Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell Carcinoma.

PURPOSE: A randomized, phase III trial demonstrated superiority of sunitinib over interferon alfa (IFN-α) in progression-free survival (primary end point) as first-line treatment for metastatic renal cell carcinoma (RCC). Final survival analyses and updated results are reported. PATIENTS AND METHODS: Seven hundred fifty treatment-naïve patients with metastatic clear cell RCC were randomly assigned to sunitinib 50 mg orally once daily on a 4 weeks on, 2 weeks off dosing schedule or to IFN-α 9 MU subcutaneously thrice weekly. Overall survival was compared by two-sided log-rank and Wilcoxon tests. Progression-free survival, response, and safety end points were assessed with updated follow-up. RESULTS: Median overall survival was greater in the sunitinib group than in the IFN-α group (26.4 v 21.8 months, respectively; hazard ratio [HR] = 0.821; 95% CI, 0.673 to 1.001; P = .051) per the primary analysis of unstratified log-rank test (P = .013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P = .049). Within the IFN-α group, 33% of patients received sunitinib, and 32% received other vascular endothelial growth factor-signaling inhibitors after discontinuation from the trial. Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-α (P < .001). Objective response rate was 47% for sunitinib compared with 12% for IFN-α (P < .001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%). CONCLUSION: Sunitinib demonstrates longer overall survival compared with IFN-α plus improvement in response and progression-free survival in the first-line treatment of patients with metastatic RCC. The overall survival highlights an improved prognosis in patients with RCC in the era of targeted therapy.

Summary from the Kidney Cancer Association's Inaugural Think Thank: Coalition for a Cure.

Close to 74,000 cases of renal cell carcinoma (RCC) are diagnosed each year in the United States. The past 2 decades have shown great developments in surgical techniques, targeted therapy and immunotherapy agents, and longer complete response rates. However, without a global cure, there is still room for further advancement in improving patient care in this space. To address some of the gaps restricting this progress, the Kidney Cancer Association brought together a group of 27 specialists across the areas of clinical care, research, industry, and advocacy at the inaugural "Think Tank: Coalition for a Cure" session. Topics addressed included screening, imaging, rarer RCC subtypes, combination drug therapy options, and patient response. This commentary summarizes the discussion of these topics and their respective clinical challenges, along with a proposal of projects for collaboration in overcoming those needs and making a greater impact on care for patients with RCC moving forward.

Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of renal cell carcinoma.

Immunotherapy has produced durable clinical benefit in patients with metastatic renal cell cancer (RCC). In the past, patients treated with interferon-alpha (IFN) and interleukin-2 (IL-2) have achieved complete responses, many of which have lasted for multiple decades. More recently, a large number of new agents have been approved for RCC, several of which attack tumor angiogenesis by inhibiting vascular endothelial growth factors (VEGF) and VEGF receptors (VEGFR), as well as tumor metabolism, inhibiting the mammalian target of rapamycin (mTOR). Additionally, a new class of immunotherapy agents, immune checkpoint inhibitors, is emerging and will play a significant role in the treatment of patients with RCC. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a Task Force, which met to consider the current role of approved immunotherapy agents in RCC, to provide guidance to practicing clinicians by developing consensus recommendations and to set the stage for future immunotherapeutic developments in RCC.

The Cost of Hope: a candid roundtable discussion.

For Amanda Bennett and her husband Terence Foley, a 7-year battle with kidney cancer resulted in a price tag of more than $600,000, most of it spent in the final 2 years of his life. Ms. Bennett's memoir, The Cost of Hope, chronicles the couple's emotional struggle and the financial irrationality she uncovered when navigating the cancer continuum. She shared her experience in her keynote address at the NCCN 18th Annual Conference, which was followed by a roundtable discussion in which panelists discussed the difficulties inherent in dealing with cancer "uncertainties," the balancing act that seeks to maintain hope in the context of a poor prognosis, and the problem of a health care system that spends too much on some aspects of care while ignoring others.

Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma.

PURPOSE: Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC. PATIENTS AND METHODS: Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR). RESULTS: Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli. CONCLUSION: Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations.

Temsirolimus: a safety and efficacy review.

INTRODUCTION: The vascular endothelial growth factor (VEGF) pathway and the mammalian Target of Rapamycin (mTOR) represent the most frequently exploited targets in renal cell carcinoma (RCC). Temsirolimus is an inhibitor of mTOR, and is a unique ester derivative of sirolimus, a macrocyclic lactone, with improved pharmaceutical properties, including stability and solubility. Temsirolimus binds to the cytoplasmic protein FKBP-12, and the complex binds and inhibits mTOR. AREAS COVERED: This review summarizes the clinical findings and safety of temsirolimus in RCC patients. EXPERT OPINION: A Phase III clinical trial has demonstrated that temsirolimus has statistically significant advantages over treatment with IFN-α in RCC patients with poor prognosis, in terms of OS (overall survival), PFS (progression-free survival), and tumor response. Median OS was improved 49% compared to IFN-α, and median PFS was approximately doubled. It is now considered the standard for RCC patients with poor prognostic features. The possibility that this agent is useful in metastatic non-clear cell carcinoma patients has also been suggested by a subset analysis of the pivotal Phase III trial. Studies in untreated favorable and intermediate risk clear cell and refractory mRCC patients are required.

Third generation tyrosine kinase inhibitors and their development in advanced renal cell carcinoma.

Angiogenesis in general and the vascular endothelial growth factor (VEGF) signaling axis in particular is a validated target in renal cell carcinoma (RCC). Clear-cell carcinoma of the kidney is now recognized as a malignancy that is sensitive to inhibitors of the VEGF pathway. Treatment options for patients with metastatic renal cell carcinoma have evolved in dramatic fashion over the past 6 years, and a new paradigm has developed. The cytokines interferon-α and interleukin-2 were previously utilized for therapy, but since December 2005, six new agents have been approved in the United States for the treatment of advanced RCC. Two are tyrosine kinase inhibitors (TKI's) including sunitinib and recently pazopanib, and the multikinase inhibitor sorafenib. The current review examines the evolving data with the next generation of TKI's, axitinib and tivozanib being developed for the treatment of advanced RCC. These agents were synthesized to provide increased target specificity and enhanced target inhibition. The preclinical and clinical data are examined, an overview of the development of these TKI's is provided, and discussion plus speculation concerning their potential roles as RCC therapy is provided.

Differing von hippel lindau genotype in paired primary and metastatic tumors in patients with clear cell renal cell carcinoma.

In sporadic clear cell renal cell carcinoma (CCRCC), the von Hippel Lindau (VHL) gene is inactivated by mutation or methylation in the majority of primary (P) tumors. Due to differing effects of wild-type (WT) and mutant (MT) VHL gene on downstream signaling pathways regulating angiogenesis, VHL gene status could impact clinical outcome. In CCRCC, comparative genomic hybridization analysis studies have reported genetic differences between paired P and metastatic (M) tumors. We thus sequenced the VHL gene in paired tumor specimens from 10 patients to determine a possible clonal relationship between the P tumor and M lesion(s) in patients with CCRCC. Using paraffin-embedded specimens, genomic DNA from microdissected samples (>80% tumor) of paired P tumor and M lesions from all 10 patients, as well as in normal tissue from 6 of these cases, was analyzed. The DNA was used for PCR-based amplification of each of the 3 exons of the VHL gene. Sequences derived from amplified samples were compared to the wild-type VHL gene sequence (GenBank Accession No. AF010238). Methylation status of the VHL gene was determined using VHL methylation-specific PCR primers after DNA bisulfite modification. In 4/10 (40%) patients the VHL gene status differed between the P tumor and the M lesion. As expected, when the VHL gene was mutated in both the P tumor and M lesion, the mutation was identical. Further, while the VHL genotype differed between the primary tumor in different kidneys or multiple metastatic lesions in the same patient, the VHL germline genotype in the normal adjacent tissue was always wild-type irrespective of the VHL gene status in the P tumor. These results demonstrate for the first time that the VHL gene status can be different between paired primary and metastatic tissue in patients with CCRCC.

A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors.

PURPOSE: This study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of TTI-237, a novel anti-tubulin drug, administered weekly in patients with refractory solid tumors. PATIENTS AND METHODS: Using an accelerated dose escalation design, patients with refractory solid tumors were enrolled in this study and treated with TTI-237 intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose was 4.5 mg/m(2). Pharmacokinetic studies were performed in patients at all dose levels. RESULT: Twenty-eight patients were enrolled and treated with TTI-237 at dose of 4.5, 9, 15, 22.5 and 31.5 mg/m(2). One dose-limiting toxicity neutropenia fever was observed at 31.5 mg/m(2), and all seven patients developed grade 3 or 4 neutropenia at that dose level. TTI-237 dosage was de-escalated to 22.5 and 18 mg/m(2). Six patients were treated at the 18 mg/m(2) dose level without dose-limiting toxicity prior to trial termination. The mean terminal-phase elimination half-life (t(1/2)) for TTI-237 was 25-29 h, and the mean area under the concentration time curve at 31.5 mg/m(2) was 2,768 ng•h/mL. CONCLUSION: A protocol defined maximum tolerated dose was not determined because of early termination of the TTI-237 trial by the sponsor. 18 mg/m(2) may be a tolerable dose of TTI-237.

A phase II study of tandutinib (MLN518), a selective inhibitor of type III tyrosine receptor kinases, in patients with metastatic renal cell carcinoma.

Therapies which target VEGF and mTOR are now available for patients with metastatic renal cell carcinoma, but there is a continued need to develop agents for patients who become refractory to these initial agents. Tandutinib is a relatively selective inhibitor of type III tyrosine kinase receptor kinases with promising activity in some tumors. In this trial, 10 patients with metastatic renal cell carcinoma refractory to previous therapy with sunitinib or sorafenib (median age 61 years, 80% performance status 0, 60% intermediate MSKCC risk classification) received tandutinib 500 mg bid daily with RECIST-defined response as the primary endpoint and progression-free survival (PFS) and overall survival (OS) as secondary endpoints. No patient had more than 2 cycles of therapy and 50% of patients only received 1 cycle with 70% of patients discontinuing for progressive disease and 30% for toxicity. Tandutinib was not well tolerated with dose reduction in 60% of patients due to adverse events. The most common grade 3 toxicity was fatigue (30%). Tandutinib had no clinical activity and due to the excessive toxicity should not be developed further in patients with sunitinib or sorafenib-refractory metastatic renal cell carcinoma.

Phase I/II trial of subcutaneous interleukin-2, granulocyte-macrophage colony-stimulating factor and interferon-α in patients with metastatic renal cell carcinoma.

OBJECTIVE: To determine, in a phase I/II trial, the maximum tolerated dose (MTD), clinical activity and safety of concurrent subcutaneous (s.c.) interleukin-2 (IL-2), interferon-α2b (IFN-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF). PATIENTS AND METHODS: Patients with metastatic renal cell carcinoma (RCC) received on a 3+3 trial design escalating doses of s.c. GM-CSF, IL-2 and IFN-α. Dose-limiting toxicities (DLTs) during the first 6-week cycle were used to determine the MTD. A phase II trial was then initiated to determine clinical activity. RESULTS: A total of sixty patients were enrolled in the study (phase I = 31; phase II = 29). Two DLTs were observed (G3 nausea/vomiting and fatigue) and the MTD was determined to be GM-CSF 5.0 µg/kg/day, IL-2 9.0 mIU/m(2)/day and IFN-α 5.0 mU/m(2)/day. Patients received a median (range) of four (one to 11) cycles of therapy. G3 adverse events were reported in 10 of 31 (32%) patients. The overall response rate was 20% (one complete response and 11 partial responses), including patients who were rendered free of disease with surgery. The median progression-free survival and overall survival were 6.0 and 23.4 months, respectively. CONCLUSIONS: Immunotherapy with concurrent s.c. GM-CSF, IL-2 and IFN-α is generally well tolerated. The overall response rate observed with this combination continues to show the efficacy of immunotherapy in a selected group of metastatic RCC patients.

Critical appraisal of pazopanib as treatment for patients with advanced metastatic renal cell carcinoma.

The management of renal cell carcinoma (RCC) has undergone significant changes during the past 10 years, with the treatment of metastatic RCC undergoing the most radical changes. These developments reflect an enhanced understanding of this tumor's underlying biology, which was then translated into the development of a new treatment paradigm. Current therapeutic approaches for the management of patients with metastatic RCC utilize knowledge of histology, molecular abnormalities, clinical prognostic factors, the natural history of this malignancy, and the treatment efficacy and toxicity of available agents. The treatment options available for patients with metastatic RCC have changed dramatically over the past 6 years. Interferon-α and interleukin-2 were the previous mainstays of therapy, but since December 2005, six new agents have been approved in the US for the treatment of advanced RCC. Three are multi-targeted tyrosine kinase inhibitors (TKI) including sunitinib, sorafenib, and pazopanib, two target the mammalian target of rapamycin (temsirolimus and everolimus), and one is a humanized monoclonal antibody (bevacizumab in combination with interferon-α). The current review focuses on the newest TKI available to treat patients with metastatic RCC, pazopanib. The development of this agent both preclinically and clinically is reviewed. The efficacy and safety data from the pivotal clinical trials are discussed, and the potential role of pazopanib in the treatment of patients with metastatic RCC in comparison to other treatment alternatives is critically appraised. This agent has a favorable overall risk benefit, and the available data demonstrate efficacy in patients with metastatic RCC who are either treatment-naïve or cytokine refractory. It therefore represents another alternative for treatment of metastatic RCC patients.

Sequential use of targeted agents in the treatment of renal cell carcinoma.

Sequential use of targeted therapies is a common practice in the treatment of advanced renal cell carcinoma (RCC) that extends disease control beyond the benefit of single therapies. After disease progression on one agent, treatment with a second targeted agent as subsequent-line therapy provides disease control and additional progression-free survival. The most effective sequence of targeted agents has yet to be determined. Results from the only trial of sequenced targeted agents support the use of mammalian target of rapamycin inhibitors after resistance develops to vascular endothelial growth factor (VEGF) inhibitors. Preliminary data suggest an antitumor effect of VEGF-targeted therapy in RCC, despite prior exposure to other VEGF-targeted therapies. The safety and efficacy of sequential therapies are currently under investigation; the optimal sequence may vary among patients to accommodate comorbid conditions or different disease stages. The current evidence supporting sequential use of targeted agents in RCC is presented in this review.

Clinical and immunomodulatory effects of bevacizumab and low-dose interleukin-2 in patients with metastatic renal cell carcinoma: results from a phase II trial.

OBJECTIVE: Low-dose interleukin-2 (IL-2) is a historical treatment for metastatic renal cell carcinoma (mRCC). Increased vascular endothelial growth factor (VEGF) levels inhibit dendritic cell (DC) differentiation and augment production of immunosuppressive regulatory T (Treg) cells. Bevacizumab is an antibody that binds to VEGF, has activity in mRCC and may augment the anti-tumour immune effects of IL-2. To determine the clinical and immunomodulatory effects of this combination, a prospective, phase II trial of bevacizumab plus low-dose IL-2 was conducted. PATIENTS AND METHODS: Patients with untreated mRCC received bevacizumab (10 mg/kg i.v. every 2 weeks) and IL-2 (125,000 units/kg/day subcutaneously from Monday to Friday for 6 consecutive weeks followed by a 2-week rest period). Endpoints included progression-free survival, Response Evaluation Criteria in Solid Tumors-defined objective response rate, immunomodulatory effects and safety. RESULTS: Between January 2005 and September 2007, twenty-six patients with untreated mRCC were enrolled. The median progression-free survival was 9.6 months (95% CI, 4.1-16.9 months) The objective response rate was 15% and an additional 38% of patients had tumour burden reduction of <30%. Grade 3 constitutional adverse events (fatigue, fever/chills) and neutropenia were observed in 42% and 12% of patients, respectively. Peripheral blood CD1c(+) myeloid and CD303(+) plasmacytoid DC increased during treatment as did IL-8 levels and CD4(+) CD25(+) FoxP3(+) Treg cells. No changes in T helper type 1/2-associated cytokines were observed. CONCLUSION: Bevacizumab plus low-dose IL-2 has modest clinical activity in mRCC. Toxicity was largely IL-2 related without enhancement of bevacizumab-related toxicity. Biological data indicate inhibition of VEGF levels and increase of immunosuppressive Treg cells without an effect on DC activation.

Predicting responses to sunitinib using single nucleotide polymorphisms: Progress and recommendations for future trials.

Targeted therapy with tyrosine kinase inhibitors has led to a substantial improvement in the standard of care for patients with advanced or metastatic clear cell renal cell carcinoma. Because the mechanism of action, metabolism and transport of tyrosine kinase inhibitors can affect outcome and toxicity, several investigators have pursued the identification of single nucleotide polymorphisms (SNPs) in genes associated with these actions. We discuss SNPs associated with outcome and toxicity following sunitinib therapy and provide recommendations for future trials to facilitate the use of SNPs in personalized therapy for this disease.

Metastatic clear cell carcinoma of the kidney: therapeutic role of bevacizumab.

The biology and pathogenesis of clear cell carcinoma of the kidney has been extensively investgated, and the role of von Hipple-Landau gene inactivation and tumor associated angiogenesis is now recognized. Development of vascular endothelial growth factor inhibitors and phase 3 clinical trials utilizing this class of agents has produced a new treatment paradigm for patients with metastatic renal cell carcinoma (RCC). One of the active regimens identified is the combination of bevacizumab and interferon-α. Recently published reports provided evidence of the clinical and biologic activity of this therapy. The current manuscript reviews the background and rationale for the activity of bevacizumab in RCC, and results from recent clinical trials with this agent alone or in combination with targeted agents or cytokines. The role of this therapy in contrast to other targeted agents is reviewed, and the potential utility as well as questions raised by recent studies are discussed.

Burden of metastatic bone disease from genitourinary malignancies.

Bone metastases are common among patients with stage IV genitourinary cancers. Most patients with bone metastases develop at least one debilitating and potentially life-limiting skeletal-related event. These events are associated with increased medical expenses and decreased quality of life. Current guidelines recommend screening for bone metastases in men with high-risk prostate cancer, but guidance for screening and treatment of bone metastases from genitourinary cancers varies by country and setting. Several bisphosphonates have been evaluated in the advanced genitourinary cancer setting. Zoledronic acid has demonstrated efficacy in significantly reducing the risk of skeletal-related events in patients with bone metastases from a broad range of solid tumors including prostate, renal and bladder cancers, and is recommended for preserving bone health.