side effects being metabolic in nature (i.e., elevated triglycerides, elevated glucose, hypophosphatemia) as a result of its inhibitory effects on the mammalian target of rapamycin-regulated lipid and glucose pathways. Asthenia, rash, and dyspnea also occur in patients receiving temsirolimus. Virtually all of the side effects associated with these agents can be managed effectively in the majority of patients with medical treatment or supportive interventions. Recognition and prompt management of side effects are important to avoid unnecessary dose reductions that may result in suboptimal efficacy.     

Alternate sunitinib schedules in patients with metastatic renal cell carcinoma

Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor exhibiting antiangiogenic activity. Sunitinib demonstrated improved outcomes in comparison to interferon-α in a large phase III study of treatment naïve patients with metastatic renal cell carcinoma. Maintaining patients on sunitinib treatment is essential for a sustained disease control as higher exposure to sunitinib has been associated with an improved overall response rate, progression-free survival and overall survival. Various studies have compared the outcomes of patients undergoing sunitinib therapy based on modifications from their standard dose and schedule. Several studies have shown that switching to an alternate schedule with more frequent dose interruptions without affecting dose density over a 6-week cycle is associated with improved outcomes and increased tolerability.     

Temisorlimus in the treatment of advanced renal cell carcinoma

Temsirolimus is a novel inhibitor of mammalian target of rapamycin (mTOR), which is a central regulator of the response of tumour cells to growth and survival signals. When heavily pretreated patients with advanced solid tumours received intravenous (IV) temsirolimus over a broad dose range, antitumour activity was observed in various tumour types, including advanced renal cell carcinoma (RCC). A study of single-agent temsiroliums in patients with cytokine-refractory metastatic RCC subsequently demonstrated antitumour activity and encouraging progression-free survival and overall survival. Temsirolimus was generally well tolerated over the 3 dose levels tested (25 mg, 75 mg or 250 mg weekly as a 30-minute IV infusion). The most frequent grade 3 or 4 treatment-related adverse events reported (n=110) were hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%). Results from a randomized phase III study that enrolled previously untreated patients with advanced RCC and poor-prognostic features have recently demonstrated a significant increase in overall survival (p=0.0089) for patients who received temsirolimus 25 mg IV, 30-minute infusion once weekly compared with those who received interferon-alpha up to 18 million units subcutaneously thrice weekly. On the basis of improved survival, temsirolimus can be considered a first-line treatment for patients with advanced RCC.     

Expanding the clinical development of bevacizumab

Bevacizumab (Avastin; Genentech, Inc.; South San Francisco, CA) is a recombinant, humanized monoclonal antibody to vascular endothelial growth factor, a key regulator of tumor angiogenesis. Bevacizumab demonstrated potent antitumor activity in preclinical models and has also shown biologic activity and clinical benefit in clinical studies. Notably, a randomized, placebo-controlled phase II trial in renal cell carcinoma demonstrated a significantly longer time to tumor progression with bevacizumab monotherapy. Furthermore, in a phase III trial for untreated advanced colorectal cancer, the addition of bevacizumab to chemotherapy led to significantly longer overall survival and progression-free survival times than chemotherapy alone. The clinical development of bevacizumab has been expanded to include confirmatory phase III trials and exploratory phase II trials in a variety of solid tumors and hematologic malignancies. Treatment regimens being examined include bevacizumab alone and in combination with conventional chemotherapy, radiation, immune therapy, and biologically targeted agents.     

Pazopanib as Second-Line Treatment After Sunitinib or Bevacizumab in Patients With Advanced Renal Cell Carcinoma: A Sarah Cannon Oncology Research Consortium Phase II Trial

BackgroundThis phase II trial examined the activity and toxicity of second-line treatment with pazopanib after failure of first-line single-agent treatment with sunitinib or bevacizumab in patients with advanced clear cell renal carcinoma.Patients and MethodsFifty-five patients with metastatic clear cell renal carcinoma who had previously received first-line treatment with sunitinib (39 patients) or bevacizumab (16 patients) were enrolled. Patients received pazopanib 800 mg orally daily and were evaluated for response after 8 weeks of treatment. Responses were measured using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, and confirmed with repeated scans after 8 weeks. Patients with objective response or stable disease continued treatment until disease progression or unacceptable toxicity occurred.ResultsFifteen of 55 patients (27%) had objective response to pazopanib. An additional 27 patients (49%) had stable disease, for a disease control rate of 76%. After a median follow-up of 16.7 months, the median progression-free survival for the entire group was 7.5 months (95% confidence interval, 5.4-9.4 months). Similar progression-free survival was observed regardless of whether previous treatment was with sunitinib or bevacizumab. The estimated overall survival rate for the entire group at 24 months was 43%.ConclusionPazopanib is an active agent for the treatment of advanced clear cell renal carcinoma, even after failure of sunitinib or bevacizumab. Treatment with pazopanib should be considered early in the sequence of therapy for patients with advanced renal cell carcinoma.     

Bévacizumab et temsirolimus: quel apport dans la stratégie de prise en charge du cancer du rein métastatique ?

Bevacizumab and temsirolimus are two drugs recently developed and integrated in the first-line therapeutic management of patients with advanced ormetastatic renal cell carcinoma. Bevacizumab, a monoclonal antibody directed against circulating VEGF, has shown a significant benefit in progression-free survival during a randomized phase III trial in comparison to alpha interferon (5.4 to 10.2 months; HR: 0.63; P < 0.0001). Temsirolimus, an agent that inhibits the mTOR pathway, has shown a significant gain in overall survival, in a randomized phase III trial conducted in a population of patients with poor risk feature of metastatic renal cell carcinoma, compared to alpha interferon (7.3 to 10.9 months; HR: 0.73; P < 0.0069).     

How to carry out retrospective studies in metastatic renal cell cancer: two caveats that should be avoided

The results achieved with targeted therapy have changed the natural course of kidney cancer not amenable to local therapy. Sunitinib, bevacizumab and pazopanib are approved in the first-line setting for patients at good/intermediate prognosis, while temsirolimus should be the first-line agent to be used in patients at poor prognosis. The oncology community has been eagerly awaiting results as far as second-line treatment is concerned. The RECORD-1 and AXIS trials provided evidence in favor of everolimus and axitinib, respectively, in patients pretreated with VEGF-directed agents. As the number of available agents grows, so does the possibility of using multiple lines of therapy with a potential benefit in overall survival. The third-line setting has been poorly investigated, and no comparative prospective trials are presently available. Retreatment with VEGF-directed therapy may be an option in everolimus-pretreated patients, with the possibility that mTOR inhibitors may reverse resistance to VEGF-directed therapy. Grunwald et al. presented retrospective data showing that retreatment with VEGF-directed targeted agents, including sunitinib, bevacizumab/interferon, dovitinib and sorafenib, was associated with a progression-free survival time of approximately 5 months. Although the evidence provided by retrospective studies is weak, their role in highlighting matters of clinical relevance deserving investigation is undoubtful, as demonstrated by the retrospective study discussed in this paper.     

Therapy innovations: tyrosine kinase inhibitors for the treatment of pancreatic neuroendocrine tumors

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) show limited sensitivity to cytotoxic agents, requiring the search for novel therapies. Recently, data from a phase III trial demonstrated that sunitinib produces a clinically significant improvement in progression-free survival in patients with unresectable, advanced, or metastatic GEP-NETs. Based on this finding, sunitinib became the first targeted drug approved for the treatment of GEP-NETs, paving the way for the approval of other anticancer agents in this drug-orphan disease. To date, results of trials involving other multitargeted tyrosine kinase inhibitors, such as sorafenib, the monoclonal antibody bevacizumab, and insulin-like growth factor 1 receptor inhibitors, have also shown promising results, and some are already being studied in phase III trials. This review updates the results of ongoing trials using inhibitors of growth factors and tyrosine kinase receptors involved in the carcinogenesis of GEP-NETs.     

Current Algorithms and Prognostic Factors in the Treatment of Metastatic Renal Cell Carcinoma

Metastatic renal cell carcinoma (RCC) is highly resistant to chemotherapy but responds modestly to cytokine therapy. The prognosis for longterm survival is poor. Approximately 10% of patients who present with metastatic disease or relapse after nephrectomy are alive at 5 years. Identification of prognostic or predictive factors for individual patient outcomes is necessary in order to develop tailored treatments that reduce the risk of relapse and enhance the chance of successful management. The relationship between pretreatment clinical features and survival has been evaluated in studies leading to the creation of a Memorial Sloan- Kettering Cancer Center (MSKCC) risk model. Additionally, the cloning of the von Hippel—Lindau tumor suppressor gene, and the elucidation of its role in upregulating growth factors associated with angiogenesis, has provided insight into RCC biology and defined a series of targets for novel therapeutic agents. These targeted agents, including sunitinib, sorafenib, temsirolimus, everolimus, and bevacizumab plus interferon-α, have shown benefit in phase III trials in first- and second-line therapy. Analysis of the data from these trials and use of prognostic models have resulted in a new paradigm for the treatment of metastatic RCC. Herein, we review these targeted agents, the MSKCC risk model, and the new paradigm for treatment of metastatic RCC.     

Targeted therapy in renal cancer

Renal cell cancer (RCC) has an increasing incidence internationally and is a disease for which there have been limited therapeutic options until recently. The last decade has seen a vastly improved understanding of the biological and clinical factors that predict the outcome of this disease. We now understand some of the different molecular underpinnings of renal clear cell carcinoma by mutation or silencing of the von Hippel Lindau (VHL) gene and subsequent deregulated proliferation and angiogenesis. Survival in advanced disease is predicted by factors (performance status, anemia, hypercalcemia, and serum lactate dehydrogenase, time from diagnosis to recurrence) incorporated into the Memorial Sloan Kettering Cancer Center (MSKCC) criteria (also referred to as 'Motzer' criteria). These criteria allow classification of patients with RCC into good, intermediate and poor risk categories with median overall survivals of 22 months, 12 months and 5.4 months, respectively. Predicated upon these advances, six new targeted drugs (sorafenib, sunitinib, temsirolimus, everolimus, bevacizumab and pazopanib) have been tested in well-designed phase III trials, selected or stratified for MSKCC risk criteria, with positive results. All of these new drugs act at least in part through vascular endothelial growth factor (VEGF) mediated pathways with other potential therapeutic impact on platelet-derived growth factor (PDGF), raf kinase and mammalian target of rapamycin (mTOR) pathways. Importantly, data from each of these trials show a consistent doubling of progression-free survival (PFS) over prior standard of care treatments. In addition, sorafenib, sunitinib and temsirolimus, have demonstrated significant overall survival (OS) benefits as well; further follow-up is required to determine whether the disease control exhibited by everolimus and pazopanib will translate into a survival advantage. These drugs are generally well tolerated, as demonstrated by quality-of-life improvement in clinical trials, and result in clinical benefit for in excess of 70% of patients treated. They have challenged the traditional outcomes of clinical trial design by achieving their benefits with relatively few radiographic responses, but high rates of disease stability. The unique side-effect profile coupled with the chronicity of therapy requires increased vigilance to maximize exposure to the drugs while maintaining quality of life and minimizing toxicity. This review focuses on the background, clinical development and practical use of these new drugs in RCC.