Publications by authors named "Ronald M Bukowski"

144 Publications

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

Clin Genitourin Cancer 2021 04 14;19(2):167-175. Epub 2020 Nov 14.

Urologic Oncology Branch, Center for Cancer Research, Mayo Clinic, Rochester, MN.

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.
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http://dx.doi.org/10.1016/j.clgc.2020.10.005DOI Listing
April 2021

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

J Immunother Cancer 2016 15;4:81. Epub 2016 Nov 15.

Georgetown-Lombardi Comprehensive Cancer Center, 3970 Reservoir Road, NW, Research Building, Room E501, Washington, DC 20057, USA.

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.
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http://dx.doi.org/10.1186/s40425-016-0180-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5109802PMC
February 2018

The Cost of Hope: a candid roundtable discussion.

J Natl Compr Canc Netw 2013 May;11(5 Suppl):633-5

Bloomberg News, USA.

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.
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http://dx.doi.org/10.6004/jnccn.2013.0189DOI Listing
May 2013

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

J Clin Oncol 2013 Jan 3;31(2):181-6. Epub 2012 Dec 3.

Dana-Farber Cancer Institute, Boston, MA, USA.

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.
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http://dx.doi.org/10.1200/JCO.2012.43.3383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532390PMC
January 2013

Temsirolimus: a safety and efficacy review.

Expert Opin Drug Saf 2012 Sep 6;11(5):861-79. Epub 2012 Aug 6.

Cleveland Clinic Taussig Cancer Center, Cleveland, OH 44195, USA.

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.
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http://dx.doi.org/10.1517/14740338.2012.713344DOI Listing
September 2012

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

Front Oncol 2012 28;2:51. Epub 2012 May 28.

Taussig Cancer Institute, Cleveland Clinic Foundation Cleveland, OH, USA.

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.
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http://dx.doi.org/10.3389/fonc.2012.00051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3361062PMC
August 2012

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

Front Oncol 2012 15;2:13. Epub 2012 Feb 15.

Cleveland Clinic Taussig Cancer Center, Cleveland Clinic Lerner College of Medicine of CWRU Pepper Pike, OH, USA.

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.
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http://dx.doi.org/10.3389/fonc.2012.00013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356077PMC
August 2012

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

Genome Med 2011 Dec 30;3(12):79. Epub 2011 Dec 30.

Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

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.
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http://dx.doi.org/10.1186/gm295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3334544PMC
December 2011

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

Cancer Manag Res 2011 10;3:273-85. Epub 2011 Aug 10.

Cleveland Clinic Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH, USA.

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.
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http://dx.doi.org/10.2147/CMR.S15557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173017PMC
November 2011

Biomarkers in renal cell carcinoma: what next?

Curr Oncol Rep 2011 Apr;13(2):87-9

Cleveland Clinic Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH, USA.

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http://dx.doi.org/10.1007/s11912-011-0155-2DOI Listing
April 2011

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

BJU Int 2012 Jan 18;109(1):63-9. Epub 2011 Jan 18.

Division of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Center and Glickman Urological and Kidney Institute, Cleveland, OH 44195, USA.

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.
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http://dx.doi.org/10.1111/j.1464-410X.2010.10011.xDOI Listing
January 2012

Genitourinary oncology: current status and future challenges.

Front Oncol 2011 10;1:32. Epub 2011 Oct 10.

Cleveland Clinic Foundation, Cleveland Clinic Taussig Cancer Center Pepper Pike, OH, USA.

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http://dx.doi.org/10.3389/fonc.2011.00032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355990PMC
August 2012

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

Cancer Manag Res 2010 Mar 26;2:83-96. Epub 2010 Mar 26.

Cleveland Clinic Taussig Cancer Center, CCF Lerner College of Medicine of CWRU Cleveland, OH, USA.

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004565PMC
http://dx.doi.org/10.2147/cmar.s7540DOI Listing
March 2010

Burden of metastatic bone disease from genitourinary malignancies.

Expert Rev Anticancer Ther 2010 Nov;10(11):1721-33

Department of Urology, University Medical Centre-Nijmegen, PO Box 9101, HB 6500, Nijmegen, The Netherlands.

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.
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http://dx.doi.org/10.1586/era.10.136DOI Listing
November 2010

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

BJU Int 2011 Feb 14;107(4):562-70. Epub 2010 Sep 14.

Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic Glickman Urological and Kidney Institute, Cleveland, OH, USA.

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.
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http://dx.doi.org/10.1111/j.1464-410X.2010.09573.xDOI Listing
February 2011

Sorafenib in patients with metastatic renal cell carcinoma refractory to either sunitinib or bevacizumab.

Cancer 2010 Dec 30;116(23):5383-90. Epub 2010 Aug 30.

Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio 44195, USA.

Background: Bevacizumab and sunitinib are standard initial therapy in metastatic renal cell carcinoma (mRCC). Despite common use, the safety and activity of sorafenib in bevacizumab- or sunitinib-refractory mRCC have not been prospectively investigated.

Methods: Metastatic RCC patients with Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease progression (PD) after treatment with either bevacizumab or sunitinib received twice daily 400 mg of sorafenib in a multicenter, prospective phase 2 study. Dose escalation was permitted in the absence of significant toxicity. The primary endpoint was tumor burden reduction rate, defined as the proportion of patients with ≥5% reduction in the sum of RECIST-defined target lesions without other PD. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival, and safety. A 2-stage accrual design was used to test the alternative hypothesis that the tumor burden reduction rate was >20% versus <5%.

Results: Forty-eight patients were enrolled. The tumor burden reduction rate was 30% (95% confidence interval [CI], 17%-45%). One unconfirmed objective partial response was observed. The median PFS was 4.4 months (95% CI, 3.6-5.9). There was no association of PFS and tumor shrinkage with response to prior therapy. Most treatment-related adverse events were of mild-to-moderate intensity, and included fatigue, hypertension, diarrhea, and palmoplantar erythrodysesthesia (PPE). Patients previously treated with bevacizumab tended to develop more PPE (P=.03) and mucositis (P=.06), whereas sunitinib-treated patients tended to develop more skin rash (P=.06).

Conclusions: Administration of sorafenib is safe and feasible in patients with mRCC refractory to either bevacizumab or sunitinib. Modest clinical activity was observed supporting current practice patterns of sequential vascular endothelial growth factor-targeted therapy in mRCC.
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http://dx.doi.org/10.1002/cncr.25327DOI Listing
December 2010

Safety and efficacy of sorafenib in elderly patients treated in the North American advanced renal cell carcinoma sorafenib expanded access program.

Oncology 2010 20;78(5-6):340-7. Epub 2010 Aug 20.

Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH 441214, USA.

Objective: In this retrospective analysis of the Advanced Renal Cell Carcinoma Sorafenib (ARCCS) program in North America, we compared the safety and efficacy of sorafenib in patients aged ≥70 with those aged <70 years.

Methods: Patients were treated with oral sorafenib twice daily until the occurrence of disease progression or treatment intolerance. The primary objective of the ARCCS program was making sorafenib available to patients with advanced renal cell carcinoma (RCC) in the USA and Canada before marketing approval was obtained; the secondary objective was the evaluation of its safety and efficacy.

Results: Of the 2,504 patients enrolled in the ARCCS program who received at least 1 dose of sorafenib, 736 (29%) were aged ≥70 years. The most common grade ≥3 adverse events included rash/desquamation (5% in both groups), hand-foot skin reaction (8% in those aged ≥70 years vs. 10% in those <70 years of age), hypertension (5 vs. 4%) and fatigue (7 vs. 4%). Partial response was seen in 4% of the patients in both age groups. The median overall survival for the ≥70-year versus <70-year groups was also similar (46 vs. 50 weeks).

Conclusions: There were no substantial differences in safety and efficacy between patients aged ≥70 and <70 years with advanced RCC treated with sorafenib.
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http://dx.doi.org/10.1159/000320223DOI Listing
October 2010

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

Invest New Drugs 2012 Feb 14;30(1):364-7. Epub 2010 Aug 14.

Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue/Desk R35, Cleveland, OH 44195, USA.

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.
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http://dx.doi.org/10.1007/s10637-010-9516-1DOI Listing
February 2012

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

Crit Rev Oncol Hematol 2011 Jan 11;77(1):48-62. Epub 2010 Aug 11.

Baylor University Medical Center, Dallas, TX 75246, United States.

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.
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http://dx.doi.org/10.1016/j.critrevonc.2010.07.018DOI Listing
January 2011

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

Invest New Drugs 2012 Feb 10;30(1):266-72. Epub 2010 Aug 10.

Department of Internal Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.

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.
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http://dx.doi.org/10.1007/s10637-010-9506-3DOI Listing
February 2012

Biomarkers predicting outcome in patients with advanced renal cell carcinoma: Results from sorafenib phase III Treatment Approaches in Renal Cancer Global Evaluation Trial.

Clin Cancer Res 2010 Oct 22;16(19):4853-63. Epub 2010 Jul 22.

Bayer HealthCare Pharmaceuticals, Montville, New Jersey 07045-1000, USA.

Purpose: Plasma proteins [vascular endothelial growth factor (VEGF), soluble VEGF receptor 2 (sVEGFR-2), carbonic anhydrase IX (CAIX), tissue inhibitor of metalloproteinase 1 (TIMP-1), and Ras p21] and one tumor gene (VHL) were analyzed to identify prognostic biomarkers or indicators of response to sorafenib in a subset of patients enrolled in the Treatment Approaches in Renal Cancer Global Evaluation Trial.

Experimental Design: Nine hundred three patients with advanced renal cell carcinoma (RCC) were randomized to 400 mg sorafenib twice a day or placebo. Samples collected at baseline and after 3 and 12 weeks were subjected to enzyme-linked immunosorbent assays. VHL exons were sequenced from tumor biopsies.

Results: Baseline biomarker data were available for VEGF (n = 712), sVEGFR-2 (n = 713), CAIX (n = 128), TIMP-1 (n = 123), Ras p21 (n = 125), and VHL mutational status (n = 134). Higher Eastern Cooperative Oncology Group performance status (ECOG PS) score correlated with elevated baseline VEGF (P < 0.0001) and a higher incidence of VHL mutations (P = 0.008), whereas higher Memorial Sloan-Kettering Cancer Center (MSKCC) score correlated with elevated VEGF (P < 0.0001), CAIX (P = 0.027), and TIMP-1 (P = 0.0001). Univariable analyses of baseline levels in the placebo cohort identified VEGF (P = 0.0024), CAIX (P = 0.034), TIMP-1 (P = 0.001), and Ras p21 (P = 0.016) as prognostic biomarkers for survival. TIMP-1 remained prognostic for survival in a multivariable analysis model (P = 0.002) that also included ECOG PS, MSKCC score, and the other biomarkers assayed. In the placebo cohort, TIMP-1 (P < 0.001) and Ras p21 (P = 0.048) levels increased at 12 weeks. In the sorafenib cohort, VEGF levels increased at 3 and 12 weeks of treatment (both weeks P < 0.0001), whereas sVEGFR-2 (both weeks P < 0.0001) and TIMP-1 levels (P = 0.002, week 3; P = 0.006, week 12) decreased.

Conclusions: VEGF, CAIX, TIMP-1, and Ras p21 levels were prognostic for survival in RCC patients. Of these, TIMP-1 has emerged as being independently prognostic.
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http://dx.doi.org/10.1158/1078-0432.CCR-09-3343DOI Listing
October 2010

Everolimus in the treatment of renal cell carcinoma and neuroendocrine tumors.

Adv Ther 2010 Aug 8;27(8):495-511. Epub 2010 Jul 8.

Barts and the London School of Medicine, London, UK.

Renal cell carcinoma (RCC) and neuroendocrine tumors (NET) are uncommon malignancies, highly resistant to chemotherapy, that have emerged as attractive platforms for evaluating novel targeted regimens. Everolimus is an oral rapamycin derivative within the mammalian target of rapamycin class of agents. Preclinical series have shown that everolimus exhibits anticancer effects in RCC and NET cell lines. A phase 3 placebo-controlled study in advanced clear-cell RCC, known as RECORD-1 (for "REnal Cell cancer treatment with Oral RAD001 given Daily"), documented that everolimus stabilizes tumor progression, prolongs progression-free survival and has acceptable tolerability in patients previously treated with the multikinase inhibitors sunitinib and/or sorafenib. Everolimus has been granted regulatory approval for use in sunitinib-pretreated and/or sorafenib-pretreated advanced RCC and incorporated into clinical practice guidelines, and the RECORD-1 safety data are being used to develop recommendations for managing clinically important adverse events in everolimus-treated patients. Ongoing clinical trials are evaluating everolimus as earlier RCC therapy (first-line for advanced disease and as neoadjuvant therapy), in non-clear-cell tumors, and in combination with various other approved or investigational targeted therapies for RCC. Regarding advanced NET, recently published phase 2 data support the ability of everolimus to improve disease control in patients with advanced NET as monotherapy or in combination with somatostatin analogue therapy, octreotide long-acting release (LAR). Forthcoming data from phase 3 placebo-controlled trials of everolimus, one focused on monotherapy for pancreatic NET and the other on combination use with octreotide LAR for patients with advanced NET and a history of carcinoid syndrome, will provide insight into its future place in NET therapy. The results of a number of ongoing phase 3 evaluations of everolimus will determine its broader applicability in treating breast cancer (in combination with chemotherapy and hormonal therapy), several advanced gastrointestinal cancers, hepatocellular carcinoma, and lymphoma (in the adjuvant setting), as well as the various lesions associated with the tuberous sclerosis complex tumor suppressor gene.
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http://dx.doi.org/10.1007/s12325-010-0045-2DOI Listing
August 2010

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

Expert Opin Pharmacother 2010 Oct;11(14):2351-62

CCF Lerner College of Medicine of CWRU, 28099 Gates Mills Blvd, Pepper Pike, OH 44124, USA.

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.
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http://dx.doi.org/10.1517/14656566.2010.499126DOI Listing
October 2010

Pazopanib: a multikinase inhibitor with activity in advanced renal cell carcinoma.

Expert Rev Anticancer Ther 2010 May;10(5):635-45

Cleveland Clinic Taussig Cancer Center, Professor of Medicine, CCF Lerner College of Medicine of CWRU, 28099, OH, USA.

Treatment options for patients with metastatic renal cell carcinoma (RCC) have changed dramatically, and a new paradigm has evolved. IFN-alpha and IL-2 were previously mainstays of therapy, but since December 2005, six new agents have been approved in the USA for the treatment of advanced RCC. Three of these new agents are multitargeted kinase inhibitors, including sunitinib, sorafenib, and recently pazopanib, two target the mTOR (temsirolimus and everolimus), and one is a humanized monoclonal antibody (bevacizumab in combination with IFN-alpha) that targets VEGF. Sunitinib has emerged as the standard of care for treatment-naive RCC patients, with the recently approved bevacizumab and IFN-alpha combination providing an additional option for this population. The recent approval of pazopanib, based on the results from sequential Phase II and III clinical trials demonstrating improved overall response rates and progression-free survival, provides yet another option for front-line therapy. The current article examines the pazopanib preclinical and clinical data, provides an overview of the development of this tyrosine kinase inhibitor, and provides some speculation concerning its role in RCC therapy.
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http://dx.doi.org/10.1586/era.10.38DOI Listing
May 2010

RANK ligand: effects of inhibition.

Curr Oncol Rep 2010 Mar;12(2):80-6

Cancer Therapy and Research Center, University of Texas Health Sciences Center, Zeller 4th Floor, 7979 Wurzbach Road, San Antonio, TX, 78229, USA.

Receptor activator of nuclear factor kappa-light-chain-enhancer of activated B-cells (RANK) and its ligand (RANKL) belong to the tumor necrosis factor (TNF) superfamily. RANK mRNA is expressed widely in bone and bone marrow. It has a significant role in stimulating osteoclast differentiation and maturation, and also in preventing apoptosis. Because osteoclast activity is an important aspect of bone resorption in malignancy, targeting these cells is a good rationale for preventing skeletal-related events in malignancies. Preclinical studies have demonstrated the efficacy of denosumab in preventing bone loss in mice and improving bone mineral density. Denosumab is a fully human monoclonal antibody against RANKL, which has been shown to be effective in reducing signaling via RANK and thus osteoclast activity. It has been demonstrated in large, randomized, phase 3 studies to be effective in preventing fractures and bone loss, and improving the bone mineral density in various cancerous and noncancerous settings. This article reviews the latest evidence of RANKL inhibition and its clinical implications.
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http://dx.doi.org/10.1007/s11912-010-0088-1DOI Listing
March 2010

Stable disease in renal cell carcinoma after using signal transduction inhibitors.

Rev Recent Clin Trials 2010 May;5(2):117-22

CTRC at University of Texas Health Sciences Center, Zeller 4 Floor, 7979 Wurzbach Rd, San Antonio, TX 78229, USA.

Malignant solid tumors have been traditionally treated utilizing cytotoxic chemotherapies, which work against rapidly multiplying tumors. The current response evaluation in solid tumor is based on the Response Evaluation Criteria in Solid Tumors (RECIST). This method relies mainly on compufterized tomography (CT scans) and other imaging modalities by which the diameter of tumors is taken into consideration to assess response to therapy. Recent years have witnessed the introduction of a series of new signal transduction inhibitors in the management of metastatic RCC. Stable disease (SD) is more frequently seen with morphologic lesion changes such as, change in attenuation, pattern of intra-tumoral enhancement / necrosis and cavitation, all of which pose a challenge for the investigator in the accurate assessment of response to therapy. This article attempts to introduce the reader to various alternate concepts of monitoring response following biologic therapy and offers a detailed analysis of a few lesions.
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http://dx.doi.org/10.2174/157488710791233635DOI Listing
May 2010

Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America.

Cancer 2010 Mar;116(5):1272-80

Department of Medicine, University of Chicago Medical Center, Chicago, Illinois.

Background: The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) program made sorafenib available to patients with advanced renal cell carcinoma (RCC) before regulatory approval.

Methods: In this nonrandomized, open-label expanded access program, 2504 patients from the United States and Canada were treated with oral sorafenib 400 mg twice daily. Safety and efficacy were explored overall and in subgroups of patients including those with no prior therapy, nonclear cell (nonclear cell) RCC, brain metastases, prior bevacizumab treatment, and elderly patients. Sorafenib was approved for RCC 6 months after study initiation, at which time patients with no prior therapy or with nonclear cell RCC could enroll in an extension protocol for continued assessment for a period of 6 months.

Results: The most common grade > or =2 drug-related adverse events were hand-foot skin reaction (18%), rash (14%), hypertension (12%), and fatigue (11%). In the 1891 patients evaluable for response, complete response was observed in 1 patient, partial response in 67 patients (4%), and stable disease for at least 8 weeks in 1511 patients (80%). Median progression-free survival in the extension population was 36 weeks (95% confidence interval [CI], 33-45 weeks; censorship rate, 56%); median overall survival in the entire population was 50 weeks (95% CI, 46-52 weeks; censorship rate, 63%). The efficacy and safety results were similar across the subgroups.

Conclusions: Sorafenib 400 mg twice daily demonstrated activity and a clinically acceptable toxicity profile in all patient subsets enrolled in the ARCCS expanded access program (clinicaltrials.gov identifier: NCT00111020).
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http://dx.doi.org/10.1002/cncr.24864DOI Listing
March 2010

Pazopanib.

Nat Rev Drug Discov 2010 Jan;9(1):17-8

In October 2009, pazopanib (Votrient; GlaxoSmithKline)--a multikinase inhibitor with targets that include vascular endothelial growth factor receptors--was approved by the US FDA for the treatment of advanced renal cell carcinoma.
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http://dx.doi.org/10.1038/nrd3073DOI Listing
January 2010
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