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Advanced Kidney Cancer COE Articles

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  • A Multicentered, Propensity Matched Analysis Comparing Laparoscopic and Open Surgery for pT3a Renal Cell Carcinoma: Expert Commentary

    Laparoscopic renal surgery (LRS) has long been recognized for its improvements over open renal surgery for patient quality of life. However, LRS efficiency in terms of oncology and recurrences has yet to be compared. This team attempted to do just that by contrasting ORS and LRS on patients with Pathologic T3a (pT3a).
    Published September 15, 2017

  • Avelumab Plus Axitinib Significantly Improved Progression-Free Survival In Previously Untreated Patients with Advanced Renal Cell Carcinoma in Phase III Study

    San Francisco, CA (UroToday.com) -- Merck KGaA, Darmstadt, Germany, and Pfizer Inc. announced positive top-line results from the pivotal Phase III JAVELIN Renal 101 study evaluating BAVENCIO® (avelumab) in combination with INLYTA® (axitinib), compared with SUTENT® (sunitinib) as initial therapy for patients with advanced renal cell carcinoma (RCC). As part of a planned interim analysis, an independent Data Monitoring Committee confirmed that the trial showed a statistically significant improvement in progression-free survival (PFS) by central review for patients treated with the combination whose tumors had programmed death ligand-1‒positive (PD-L1+) expression greater than 1% (primary objective), as well as in the entire study population regardless of PD-L1 tumor expression (secondary objective).
    Published September 12, 2018

  • Axitinib Versus Placebo as an Adjuvant Treatment for Renal Cell Carcinoma: Results From the ATLAS Trial

    The ATLAS trial compared axitinib versus placebo in patients with locoregional renal cell carcinoma (RCC) at risk of recurrence after nephrectomy. 

    Patients and Methods
    In a phase III, randomized, double-blind trial, patients had >50% clear-cell RCC, had undergone nephrectomy, and had no evidence of macroscopic residual or metastatic disease (independent review committee [IRC] confirmed). The intent-to-treat population included all randomized patients (≥pT2 and/or N+, any Fuhrman grade [FG], Eastern Cooperative Oncology Group status 0/1). Patients (stratified by risk group/country) received (1:1) oral twice-daily axitinib 5 mg or placebo for ≤3 years, with a 1-year minimum unless recurrence, occurrence of second primary malignancy, significant toxicity, or consent withdrawal. The primary end point was disease-free survival (DFS) per IRC. A prespecified DFS analysis in the highest-risk subpopulation (pT3, FG ≥ 3 or pT4 and/or N+, any T, any FG) was conducted.
    Published October 20, 2018

  • Biomarker-Based Phase II Trial of Savolitinib in Patients with Advanced Papillary Renal Cell Cancer

    PURPOSE: Patients with advanced papillary renal cell carcinoma (PRCC) have limited therapeutic options. PRCC may involve activation of the MET pathway, for example, through gene amplification or mutations. Savolitinib (AZD6094, HMPL-504, volitinib) is a highly selective MET tyrosine kinase inhibitor. We report results of a single-arm, multicenter, phase II study evaluating the safety and efficacy of savolitinib in patients with PRCC according to MET status.
    Published December 9, 2018

  • Cabozantinib versus Everolimus in Advanced Renal Cell Carcinoma (METEOR): Final Results from a Randomised, Open-label, Phase 3 Trial

    BACKGROUND: Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis. 
    Published December 3, 2018

  • Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma

    BACKGROUND: Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. 
    Published December 3, 2018

  • Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial

    Cabozantinib is an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL and is a standard second-line therapy for metastatic renal cell carcinoma (mRCC). This randomized phase II multicenter trial evaluated cabozantinib compared with sunitinib as first-line therapy in patients with mRCC.
    Published September 11, 2017

  • Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial.

    Purpose Cabozantinib is an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL and is a standard second-line therapy for metastatic renal cell carcinoma (mRCC). This randomized phase II multicenter trial evaluated cabozantinib compared with sunitinib as first-line therapy in patients with mRCC.
    Published March 19, 2018

  • EAU 2019: Post-Nephrectomy Adjuvant Therapy for Localized Renal Cell Carcinoma: CheckMate 914 Study of Nivolumab + Ipilimumab in Patients at High Risk of Relapse

    Barcelona, Spain (UroToday.com) The current standard for advanced localized renal cell carcinoma (RCC) is nephrectomy. Unfortunately, for better or worse, the series of adjuvant therapy trials in patients with advanced localized RCC with targeted therapies (sutent, sorafenib, axitinib, pazopanib) have been either negative – or slightly positive and associated with significant adverse events.
    Published March 19, 2019

  • EAU 2019: The Challenging Landscape in Advanced Renal Cell Cancer Management

    Barcelona, Spain (UroToday.com) Dr. Marc-Oliver Grimm provided an overview of the many changes in the landscape for advanced renal cell carcinoma at the urogenital cancer treatment at a glance session. He started by highlight that the guidelines for advanced kidney cancer have been revamped recently and provided the following two figures based on the: 
    Published March 18, 2019

  • ESMO 2018: Safety and Tolerability of Atezolizumab plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma: IMmotion 150 and IMmotion 151

    Munich, Germany (UroToday.com) IMmotion 150 (Phase II) compared the efficacy of atezolizumab (atezo) plus bevacizumab (bev) with atezolizumab alone and sunitinib alone and then allowed for crossover in the latter 2 arms to atezolizumab plus bevacizumab.1 IMmotion 151  (Phase III) compared the efficacy of atezolizumab plus bevacizumab vs sunitinib for first-line therapy of metastatic renal cell carcinoma2.
    Published October 22, 2018

  • ESMO 2019: Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse, Results from the SORCE Trial

    Barcelona, Spain (UroToday.com) Four large, randomized Phase 3 clinical trials (S-TRAC, ASSURE, PROTECT, and ATLAS) evaluated adjuvant VEGF tyrosine kinase inhibitors in patients with resected renal cell carcinoma (RCC). Only S-TRAC met the primary endpoint of improvement in disease-free survival (DFS). None of these studies demonstrated improvement in overall survival (OS). Dr. Tim Eisen presents the primary efficacy results from the SORCE trial, an international, randomized, double-blind Phase 3 trial that evaluated adjuvant sorafenib for RCC at intermediate or high risk of relapse.
    Published September 28, 2019

  • Everolimus versus Sunitinib for Patients with Metastatic Non-clear Cell Renal Cell Carcinoma (ASPEN): a Multicentre, Open-label, Randomised Phase 2 Trial

    BACKGROUND: Non-clear cell renal cell carcinomas are histologically and genetically diverse kidney cancers with variable prognoses and their optimum initial treatment are unknown. We aimed to compare the mTOR inhibitor everolimus and the VEGF receptor inhibitor sunitinib in patients with non-clear cell renal cell carcinoma. 
    Published December 3, 2018

  • Exelixis’ Partner Ipsen Announces Health Canada’s Approval of Cabozantinib Tablets for the Treatment of Adults with Previously Treated Advanced Renal Cell Carcinoma

    – Approval based on the improvement in overall survival, progression-free survival and objective response rate for cabozantinib versus everolimus in the phase 3 pivotal METEOR trial –

    San Francisco, CA (UroToday.com) -- Exelixis, Inc. announced that its partner Ipsen Biopharmaceuticals Canada Inc. received approval from Health Canada of CABOMETYX® (cabozantinib) tablets for the treatment of adults with advanced renal cell carcinoma (RCC) who have received prior vascular endothelial growth factor (VEGF) targeted therapy. Health Canada granted CABOMETYX priority review status, which provided an accelerated review of Ipsen’s new drug submission.
    Published September 19, 2018

  • Exposure to Multiple Lines of Treatment and Survival of Patients With Metastatic Renal Cell Carcinoma: A Real-world Analysis - Beyond the Abstract

    In the past decade, the introduction of new therapeutic agents has improved the survival of patients with metastatic RCC (mRCC). The 5-year survival for RCC has improved from 52% in 1975 to 74% in 2014. 
    Published April 3, 2018

  • FDA Accepts sBLA and Grants Priority Review for BAVENCIO® (avelumab) Plus INLYTA® (axitinib) for the Treatment of Advanced Renal Cell Carcinoma

    San Francisco, CA USA (UroToday.com) -- EMD Serono, the biopharmaceutical business of Merck KGaA, Darmstadt, Germany in the US and Canada, and Pfizer Inc. announced that the US Food and Drug Administration (FDA) has accepted for Priority Review the supplemental Biologics License Application (sBLA) for BAVENCIO® (avelumab) in combination with INLYTA® (axitinib)* for patients with advanced renal cell carcinoma (RCC). The application has been given a target action date in June 2019.
    Published February 12, 2019

  • FDA Accepts sBLA and Grants Priority Review for BAVENCIO® (avelumab) Plus INLYTA® (axitinib) for the Treatment of Advanced Renal Cell Carcinoma

    San Francisco, CA USA (UroToday.com) -- EMD Serono, the biopharmaceutical business of Merck KGaA, Darmstadt, Germany in the US and Canada, and Pfizer Inc. announced that the US Food and Drug Administration (FDA) has accepted for Priority Review the supplemental Biologics License Application (sBLA) for BAVENCIO® (avelumab) in combination with INLYTA® (axitinib)* for patients with advanced renal cell carcinoma (RCC). The application has been given a target action date in June 2019.
    Published February 15, 2019

  • First Line Therapy of Metastatic Clear Cell RCC

    Background

    Kidney cancer represents 5% of all new cancer diagnoses in the United States, with approximately 64,000 new cases and 14,970 deaths in 2018.1,2 The most common type of kidney cancer is renal cell carcinoma (RCC) and the most common histologic subtype of RCC is clear cell RCC, accounting for over 80% of cases.3 RCC is more common in men than women and typically occurs in the sixth to eighth decade of life.1 Localized kidney cancer can often be cured with definitive surgery, with 5-year survival reaching over 90%.4 However, for patients with advanced disease, 5-year survival remains poor at 11.7% and much progress is needed to develop novel therapies for advanced RCC.4

    Risk Stratification

    The current treatment paradigm for metastatic clear cell RCC requires stratification of patients into favorable, intermediate, or poor risk disease. Several validated models for risk stratification exist, including the International Metastatic Renal Cell Carcinoma Database Consortium model (IMDC)5 and Memorial Sloan Kettering Cancer Center model (MSKCC).6 Both criteria include time from diagnosis to systemic treatment of less than one year, performance status, as well as hemoglobin and calcium (Table 1). The main differences between these models are that the MSKCC model includes LDH and the IMDC includes neutrophil and platelet count as unique risk factors. Patients with no risk factors fall into the favorable risk group, patients with one to two risk factors are in the intermediate risk group, and those with three or more risk factors are in the high-risk group for both prognostic models. Contemporary clinical trials have found that drug effectiveness may vary depending on risk stratification which has led the FDA to approve some therapies for only certain risk groups.7 Thus, risk stratification is important for the clinician, not only for discussing prognosis with patients, but also for treatment selection. 
    table-1-first-line-therapy-clear-cell-RCC@2x.jpg

    Favorable Risk Patients

    For patients with no adverse risk factors, sunitinib and pazopanib are the preferred first line treatment options, recommended by both the National Comprehensive Cancer Network (NCCN) as well as the European Association of Urology (EAU).8,9 Sunitinib is an oral multikinase inhibitor which targets vascular endothelial growth factor receptors (VEGFR) and platelet derived growth factor receptors (PDGFR). A phase III trial comparing sunitinib to interferon-α showed that sunitinib significantly improved median progression free survival (11 months vs 5 months) and had a higher overall response rate as well when compared with interferon alfa (31% vs 6%).10 Sunitinib also demonstrated longer overall survival in a follow up study, 26.4 months vs 21.8 months.11 Severe adverse events (grade 3-4 toxicities) were minimal, and the most common adverse events were diarrhea, fatigue, and nausea. Hypertension was one notable side effect of sunitinib, which was not seen with interferon alfa. Based on the data above, sunitinib was granted FDA approval in 2007 and has been the benchmark for many future clinical trials in the mRCC space. 

    Pazopanib is another oral multikinase inhibitor, which targets VEGFR-1,2,3, PDGFR- and , and c-KIT.12 Pazopanib was established as a safe and efficacious therapy for mRCC based on a large randomized, placebo controlled trial in patients who were treatment naive or cytokine pretreated.12 In this trial of 435 patients, pazopanib increased progression-free survival (9.2 months vs 4.2 months) compared with placebo, both in the treatment naïve cohort as well as the cytokine pretreated cohort. The objective response rate to pazopanib was 30% and pazopanib was well tolerated. Unique toxicities of pazopanib included notable grade 3 hepatotoxicity  30% of patients had elevated ALT and 21% had elevated AST. These results granted pazopanib FDA approval in October 2009. A subsequent phase III study (COMPARZ) with 1,110 patients compared sunitinib to pazopanib, and pazopanib was found to be noninferior to sunitinib with respect to progression-free survival and overall survival.13 Median overall survival was 28.4 months in the pazopanib arm compared with 29.3 months in the sunitinib arm. In terms of safety, similar percentages of patients in both sunitinib and pazopanib experienced dose interruptions of one week or greater, 44% and 49% respectively. Patients in the pazopanib arm more frequently discontinued therapy based on abnormal liver function tests. Patients taking sunitinib had a higher risk of abnormal hematologic labs including leukopenia, thrombocytopenia, neutropenia, and anemia. 

    Additional FDA approved therapies for first line management of favorable risk patients include high dose interleukin 2 (HD IL-2)14-17, interferon plus bevacizumab18, and sorafenib.19 These therapies are less commonly used given their tolerability and toxicity profiles. HD IL-2 deserves special mention here given its ability to induce complete responses in a small subset of patients. A recent abstract describing overall survival from the PROCLAIM database show that of favorable risk patients, median overall survival is 63.3 months and 2 year overall survival is 77.6%.14 Of course, patients who are given HD IL-2 are a very carefully selected robust cohort, and cross-trial comparisons are challenging to make. 

    Intermediate and Poor Risk

    Per the IMDC and MSKCC prognostic models, patients with one or two risk factors are classified as intermediate risk, and poor risk if they have three or more risk factors. Currently, the two major newcomers in this space are cabozantinib and the combination of ipilimumab and nivolumab.  Cabozantinib is a multikinase inhibitor of VEGFR, MET, and AXL.20 In the phase II CABOSUN study, 157 intermediate or poor risk patients were randomized to cabozantinib or sunitinib. In this population, cabozantinib increased median progression free survival (8.2 months vs 5.6 months) and improved overall response rate (33% vs to 12%) compared with sunitinib. Both sunitinib and cabozantinib had about a 67% grade 3/4 adverse event rate and had a similar toxicity profile, including fatigue, hypertension, and diarrhea. Sunitinib had a lower incidence of hand foot syndrome and weight loss compared with cabozantinib, but higher rates of neutropenia and thrombocytopenia. Given this data, Cabozantinib obtained FDA approval for the front-line treatment of mRCC in December 2017. 

    The newest therapy to obtain FDA approval is the combination checkpoint inhibitor duo Ipilimumab and Nivolumab (Ipi/Nivo); it was approved in April of 2018, based on the results of CheckMate214.7 CheckMate 214 was a randomized, open-label trial comparing sunitinib with Ipi/Nivo. 1096 patients were enrolled, of which 847 were intermediate or poor risk. This study had a coprimary endpoint of overall survival, objective response rate, and progression free survival among patients who were intermediate or poor risk. The overall response rate was 42% with ipi/nivo vs 27% with sunitinib, with a complete response rate of 9% vs 1%. Median overall survival has not been reached with ipi/nivo vs 26 months for sunitinib. Progression free survival was 11.6 months for ipi/nivo compared with 8.4 months for sunitinib. 46% of patients receiving ipi/nivo experienced grade 3/4 toxicities compared with 63% of patients receiving sunitinib. The most common grade 3/4 adverse events with ipi/nivo was fatigue, diarrhea, and elevated lipase compared with hypertension, hand-foot syndrome, and increased lipase with sunitinib. 35% of patients required high dose corticosteroids for immune related toxicities with ipi/nivo.  With this data, the European Association of Urology has recommended that ipi/nivo be the new standard of care for patients with intermediate and poor risk disease, and the NCCN has also listed ipi/nivo as a category 1, preferred treatment option for patients with intermediate and poor risk disease.8,9
    table-2-first-line-therapy-clear-cell-RCC@2x.png

    Future Therapies

    Front-line treatment options for mRCC are rapidly evolving.24 Data shown at ASCO and GU ASCO has demonstrated that antiangiogenic agents in combination with checkpoint inhibitors may prolong progression-free survival when compared with kinase inhibitors.25 Several phase III trials exploring this hypothesis are now underway (Table 3). IMmotion 151 is a randomized phase III trial comparing the combination of atezolizumab + bevacizumab vs sunitinib. Progression-free survival was 11.2 months in the intention to treat analysis for patients atezolizumab and bevacizumab, compared with 8.4 months in the sunitinib arm. JAVELIN Renal 100 is investigating avelumab in combination with axitinib and phase I results show a promising overall response rate of 54.5% out of 55 patients.26 KEYNOTE-426 is investigating pembrolizumab in combination with axitinib, compared with sunitinib alone.27 These trials are important and exciting for our patients with mRCC and their future results may alter the standard of care for frontline mRCC.
    table-3-first-line-therapy-clear-cell-RCC@2x.png


    Published Date: January 29th, 2019
    Written by: Jason Zhu, MD
    References:
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: A Cancer Journal for Clinicians 2018;68:7-30.2018. at https://www.cancer.org/cancer/kidney-cancer/about/key-statistics.html.)
    2. Moch H, Gasser T, Amin MB, Torhorst J, Sauter G, Mihatsch MJ. Prognostic utility of the recently recommended histologic classification and revised TNM staging system of renal cell carcinoma. Cancer 2000;89:604-14.
    3. Motzer RJ, Jonasch E, Agarwal N, et al. Kidney cancer, version 2.2017, NCCN clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network 2017;15:804-34.
    4. Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. The lancet oncology 2013;14:141-8.
    5. Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. Journal of clinical oncology 1999;17:2530-.
    6. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. New England Journal of Medicine 2018;378:1277-90.
    7. Motzer R, Jonasch E, Agarwal N. Kidney Cancer: NCCN Evidence Blocks, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. 2017.
    8. Powles T, Albiges L, Staehler M, et al. Updated European Association of Urology Guidelines: Recommendations for the Treatment of First-line Metastatic Clear Cell Renal Cancer. European Urology 2018;73:311-5.
    9. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus Interferon Alfa in Metastatic Renal-Cell Carcinoma. New England Journal of Medicine 2007;356:115-24.
    10. Motzer RJ, Hutson TE, Tomczak P, et al. Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell Carcinoma. Journal of Clinical Oncology 2009;27:3584-90.
    11. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial. Journal of Clinical Oncology 2010;28:1061-8.
    12. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus Sunitinib in Metastatic Renal-Cell Carcinoma. New England Journal of Medicine 2013;369:722-31.
    13. Fishman MN, Clark JI, Alva AS, et al. Overall survival (OS) by clinical risk category for high dose interleukin-2 (HD IL-2) treated metastatic renal cell cancer (RCC): Data from PROCLAIM. Journal of Clinical Oncology 2018;36:4578-.
    14. Amin A, White RL. Interleukin-2 in Renal Cell Carcinoma: A Has-Been or a Still-Viable Option? Journal of Kidney Cancer and VHL 2014;1:74-83.
    15. Alva A, Daniels GA, Wong MKK, et al. Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma. Cancer Immunology, Immunotherapy 2016;65:1533-44.
    16. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. Journal of clinical oncology 1995;13:688-96.
    17. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. The Lancet 2007;370:2103-11.
    18. Escudier B, Szczylik C, Hutson TE, et al. Randomized Phase II Trial of First-Line Treatment With Sorafenib Versus Interferon Alfa-2a in Patients With Metastatic Renal Cell Carcinoma. Journal of Clinical Oncology 2009;27:1280-9.
    19. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma. The New England journal of medicine 2015;373:1814-23.
    20. Escudier B, Bellmunt J, Négrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 2010;28:2144-50.
    21. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma. New England Journal of Medicine 2007;356:2271-81.
    22. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. Journal of Clinical Oncology 2017;35:591-7.
    23. Zarrabi K, Wu S. Current and emerging therapeutic targets for metastatic renal cell carcinoma. Current oncology reports 2018;20:41.
    24. Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC). Journal of Clinical Oncology 2018;36:578-.
    25. Choueiri TK, Larkin JMG, Oya M, et al. First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): Results from a phase Ib trial. Journal of Clinical Oncology 2017;35:4504-.
    26. Rini BI, Powles T, Chen M, Puhlmann M, Atkins MB. Phase 3 KEYNOTE-426 trial: Pembrolizumab (pembro) plus axitinib versus sunitinib alone in treatment-naive advanced/metastatic renal cell carcinoma (mRCC). Journal of Clinical Oncology 2017;35:TPS4597-TPS.
    Published January 29, 2019

  • How I Manage First-Line Therapy for Advanced Kidney Cancer

    Published in Everyday Urology - Oncology Insights: Volume 3, Issue 1
    Published Date: March 2018

    Urologists are primed to acquire the knowledge to use targeted agents and immuno-oncologic (IO) therapies for the treatment of advanced and metastatic renal cell carcinoma (RCC). Toxicities are manageable given appropriate patient/caregiver education, on-call, and nursing support, and multi-disciplinary care with consulting specialists. 
    Published August 14, 2018

  • Impact of Positive Surgical Margins on Overall Survival After Partial Nephrectomy, a Matched Comparison Based on the National Cancer Database - Beyond the Abstract

    En-bloc resection with negative surgical margins (NSM) has been a key fundamental in the surgical treatment of almost all localized tumors. Positive surgical margins (PSM) is often considered equivalent to failure for oncologic clearance, and results in additional adjuvant treatments, more frequent clinical visits and more anxiety among patients. Interestingly, many studies on partial nephrectomy (PN) seem to suggest that cancer-specific and overall survivals (OS) are not affected by PSM. Concurrently, owing to the increasing use of high-definition imaging modalities, most renal cancers (RCC) are diagnosed as small renal masses (SRMs). Over time, the ‘gold standard’ treatment of SRMs shifted from radical nephrectomy to PN, which results in better OS. Various adjuncts, such as pre-operative 3-dimensional CT reconstruction, renal arterial mapping, intra-operative frozen sections, on-table ultrasound and florescence imaging, have been used to reduce PSM in PN. Having the largest matched samples in the published literature and working from a well-known national database, we showed that PSM do impact on OS after PN.
    Published January 18, 2018

  • MDACC 2018: Debate: Adjuvant Therapy for Locally Advanced Renal Cell Carcinoma: Is it Ready for Prime Time?

    Houston, TX (UroToday.com) Jose A. Karam, MD opened the debate by emphasizing the importance of patient selection for adjuvant therapy.  Those that would most benefit from adjuvant therapy are those that are at high risk of recurrence.  This can be defined by scoring systems such as the UCLA Integrated Staging System (UISS)1 and Leibovich score2. Dr. Karam referenced a useful online resourceprovided by Fox Chase to assist physcians in identifying those at high risk of recurrence:
    Published November 10, 2018

  • MDACC 2018: Debate: Is There Still a Role for Cytoreductive Nephrectomy in the Setting of Metastatic Renal Cell Carcinoma?

    Houston, TX (UroToday.com) Dr. Karam started out reviewing trials from the pre-targeted therapy era opening with the results of the EORTC trial comparing cytoreductive nephrectomy (CN) plus interferon-alpha versus interferon alpha alone1.
    Published November 11, 2018

  • MDACC 2018: Debate: What is the Best Front-Line Systemic Therapy for Metastatic Clear Cell Renal Cell Carcinoma?

    Houston, TX (UroToday.com) Dr. Gao defended Nivolumab plus ipilimumab as the best front-line systemic therapy for mRCC.  The argument was centered around the results of Checkmate 214 trial1.  This phase III trial compared Nivolumab (Nivo) plus ipilimumab (Ipi) versus Sunitinib in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate risk and poor-risk patients. 
    Published November 11, 2018

  • MDACC 2018: Debate: What is the Best Salvage Therapy After Failure of Immune Checkpoint Inhibition?

    Houston, TX (UroToday.com) Dr. Msaouel opened the debate supporting the use of Cabozantinib for salvage therapy after failure of immune checkpoint inhibitors.  His argument was broken down into three points: Use of previously established first line, use of previously established second line and assumption that after failure of an immune checkpoint inhibition is a unique biologic scenario. 
    Published November 11, 2018

  • MDACC 2018: Promising Emerging Systemic Therapies for mRCC

    Houston, TX (UroToday.com) Treating mRCC successfully lays in harnessing the IL-2 pathway in such a way that increases tumor-infiltrating lymphocytes (TILs).  NKTR-214 is a prodrug being developed by Nektar that when it binds to CD122, triggers the release of TILs.   The slide below summarizes the differences between NKTR-214 and HD IL-2. 
    Published November 11, 2018

  • Molecular Subtypes of Clear Cell Renal Cell Carcinoma are Associated with Outcome During Pazopanib Therapy in the Metastatic Setting - Beyond the Abstract

    Over the past decade, systemic treatment for advanced clear-cell renal cell carcinoma (ccRCC) has evolved from hardly any efficacious therapy available to an abundance of options: several angiogenesis inhibitors, immune checkpoint inhibitors and, to a lesser extent, mTOR inhibitors. 1 While these drugs have improved the prognosis of advanced ccRCC, patient responses to different drug categories are very variable and no molecular biomarkers for patient selection have entered the clinic so far. Response to immune checkpoint inhibitors has been linked to high PD-L1 expression, to a T-effector cell gene signature and to IMDC intermediate/poor risk category in the Checkmate025, IMmotion150 and Checkmate214 trials respectively.2-4 Response to the angiogenesis inhibitor sunitinib has been linked to a pro-angiogenic gene signature and to IMDC good risk category in the IMmotion150 trial and our own patient series and in the Checkmate214 trial respectively.3-5 
    Published January 8, 2018

  • Multi-Institutional Survival Analysis of Incidental Pathologic T3a Upstaging in Clinical T1 Renal Cell Carcinoma Following Partial Nephrectomy - Beyond the Abstract

    Over the past two decades, there has been a dramatic shift in the identification and management of small renal masses. Historically, the vast majority of renal cell carcinomas (RCC) were symptomatic at presentation, typically indicative of disease requiring radical intervention for cure or disease control. This paradigm has rapidly changed with the widespread utilization of cross-sectional imaging, which has resulted in the increased detection of incidental small renal masses < 4 cm. While small renal masses were previously a rare entity, they now represent the most common RCC presentation. As the rate of small renal mass detection has increased, so too has the utilization of nephron-sparing approaches (partial nephrectomy, ablation, and stereotactic radiation) for the management of these lesions.
    Published May 11, 2018

  • Oncologic Outcomes for Open and Laparoscopic Radical Nephroureterectomy in Patients with Upper Tract Urothelial Carcinoma – Beyond the Abstract

    Laparoscopic radical nephroureterectomy (LNU) has become popular as a minimally-invasive surgical alternative. Several studies have compared the oncologic outcomes between open radical nephroureterectomy (ONU) and LNU in patients with upper tract urothelial carcinoma (UTUC) and have demonstrated comparative outcomes between these. However, other studies have shown an increased risk of recurrence with LNU. Due to limitations of the heterogeneity of study population, sample size, and surgical techniques, the oncologic efficacy of LNU to ONU has remained undetermined. In addition, several guidelines have recommended laparoscopic procedures for localized (stage cT2 or less) disease, but their use remains unclear for locally-advanced (stages cT3-4 and/or cN+) disease. In this study, we retrospectively compared the oncologic outcomes between ONU (n = 181) and LNU (n = 48) in a multi-institutional cohort of patients with locally-advanced UTUC using inverse probability of treatment weighting (IPTW)–adjusted Cox regression analyses. 
    Published February 16, 2018

  • Outcomes of Patients with Renal Carcinoma and Sarcomatoid Dedifferentiation Treated with Nephrectomy and Systemic Therapies: Comparison between the Cytokine and Targeted Therapy Eras: Expert Commentary

    Though nephrectomy is the gold standard treatment for renal cell carcinoma, 20%-40% of patients have a recurrence and 20-30% of patients present with metastatic disease1. Sarcomatoid dedifferentiation is found in approximately 5% of all RCC and can be an associated feature with any RCC histological subtype. But they are historically associated with a poor prognosis and a median overall survival of 4 to 9 months2-4. The objective of this study was to then analyze the outcome of patients with metastatic sRCC in different therapeutic eras and explore factors associated with patient survival.
    Published November 15, 2017

  • Partial Versus Radical Nephrectomy for T1-T2 Renal Masses in the Elderly: Comparison of Complications, Renal Function, and Oncologic Outcomes- Beyond the Abstract

    The incidence of renal cell carcinoma (RCC) has been increasing with improved imaging and a growing aging population. For patients with localized renal masses (cT1-T2) both partial and radical nephrectomy (PN and RN, respectively) is effective treatment options. Relative to their younger counterparts, patients in the geriatric community have lower baseline kidney function, have more significant chronic systemic disease, and have greater difficulty with complications and recovery.
    Published January 16, 2017

  • Pazopanib for Metastatic Renal Cell Carcinoma - Beyond the Abstract

    The number of studies evaluating pazopanib for first-line therapy of metastatic renal cell carcinoma (mRCC) in the real-world setting is relatively low due to the short duration of pazopanib availability in comparison with sunitinib, another standard first-line drug for mRCC. 
    Published January 8, 2018

  • Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial

    PURPOSE: Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). 
    Published December 3, 2018

  • Radical Nephrectomy With or Without Lymph Node Dissection for Nonmetastatic Renal Cell Carcinoma: A Propensity Score-based Analysis: Beyond the Abstract

    Lymph node dissection (LND) for renal cell carcinoma (RCC) dates back to Robson’s original description of radical nephrectomy in 1969[1].  Indeed, Robson and colleagues suggested a therapeutic benefit to LND, attributing, in part, the improved survival in their series compared to contemporaneous studies to “removal of the lymphatic drainage system,” which was involved by RCC in in 22.7% of patients. 
    Published November 21, 2016

  • Sarcomatoid Renal Cell Carcinoma: Biology and Treatment Advances - Beyond the Abstract

    Sarcomatoid renal cell carcinoma (sRCC) is defined by the differentiation of the typical epithelial cell morphology seen in renal cell carcinoma (RCC) to malignant spindle shaped cells. About 5% of RCC samples contain sRCC components1. It is not a distinct histologic subtype of RCC, but rather occurs in variable proportions with other subtypes of RCC, most commonly with clear cell and chromophobe tumors. sRCC confers an aggressive phenotype and a grade 4 designation by the ISUP grading system2, with a median survival of around 6 months and a suboptimal response to conventional therapies.
    Published February 5, 2018

  • Systemic Therapy for Advanced Renal Cell Carcinoma

    As highlighted in prior articles on the Etiology and Epidemiology of Kidney Cancer, cancers of the kidney and renal pelvis comprise the 6th most common newly diagnosed tumors in men and 10th most common in women1 and account for an estimated 65,340 people new diagnoses and 14,970 cancer-related deaths in 2018 in the United States. Despite a previously mentioned stage migration due to an increase in incidental detection, a large proportion (up to 35%) of patients present with advanced disease, including metastases.2 Historically, metastatic RCC has been early uniformly fatal, with 10-year survival rates less than 5%.3

    As emphasized in the article on Malignant Renal Tumors, clear cell renal cell carcinoma (ccRCC) is the most common histologic subtype of renal cell carcinoma (RCC). Likely due to its much higher prevalence, the vast majority of systemic therapies for RCC have been investigated among patients with ccRCC. Historically, treatment for metastatic RCC (mRCC) had been limited to cytokine therapies (interleukin-2 and interferon-alfa). However, the development of tyrosine kinase inhibitors (TKIs), which target vascular endothelial growth factors (VEGF), and mammalian target of rapamycin (mTOR) inhibitors have replaced cytokine-based therapies as the standard of care. More recently, immunotherapy-based approaches using checkpoint inhibitors have demonstrated significant benefits and have joined the repertoire of available agents for patients with metastatic RCC.

    Cytokine Therapies for Advanced ccRCC

    The host immune system has long been implicated with RCC tumor biology. As a result, modulators of the immune system were among the first therapeutic targets for advanced ccRCC.

    Interferon-α was one of the first cytokines assessed for the treatment of metastatic ccRCC. Interferons have a range of biologic functions, including immunomodulation. Early data demonstrated response rates in the range of 10 to 15% for patients treated with interferon-α.4 Compared with other available systemic therapies available at the time, interferon therapy conferred a survival benefit.5

    An alternative form of immunologic modulation was examined using interleukin-2. While response rates were similar to interferon-based therapies (~15 to 20%)6, interleukin-2 was distinct in that durable complete responses were observed in approximately 7 to 9% of patients.7 On the basis of these data, high-dose IL-2 was approved by the U.S. Food and Drug Administration (FDA) in 1992. However, IL-2 is associated with considerable toxicity which has limited its widespread utilization. Most worrisome is vascular leak syndrome which leads to intravascular depletion, hypovolemia, respiratory compromise and multi-organ failure. Alternatives to the high-dose intravenous bolus administration were explored but lead to worse oncologic outcomes. Thus, high-dose IL-2 is the only recommended approach for patients undergoing cytokine therapy.

    Subsequently, combinations of interferon and interleukin therapies were explored. These demonstrated some improvement in response rate but no difference in overall survival.8 Combination therapy resulted in significantly increased toxicity compared to monotherapy with either agent.

    With the introduction of VEGF and mTOR targeting agents, interferon is no longer utilized as first-line therapy. However, IL-2 remains an available, though not widely utilized, option on the basis of its ability to induce durable complete responses which these new agents lack. 

    Inhibitors of the VEGF Pathway for Advanced ccRCC

    Based on work into the molecular biology underlying ccRCC led to “rational targeted therapeutics” including targeting of the VEGF pathway.

    The first inhibitor of the VEGF pathway used in clinical trials was bevacizumab, a humanized monoclonal antibody against VEGF-A. While this approach was first explored in patients who had progressed on cytokine-based therapies, it was soon evaluated head-to-head against interferon in previously untreated patients.9,10 The addition of bevacizumab to interferon resulted in significant improvements in response rate and progression-free survival. Today, bevacizumab is uncommonly used as monotherapy in untreated patients but is considered as second-line therapy in patients who have failed prior therapy with tyrosine kinase inhibitors.

    Tyrosine-kinase inhibitors also target the VEGF pathway, through inhibition of a combination of VEGFR-2, PDGFR-β, raf-1 c-Kit, and Flt3 (sunitinib and sorafenib). In 2006, sorafenib was shown to have biologic activity in ccRCC. Subsequent studies demonstrated improvements in progression-free survival compared with placebo in patients who have previously failed cytokine therapy and improvements in tumor regression compared to interferon in previously untreated patients. Despite FDA approval, sorafenib is rarely used as first-line therapy today. More widely used is sunitinib. As with agents discussed, sunitinib was first evaluated among patients who had previously received cytokine treatment. Subsequently, it was compared to interferon-α in a large phase III randomized trial.11 While the initial analysis demonstrated significant improvement in progression-free survival and overall response rate, subsequent follow-up has demonstrated a strong trend towards improved overall survival. On account of these data, sunitinib is widely used as first-line treatment of RCC. 

    Tyrosine-kinase inhibitors exhibit a class-based toxicity profile including gastrointestinal events, dermatologic complications including hand-foot desquamation, hypertension, and general malaise. However, quality of life appears to be better with these agents than with interferon.11 

    Subsequently, a number of more targeted tyrosine kinase inhibitors have been developed with the goal to decrease the toxicity of this treatment strategy. Such agents include pazopanib, axitinib, and tivozanib. Comparative data of pazopanib and sunitinib have demonstrated non-inferior oncologic outcomes with decreased toxicity among patients receiving pazopanib.12 Axitinib was evaluated as second-line therapy compared to sorafenib among patients who had previously received sunitinib, bevacizumab, temsirolimus, or cytokine therapy. Axitinib was associated with improved progression-free survival; on the basis of these data, this agent was approved for second-line therapy of metastatic RCC.13 Finally, tivozanib has been compared to sorafenib among patients who had not previously received VEGF or mTOR-targeting therapies. While this study demonstrated tivozanib’s activity, it was not FDA approved and is therefore not used.

    Most recently, a multikinase inhibitor, cabozantinib, has been approved for the first-line treatment of mRCC. In the phase II CABOSUN trial, cabozantinib demonstrated improved progression-free survival compared to sunitinib.14 However, these results have proven controversial, with a number of concerns raised including a potential exaggerated effect due to the poor efficacy of sunitinib compared to what would be expected based on previous reports.15

    Despite the efficacy of VEGF targeted therapies, resistance to VEGF-inhibition almost inevitably results. Therefore, research into the development of these resistance mechanisms and ways to target these pathways has been undertaken. Agents including nintedanib and dovitinib have been explored though these are not yet in routine practice.

    Inhibitors of mTOR for Advanced ccRCC

    Mammalian target of rapamycin (mTOR) plays a key role in regulating HIF-α, thus modulating the pathway between abnormalities in VHF and proliferation. Two analogous of sirolimus have demonstrated efficacy in treating advanced RCC, temsirolimus and everolimus.

    A three-arm trial comparing temsirolimus, interferon, and the combination was undertaken among patients with pre-defined poor risk disease who had not previously received systemic therapy for RCC.16 This demonstrated improvements in progression-free survival and overall survival for patients receiving temsirolimus. Notably, the combination arm did not offer a benefit compared to interferon alone. Unlike temsirolimus which must be administered intravenously, everolimus is an oral agent. Among patients progressing on sunitinib and/or sorafenib, everolimus demonstrated significantly improved progression-free survival compared to placebo.17

    Checkpoint Inhibitors for Advanced ccRCC

    The immunologic basis for treatment of advanced RCC has been well established, including the aforementioned cytokine therapies. Recently, immune checkpoint inhibitors have been examined in the treatment of advanced RCC. Two particular regimes warrant focus – nivolumab and ipilimumab and atezolizumab.

    First presented at ESMO in the fall of 2017 and subsequently published in the spring of 2018, CheckMate 214 demonstrated an overall survival (OS) benefit for first-line nivolumab plus ipilimumab vs. sunitinib.18 More details regarding this study may be found in the UroToday coverage of ESMO 2017. In short, among the subgroup of patients with intermediate or poor-risk RCC, treatment with nivolumab plus ipilimumab resulted in significantly improved overall response rate, comparable progression-free survival, and significantly improved overall survival.

    Similarly, first presented at GU ASCO in the spring of 2018 and subsequently published, IMmotion151 reported a progression-free survival (PFS) benefit for first-line atezolizumab + bevacizumab vs. sunitinib.19 This regime was active with a significant benefit in progression-free survival among the whole cohort of patients, as well as a subset of PD-L1+ patients. More details regarding this study may be found in the UroToday coverage of GU ASCO 2018.

    These trials are notable in that they demonstrated improved outcomes in first-line treatment, compared to the current standard of care, sunitinib.

    Other Agents for Advanced ccRCC

    Numerous chemotherapeutic agents have been explored in ccRCC. These include 5-FU, gemcitabine, vinblastine, bleomysin, and platinums. Meta-analyses of these data demonstrate poor response20 and thus cytotoxic chemotherapy is not indicated in the treatment of advanced RCC. Similarly, hormonal therapies including medroxyprogesterone have been explored but have no role in modern management of advanced RCC.

    Treatment of Advanced non-ccRCC

    There is a relative dearth of data for treatment of advanced non-clear cell RCC. Therefore, patients with these tumors may receive agents on the basis of their activity in ccRCC. However, VEGF-receptor inhibitors have been shown to have relatively low activity in patients with papillary RCC.21 Responses were somewhat better in patients with chromophobe RCC. Temsirolimus and everolimus appear to have some activity in patients with non-clear cell histology. Similarly, nivolumab monotherapy appears to have biologic activity in patients with non-ccRCC.22

    Integration of treatment options for patients with advanced RCC

    With so many active agents available for the treatment of advanced RCC, it may be difficult to ascertain which treatment to offer patients who present in clinic. There are a number of ways to approach this issue – first, one may take a quantitative approach, utilizing the available comparative data in a network meta-analysis; second, one may rely upon eminence, as in expert-informed guidelines; finally, one may rely on individual clinical experience. In this setting, all three options are available.

    First, assessing this in a quantitative fashion, we performed a network meta-analysis of agents for the treatment of advanced RCC.23 While there are limitations to this approach including the reliance on the assumption of transitivity between studies, interesting conclusions may be drawn. First, assessing progression-free survival, we found that it was highly likely (91% chance) that cabozantinib provided the greatest benefit. However, when assessing overall survival, nivolumab plus ipilimumab had the highest likelihood of being the preferred treatment choice. Finally, when assessing adverse events, it was highly likely that nivolumab plus ipilimumab had the most favorable toxicity profile.

    Second, considering a panel of expert opinion, the European Association of Urology updated their guidelines on the treatment of renal cell carcinoma recently. Their recommendations are highlighted in the following figure, taken from the EAU guidelines:
    diagram-systemic-therapy@2x.jpg

    Finally, we may rely on the guidance of individual clinical experience. Anil Kapoor, MD who has extensive experience in the treatment of both localized and advanced RCC, offered his treatment approach recently to UroToday.

    Published Date: January 21st, 2019
     
    Written by: Christopher J.D. Wallis, MD, PhD
    References:
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians. 2018;68(1):7-30.
    2. Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. Journal of Clinical Oncology. 1999;17:2530-2540.
    3. Negrier S, Escudier B, Gomez F, et al. Prognostic factors of survival and rapid progression in 782 patients with metastatic renal carcinomas treated by cytokines: a report from the Groupe Francais d'Immunotherapie. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2002;13(9):1460-1468.
    4. Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2002;20(1):289-296.
    5.  Coppin C, Porzsolt F, Awa A, Kumpf J, Coldman A, Wilt T. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev. 2005(1):CD001425.
    6. Dutcher JP, Atkins M, Fisher R, et al. Interleukin-2-based therapy for metastatic renal cell cancer: the Cytokine Working Group experience, 1989-1997. Cancer J Sci Am. 1997;3 Suppl 1:S73-78.
    7. Rosenberg SA, Yang JC, White DE, Steinberg SM. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg. 1998;228(3):307-319.
    8. Negrier S, Escudier B, Lasset C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d'Immunotherapie. The New England journal of medicine. 1998;338(18):1272-1278.
    9. Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2008;26(33):5422-5428.
    10. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370(9605):2103-2111.
    11. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. The New England journal of medicine. 2007;356(2):115-124.
    12. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. The New England journal of medicine. 2013;369(8):722-731
    13. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939.
    14. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2017;35(6):591-597
    15. Buti S, Bersanelli M. Is Cabozantinib Really Better Than Sunitinib As First-Line Treatment of Metastatic Renal Cell Carcinoma? Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2017;35(16):1858-1859.
    16.  Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. The New England journal of medicine. 2007;356(22):2271-2281.
    17. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637):449-456.
    18.  Escudier B, Tannir NM, McDermott D, et al. LBA5 - CheckMate 214: Efficacy and safety of nivolumab 1 ipilimumab (N1I) v sunitinib (S) for treatment-naive advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. Annals of Oncology. 2017;28(Supplement 5):621-622.
    19.  Motzer R, Powles T, Atkins M, et al. IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma. Journal of Clinical Oncology. 2018;36(Suppl 6S).
    20.  Yagoda A, Abi-Rached B, Petrylak D. Chemotherapy for advanced renal-cell carcinoma: 1983-1993. Semin Oncol. 1995;22(1):42-60.
    21. Choueiri TK, Plantade A, Elson P, et al. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26(1):127-131
    22. Koshkin VS, Barata PC, Zhang T, et al. Clinical activity of nivolumab in patients with non-clear cell renal cell carcinoma. J Immunother Cancer. 2018;6(1):9.
    23. Wallis CJD, Klaassen Z, Bhindi B, et al. First-line Systemic Therapy for Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis. European urology. 2018;74(3):309-321.
    Published January 21, 2019

  • Systemic Therapy Options for Renal Cell Carcinoma - Monty Pal

    Monty Pal and Charles Ryan discuss systemic therapeutic options and current clinical trials in the renal cell carcinoma space. Monty explains the clinical applications, considering appropriate patient selection and toxicity profile relevant in decision making. 

    Biographies:

    Sumanta (Monty) Kumar Pal, MD

    Charles J. Ryan, MD

    Related Content: 

    Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial

    Cabozantinib, a New Standard of Care for Patients With Advanced Renal Cell Carcinoma and Bone Metastases? Subgroup Analysis of the METEOR Trial

    Molecular Correlates Differentiate Response to Atezolizumab plus Bevacizumab vs Sunitinib: Results From a Phase III Study IMmotion151 in Untreated mRCC

    Axitinib vs. Placebo in Patients at High Risk of Recurrent Renal Cell Carcinoma (RCC): ATLAS Trial Results

    A phase III study of atezolizumab vs placebo as adjuvant therapy in renal cell carcinoma patients at high risk of recurrence following resection (IMmotion010)

    A Phase 1b Dose-Escalation Study of Cabozantinib (XL184) Administered Alone or in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors
    Published November 8, 2018

  • The Evolving Landscape of First-Line Therapy for Metastatic Clear Cell Renal Cell Carcinoma

    Published in Everyday Urology - Oncology Insights: Volume 5, Issue 4
    Published January 2021

    When examined at a national level in the United States, cancers of the kidney and renal pelvis (despite different histology) are considered in aggregate and represent the sixth most common newly diagnosed tumors in men and eighth most common in women in the United States in 2020,1 representing an estimated 73,750 new diagnoses and 14,830 deaths. The vast majority of these cancers will be renal parenchymal tumors with renal cell carcinoma (RCC) comprising the preponderance of these lesions. As previous UroToday Center of Excellence articles have highlighted, clear cell renal cell carcinoma (ccRCC) is the most common histologic subtype of renal cell carcinoma (RCC). Likely due to its much higher prevalence, the vast majority of systemic therapies for RCC have been investigated among patients with ccRCC. However, there have been important recent advances in treatment for patients with non-clear cell renal cell carcinomas (nccRCC) as well in recent years.


    Despite ongoing stage migration as a result of widespread use of axial abdominal imaging for non-specific abdominal complaints,2 a large proportion (up to 35%) of patients present with advanced disease, including metastases.3 Historically, metastatic RCC has been early uniformly fatal, with 10-year survival rates less than 5%.4 However, there has been a transformational change in this disease space over the past fifteen years and, with newer immunotherapy-based approaches, the potential for long-term cure is something that may be considered. Certainly, a significantly longer natural history is feasible given available therapeutic options.
    Published January 5, 2021

  • Treatment of Metastatic Non-Clear Cell RCC

    Background 

    Kidney cancer is the 12th most common cancer in the world, with over 300,000 new cases annually, of which 65,340 new cases will be diagnosed in the United States in 2018.1 The incidence of renal cell carcinoma (RCC) varies substantially based on the country – rates of RCC are higher in Europe and North America and much lower in Asia and South America.2

    Most kidney cancers (>90%) are renal cell carcinomas, and of renal cell carcinomas, the majority of cases (80%) will be the clear cell subtype.3 Of the remaining 20% of cases, the two major histological subtypes are papillary (10-14%) and chromophobe (5%)3,4, but also include collecting duct, translocation carcinoma, medullary carcinoma, and unclassified RCC. These histological subtypes are distinct from clear cell carcinoma and independently predict for survival.3 For example, after controlling for TNM status, age, gender, and tumor size, patients with early stage clear cell RCC are more than twice as likely to die of RCC than patients with papillary or chromophobe RCC.3 Some of these subtypes also have unique risk factors. For example, renal medullary carcinomas are an aggressive non-clear cell carcinoma that are almost exclusively associated with patients with sickle cell trait.5

    diagram-1-treatment-non-clear-cell-RCC@2x.jpg

    Non-clear cell RCCs (ncRCC) also have unique mutational landscapes.6 For example, MET mutations can be found in 15-30% of papillary RCCs.6,7 Papillary RCCs also have a higher mutation rate compared with chromophobe RCCs and renal oncocytomas. Durinck et al evaluated 167 primary human tumors including papillary, chromophobe and translocation subtypes and were able to use a five gene set to help molecularly distinguish between chromophobe carcinoma, renal oncocytoma and papillary carcinoma.6

    Treatment

    Given the rarity of non-clear cell RCC (ncRCC), there is a paucity of large randomized phase III trials to help guide the optimal therapy for ncRCC. Some trials for ncRCC have had to stop due to slow accrual. Given this lack of data, patients are encouraged to participate in clinical trials when they are available and appropriate. Below is a summary of the most common systemic therapies in use for ncRCC.
    table-1-treatment-non-clear-cell-RCC@2x.jpg

    Sunitinib

    Single agent sunitinib has been evaluated as part of an expanded access trial as well as several small phase II trials (Table 1). In a single arm phase II clinical trial, 23 patients were given sunitinib 50 mg in cycles of four weeks on followed by 2 weeks off. The trial was stopped early due to slow accrual and the median progression free survival (PFS) was 5.5 months.8  In a another phase II trial evaluating both sunitinib and sorafenib, 19 patients with ncRCC were given sunitinib – median PFS was 11.9 months in the papillary arm and 8.9 months in the chromophobe arm.9 The largest of these studies was reported by Gore et al, which included 588 ncRCC patients who received sunitinib as part of the expanded access study encompassing 4564 RCC patients who received sunitinib.10 In their study, 11% of patients had an objective response and median PFS was 7.8 months. Some trials have stratified outcomes by histological subtypes such as chromophobe or papillary, and one trial reported results broken down by type 1 papillary RCC vs type 2 papillary RCC11. Overall, most studies demonstrated that sunitinib led to a median PFS of about 6-7 months for ncRCC.
    table-2-treatment-non-clear-cell-RCC@2x.jpg

    Everolimus and Temsirolimus

    mTOR inhibitors Everolimus and Temsirolimus have been evaluated by a few phase II trials for ncRCC (Table 2). Everolimus was evaluated in a subgroup of REACT (RAD001 Expanded Access Clinical Trial in RCC) and in RAPTOR (RAD001 in Advanced Papillary Tumor Program in Europe).15,16 In REACT, 1.3% of patients with ncRCC had a partial response and 49.3% had stable disease.15 In RAPTOR, the median progression free survival (mPFS) was 4.1 months and median OS was 21.4 months. For patients with chromophobe RCC, mTOR directed therapy may be especially effective – case reports show partial responses and stable disease to both Everolimus or Temsirolimus.17,18 This may be due to the hypothesis that a high number of chromophobe RCC’s have PI3K-mTOR pathway activation as well as frequent TSC1/TSC2 mutations which may sensitize these tumors to mTOR inhibition.19 

    Sunitinib vs Everolimus

    Sunitinib and everolimus have also been examined head to head. The largest trial was ASPEN (Everolimus versus sunitinib for patients with metastatic non-clear-cell renal cell carcinoma), a multicenter open-label, randomized phase II trial which randomized 108 patients to receive either sunitinib or everolimus.22 The primary endpoint of this study was progression free survival. The majority of patients had papillary histology (65%). Median overall survival was 13.2 months in the everolimus group and 31.5 months in the sunitinib group. However, overall survival was not statistically different between the two treatment groups (HR 1.12, 95%CI 0.7-2.1, p=0.6). A second study, ESPN (Everolimus Versus Sunitinib Prospective Evaluation in Metastatic Non–Clear Cell Renal Cell Carcinoma) came to a similar conclusion and found that the median overall survival was 16.2 months with sunitinib and 14.9 months with everolimus (p=0.18).23

    While overall survival between everolimus and sunitinib were not statistically different for the unselected cohorts, ASPEN did find differences in objective responses between the different subtypes, suggesting that each subtype of ncRCC may respond differently to therapies. In ASPEN, 24% (8/33) of papillary RCCs achieved a partial or complete radiographic response on sunitinib compared with 5% of patients on everolimus (2/37). Interestingly, clinical outcomes after receipt of either sunitinib or everolimus also varied based on risk stratification. Patients with good or intermediate risk had improved median progression free survival (mPFS) with first line sunitinib than everolimus. However, patients with poor risk had improved PFS with everolimus over sunitinib. This is concurrent with the ARCC trial, which also demonstrated improved overall survival with an mTOR inhibitor (temsirolimus) in poor risk patients with ncRCC.24

    A meta-analysis of five studies (ESPN, ASPEN, RECORD3, ARCC, and SWOG1107) found a nonstatistical trend favoring sunitinib over everolimus for ncRCC but does note that there is considerable patient heterogeneity in these small studies and there was no statistical difference in PFS between these two therapies.25 In the absence of clinical trial options, sunitinib is a reasonable first line choice for treatment naïve patients with ncRCC, especially for those with papillary RCC or MSKCC good risk RCC.

    Special Populations

    It is well recognized that ncRCC is a heterogenous mix of patients which respond differently to therapies. Thus, there have been a few biomarker or histology driven trials looking at specific subsets of ncRCC. For example, for patients with hereditary leiomyomatosis and papillary RCC, a phase II study of 41 patients found that patients treated bevacizumab plus erlotinib had a median PFS of 24.2 months, compared to 7.4 months for patients with sporadic papillary RCC.26 Patients with papillary RCC frequently have MET mutations and a variety of MET inhibitors including crizotinib, savolitinib, and cabozantinib are being evaluated in clinical trials.27-29 For example, in a study of 41 patients with type 1 papillary RCC, of the 4 patients with MET+ tumors, 2 had achieved a partial response and one had stable disease with crizotinib.28 In a study with Savolitinib, another selective MET inhibitor, patients with MET “driven” tumors had a median PFS of 6.2 months, compared with 1.7 months for MET independent tumors.29

    table-3-treatment-non-clear-cell-RCC@2x.jpg

    Future Direction

    A number of active clinical trials are in progress, investigating various MET inhibitors as well as checkpoint inhibitors for ncRCC (Table 3). Preliminary data suggest that PD-1 or PD-L1 blockade may have some activity in this population.30,31 Given the dearth of data and rarity of ncRCC, it is important to consider these patients for clinical trials, whenever possible.

    Published Date: November 29th, 2018
    Written by: Jason Zhu, MD
    References:

    1. Motzer R, Jonasch E, Agarwal N. Kidney Cancer: NCCN Evidence Blocks, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. 2017.

    2. Chow W-H, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nature Reviews Urology 2010;7:245.

    3. Leibovich BC, Lohse CM, Crispen PL, et al. Histological Subtype is an Independent Predictor of Outcome for Patients With Renal Cell Carcinoma. The Journal of Urology 2010;183:1309-16.

    4. Moch H, Gasser T, Amin MB, Torhorst J, Sauter G, Mihatsch MJ. Prognostic utility of the recently recommended histologic classification and revised TNM staging system of renal cell carcinoma. Cancer 2000;89:604-14.

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    8. Molina AM, Feldman DR, Ginsberg MS, et al. Phase II trial of sunitinib in patients with metastatic non-clear cell renal cell carcinoma. Investigational New Drugs 2012;30:335-40.

    9. Choueiri TK, Plantade A, Elson P, et al. Efficacy of Sunitinib and Sorafenib in Metastatic Papillary and Chromophobe Renal Cell Carcinoma. Journal of Clinical Oncology 2008;26:127-31.

    10. Gore ME, Szczylik C, Porta C, et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. The Lancet Oncology 2009;10:757-63.

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    Published November 29, 2018

  • U.S. FDA Approves CABOMETYX® (cabozantinib) Tablets for Previously Untreated Advanced Renal Cell Carcinoma

    Truckee, CA (UroToday.com)  Exelixis, Inc. announced that the U.S. Food and Drug Administration (FDA) approved CABOMETYX® (cabozantinib) tablets for the expanded indication of patients with advanced renal cell carcinoma (RCC). RCC is the most common form of kidney cancer in adults. The FDA’s priority review and approval of CABOMETYX was based on results from the randomized phase 2 CABOSUN trial in patients with previously untreated RCC, which demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) versus sunitinib, a current standard of care. Today’s label expansion follows the initial FDA approval of CABOMETYX in April 2016 for the treatment of patients with advanced RCC who have previously received anti-angiogenic therapy.
    Published December 20, 2017

  • Utilization and Efficacy of Second-line Targeted Therapy in Metastatic Renal Cell Carcinoma - Beyond the Abstract

    There are numerous targeted agents available for the second-line therapy of metastatic renal cell carcinoma (mRCC). Cabozantinib, nivolumab and lenvatinib/everolimus combination are novel options that have become available only recently.  In the face of diverse treatment options and sequences, it is important to re-evaluate the results obtained with currently available drugs in this setting.

    The aim of this study was to assess the outcomes of patients treated with second-line agents in the real-world practice based on data from a national registry. Sunitinib-everolimus was the most frequently used sequence (n = 390, 38%), followed by sunitinib-sorafenib (n = 232, 23%), sorafenib-sunitinib (n = 139, 14%) and sorafenib-everolimus (n = 93, 9%).

    As shown in the table below, overall survival and combined progression-free survival were similar regardless of the sequence used, although the outcomes were numerically superior for the sunitinib → everolimus sequence. There results provide a benchmark for evaluation of novel second-line agents in mRCC. Patient registries are important tools for assessing various sequencing strategies which are rarely the subject of randomised trials. 

    Buchler fig1a

    Written by:
    Tomas Buchler, MD, PhD, Associate Professor of Oncology, Department of Oncology First Faculty of Medicine, Charles University and Thomayer Hospital, Czech Republic

    Read the Abstract

    References: 
    Published January 8, 2018

  • When Partial Nephrectomy Is Unsuccessful: Understanding the Reasons for Conversion From Robotic Partial to Radical Nephrectomy at a Tertiary Referral Center - Expert Commentary

    Partial nephrectomies are the standard of care with treatment of T1a or T1b tumors due to their better functional outcomes and decrease cardiovascular morbidity. However, with the increasing trend of using robotic partial nephrectomy (RPN) to treat more and more complex tumors, there is a greater risk of conversion to radical nephrectomy (RN). As there is little literature about analyzing the conversion rate and risks, these authors investigated the incidence of RPN to RN conversion and analyzed the preoperative factors that could possibly lead to a RN without having to convert. 
    Published September 20, 2017