Sunitinib in kidney cancer: 10 years of experience and development

ABSTRACT Introduction: Sunitinib is a multi-target, anti-angiogenic tyrosine kinase inhibitor and a key molecule in the treatment of metastatic renal cell carcinoma (mRCC). Since it first demonstrated its efficacy ten years ago, overall survival of mRCC has more than doubled, in part due to sunitinib. In most recent years, progress has been made in the comprehension of its mechanism of action and resistance. Areas Covered: In this article, clinical trials involving sunitinib in kidney cancer have been reviewed, defining its different indications in metastatic and localized RCC. The rationale of sunitinib’s efficacy, preclinical trials, past-clinical trials and ongoing clinical trials are summarized. Dose and scheme base are discussed, as the recommended dosage is frequently not well tolerated. Combination therapies appear to be toxic. Novel immunotherapies are changing the landscape of mRCC treatment and challenging sunitinib. Special attention has been paid towards cancer cell biology and immunity involved in treatment response. Expert Commentary: Sunitinib’s place in the therapeutic arsenal is being redefined with the arrival of major challengers. Dosage and scheduling of sunitinib remains a major challenge.

[1]  Chad A. LaGrange,et al.  Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. , 2017, Journal of the National Comprehensive Cancer Network : JNCCN.

[2]  J. Patard,et al.  Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. , 2016, The New England journal of medicine.

[3]  S. Oudard,et al.  Long-term use of sunitinib in metastatic renal cell carcinoma: no unpleasant surprises about tolerability , 2016 .

[4]  T. Choueiri,et al.  CABOzantinib versus SUNitinib (CABOSUN) as initial targeted therapy for patients with metastatic renal cell carcinoma (mRCC) of poor and intermediate risk groups: Results from ALLIANCE A031203 trial , 2016 .

[5]  P. Hegde,et al.  Atezolizumab, an Anti-Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  Suzanne F. Jones,et al.  Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma , 2016, Nature Communications.

[7]  S. Oudard,et al.  Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma-Results of the REchallenge with SUnitinib in MEtastatic RCC (RESUME) Study. , 2016, European journal of cancer.

[8]  J. Manola,et al.  Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial , 2016, The Lancet.

[9]  P. Tamboli,et al.  Everolimus Versus Sunitinib Prospective Evaluation in Metastatic Non-Clear Cell Renal Cell Carcinoma (ESPN): A Randomized Multicenter Phase 2 Trial. , 2016, European urology.

[10]  P. Tamboli,et al.  Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma , 2016, Oncogene.

[11]  L. Devine,et al.  Phase I study of safety and tolerability of sunitinib in combination with sirolimus in patients with refractory solid malignancies and determination of VEGF (VEGF-A) and soluble VEGF-R2 (sVEGFR2) in plasma , 2016, Cancer Chemotherapy and Pharmacology.

[12]  J. Hainsworth,et al.  Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. , 2016, The Lancet. Oncology.

[13]  C. Porta,et al.  Long-term Safety of Sunitinib in Metastatic Renal Cell Carcinoma. , 2016, European urology.

[14]  C. Porta,et al.  Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis. , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[15]  B. Escudier,et al.  Sorafenib-Sunitinib Sequence: The Jury Is Out. , 2015, European urology.

[16]  J. Ahn,et al.  RandomizEd phase II trial of Sunitinib four weeks on and two weeks off versus Two weeks on and One week off in metastatic clear-cell type REnal cell carcinoma: RESTORE trial. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[17]  M. Staehler,et al.  SWITCH: A Randomised, Sequential, Open-label Study to Evaluate the Efficacy and Safety of Sorafenib-sunitinib Versus Sunitinib-sorafenib in the Treatment of Metastatic Renal Cell Cancer. , 2015, European urology.

[18]  Mellar P. Davis,et al.  Sunitinib-associated hypertension and neutropenia as efficacy biomarkers in metastatic renal cell carcinoma patients , 2015, British Journal of Cancer.

[19]  S. Signoretti,et al.  Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor‐risk metastatic renal cell carcinoma , 2015, Cancer.

[20]  E. Tartour,et al.  Poster Session (Monday, 28 September)Translational ResearchPOSTER223 Predictive biomarkers in metastatic Renal Cell Carcinoma (mRCC) patients treated with neoadjuvant sunitinib (PREINSUT trial) , 2015 .

[21]  A. Ravaud,et al.  Trebananib (AMG 386) in Combination With Sunitinib in Patients With Metastatic Renal Cell Cancer: An Open-Label, Multicenter, Phase II Study. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  J. Larkin,et al.  First-line treatment in the management of advanced renal cell carcinoma: systematic review and network meta-analysis , 2015, Expert opinion on pharmacotherapy.

[23]  David C. Smith,et al.  Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  A. Ravaud,et al.  First-line treatment with sunitinib for type 1 and type 2 locally advanced or metastatic papillary renal cell carcinoma: a phase II study (SUPAP) by the French Genitourinary Group (GETUG)†. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[25]  R. Motzer,et al.  Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  I. Derweesh,et al.  Presurgical sunitinib reduces tumor size and may facilitate partial nephrectomy in patients with renal cell carcinoma. , 2015, Urologic oncology.

[27]  G. Freeman,et al.  Orchestration and Prognostic Significance of Immune Checkpoints in the Microenvironment of Primary and Metastatic Renal Cell Cancer , 2015, Clinical Cancer Research.

[28]  E. Tartour,et al.  VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors , 2015, The Journal of experimental medicine.

[29]  E. Jonasch,et al.  Alternate sunitinib schedules in patients with metastatic renal cell carcinoma. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[30]  N. Rioux-Leclercq,et al.  Molecular Subtypes of Clear Cell Renal Cell Carcinoma Are Associated with Sunitinib Response in the Metastatic Setting , 2015, Clinical Cancer Research.

[31]  A. Kiss,et al.  Reprint of: Outcomes in patients with metastatic renal cell cancer treated with individualized sunitinib therapy: Correlation with dynamic microbubble ultrasound data and review of the literature. , 2014, Urologic oncology.

[32]  M. van Engeland,et al.  Resistance to sunitinib in renal cell carcinoma: From molecular mechanisms to predictive markers and future perspectives. , 2015, Biochimica et biophysica acta.

[33]  S. Signoretti,et al.  Correlation of PD-L1 Tumor Expression and Treatment Outcomes in Patients with Renal Cell Carcinoma Receiving Sunitinib or Pazopanib: Results from COMPARZ, a Randomized Controlled Trial , 2014, Clinical Cancer Research.

[34]  H. Kohrt,et al.  Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients , 2014, Nature.

[35]  Tae Min Kim,et al.  Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  C. L. Le Rest,et al.  853PPREDICTION OF RESPONSE OF PRIMARY TUMORS TO NEOADJUVANT SUNITINIB USING PERFUSION (DCE) COMPUTED TOMOGRAPHY (CT) IN METASTATIC RENAL CELL CARCINOMA (MRCC) PATIENTS (PREINSUT TRIAL). , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[37]  B. Redman,et al.  A phase I/II study of lenalidomide in combination with sunitinib in patients with advanced or metastatic renal cell carcinoma. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[38]  R. Figlin,et al.  Investigation of novel circulating proteins, germ line single-nucleotide polymorphisms, and molecular tumor markers as potential efficacy biomarkers of first-line sunitinib therapy for advanced renal cell carcinoma , 2014, Cancer Chemotherapy and Pharmacology.

[39]  E. Rasmussen,et al.  A phase I, open-label study of trebananib combined with sorafenib or sunitinib in patients with advanced renal cell carcinoma. , 2014, Clinical genitourinary cancer.

[40]  E. Plimack,et al.  Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC). , 2014 .

[41]  C. Porta,et al.  Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  E. Tartour,et al.  Prognostic factors in patients with advanced renal cell carcinoma treated with VEGF-targeted agents , 2014, Expert review of anticancer therapy.

[43]  Y. Najjar,et al.  A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. , 2014, European journal of cancer.

[44]  T. Bathala,et al.  Clinical outcomes for patients with metastatic renal cell carcinoma treated with alternative sunitinib schedules. , 2014, The Journal of urology.

[45]  C. Porta,et al.  Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[46]  A. Kiss,et al.  Outcomes in patients with metastatic renal cell cancer treated with individualized sunitinib therapy: correlation with dynamic microbubble ultrasound data and review of the literature. , 2014, Urologic oncology.

[47]  J. Reeves,et al.  Pazopanib versus sunitinib in metastatic renal-cell carcinoma. , 2013, The New England journal of medicine.

[48]  B. Neri,et al.  Biweekly sunitinib regimen reduces toxicity and retains efficacy in metastatic renal cell carcinoma: A single‐center experience with 31 patients , 2013, International journal of urology : official journal of the Japanese Urological Association.

[49]  J. Patard,et al.  Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib , 2013, British Journal of Cancer.

[50]  E. Ibrahim,et al.  Sunitinib adverse events in metastatic renal cell carcinoma: a meta-analysis , 2013, International Journal of Clinical Oncology.

[51]  Lisa L. Smith,et al.  A phase 2 trial of sunitinib in patients with advanced non-clear cell renal cell carcinoma. , 2012, European urology.

[52]  B. Escudier,et al.  Neoadjuvant treatment in advanced renal cell carcinoma: current situation and future perspectives , 2012, Expert review of anticancer therapy.

[53]  S. Oudard,et al.  Sequential therapy with targeted agents in patients with advanced renal cell carcinoma: optimizing patient benefit. , 2012, Cancer treatment reviews.

[54]  C. Sternberg,et al.  Dose Escalation and Pharmacokinetics Study of Enzastaurin and Sunitinib Versus Placebo and Sunitinib in Patients With Metastatic Renal Cell Carcinoma , 2012, American journal of clinical oncology.

[55]  J. Ahn,et al.  Multicenter phase II study of sunitinib in patients with non-clear cell renal cell carcinoma. , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[56]  J. Kaouk,et al.  The effect of sunitinib on primary renal cell carcinoma and facilitation of subsequent surgery. , 2012, The Journal of urology.

[57]  J. Burke,et al.  Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[58]  R. Motzer,et al.  Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma , 2012, Cancer.

[59]  C. Barrios,et al.  Phase II trial of continuous once‐daily dosing of sunitinib as first‐line treatment in patients with metastatic renal cell carcinoma , 2012, Cancer.

[60]  D. Brizel,et al.  National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology , 2012 .

[61]  D. Berney,et al.  The outcome of patients treated with sunitinib prior to planned nephrectomy in metastatic clear cell renal cancer. , 2011, European urology.

[62]  A. Ganser,et al.  Efficacy of Sunitinib Re-Exposure after Failure of an mTOR Inhibitor in Patients with Metastatic RCC , 2011, Oncology Research and Treatment.

[63]  R. Figlin,et al.  Hypertension as a Biomarker of Efficacy in Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib , 2011, Journal of the National Cancer Institute.

[64]  B. Rini,et al.  Phase 1 dose‐escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma , 2011, Cancer.

[65]  E. Tartour,et al.  Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy , 2011, Cancer and Metastasis Reviews.

[66]  J. Haanen,et al.  A Phase I study of recombinant human interleukin-21 (rIL-21) in combination with sunitinib in patients with metastatic renal cell carcinoma (RCC) , 2011, Acta oncologica.

[67]  G. Wilding,et al.  A phase II study of 2-methoxyestradiol nanocrystal colloidal dispersion alone and in combination with sunitinib malate in patients with metastatic renal cell carcinoma progressing on sunitinib malate , 2012, Investigational New Drugs.

[68]  V. Reuter,et al.  Phase II trial of sunitinib in patients with metastatic non-clear cell renal cell carcinoma , 2012, Investigational New Drugs.

[69]  T. Choueiri,et al.  Sunitinib rechallenge in metastatic renal cell carcinoma patients , 2010, Cancer.

[70]  E. Tartour,et al.  A Decrease of Regulatory T Cells Correlates With Overall Survival After Sunitinib-based Antiangiogenic Therapy in Metastatic Renal Cancer Patients , 2010, Journal of immunotherapy.

[71]  I. Derweesh,et al.  Feasibility and efficacy of neoadjuvant sunitinib before nephron‐sparing surgery , 2010, BJU international.

[72]  B. Teh,et al.  Prospective clinical trial of preoperative sunitinib in patients with renal cell carcinoma. , 2010, The Journal of urology.

[73]  Karl J. Dykema,et al.  Reversible Epithelial to Mesenchymal Transition and Acquired Resistance to Sunitinib in Patients with Renal Cell Carcinoma: Evidence from a Xenograft Study , 2010, Molecular Cancer Therapeutics.

[74]  G. Demetri,et al.  Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis , 2010, Cancer Chemotherapy and Pharmacology.

[75]  B. Rini,et al.  Correction: A Phase I Study of Sunitinib plus Bevacizumab in Advanced Solid Tumors , 2009, Clinical Cancer Research.

[76]  Helen X. Chen,et al.  A Phase I Study of Sunitinib plus Bevacizumab in Advanced Solid Tumors , 2009, Clinical Cancer Research.

[77]  U. Harmenberg,et al.  Phase II study of sunitinib administered in a continuous once-daily dosing regimen in patients with cytokine-refractory metastatic renal cell carcinoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[78]  C. Porta,et al.  Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. , 2009, The Lancet. Oncology.

[79]  Xin Huang,et al.  Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell Carcinoma , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[80]  S. Oudard,et al.  Salvage therapy with bevacizumab-sunitinib combination after failure of sunitinib alone for metastatic renal cell carcinoma: a case series. , 2009, European urology.

[81]  B. Teh,et al.  Complexity of tumor vasculature in clear cell renal cell carcinoma , 2009, Cancer.

[82]  R. Motzer,et al.  Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[83]  R. Figlin,et al.  Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. , 2009, Cancer research.

[84]  Masahiro Inoue,et al.  Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. , 2009, Cancer cell.

[85]  R. Motzer,et al.  Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma. , 2008, Clinical genitourinary cancer.

[86]  M. Michaelson,et al.  Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[87]  R. Motzer,et al.  Quality of life in patients with metastatic renal cell carcinoma treated with sunitinib or interferon alfa: results from a phase III randomized trial. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[88]  Gabriele Bergers,et al.  Modes of resistance to anti-angiogenic therapy , 2008, Nature Reviews Cancer.

[89]  C. Charbonneau,et al.  Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. , 2008, Cancer treatment reviews.

[90]  M. Koch,et al.  Tumor Escape from Endogenous, Extracellular Matrix–Associated Angiogenesis Inhibitors by Up-Regulation of Multiple Proangiogenic Factors , 2008, Clinical Cancer Research.

[91]  F. Kabbinavar,et al.  A phase I and pharmacokinetic study of sunitinib administered daily for 2 weeks, followed by a 1-week off period , 2008, Cancer Chemotherapy and Pharmacology.

[92]  J. Christensen,et al.  A preclinical review of sunitinib, a multitargeted receptor tyrosine kinase inhibitor with anti-angiogenic and antitumour activities. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[93]  Phillip H. Lai,et al.  Sunitinib (Sutent®): A novel agent for the treatment of metastatic renal cell carcinoma , 2007, Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners.

[94]  L. Chow,et al.  Sunitinib: from rational design to clinical efficacy. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[95]  R. Figlin,et al.  Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. , 2007, The New England journal of medicine.

[96]  N. Normanno,et al.  Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions. , 2006, The oncologist.

[97]  R. Motzer,et al.  Sunitinib in patients with metastatic renal cell carcinoma. , 2006, JAMA.

[98]  R. Figlin,et al.  Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[99]  E. Raymond,et al.  Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[100]  Randy Allred,et al.  A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. , 2005, Blood.

[101]  M. Krzakowski,et al.  Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial--the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[102]  E. Messing,et al.  Overproduction of vascular endothelial growth factor related to von Hippel-Lindau tumor suppressor gene mutations and hypoxia-inducible factor-1 alpha expression in renal cell carcinomas. , 2003, The Journal of urology.

[103]  Juthamas Sukbuntherng,et al.  In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[104]  R. Motzer,et al.  Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[105]  A. Ravaud,et al.  Recombinant Human Interleukin-2, Recombinant Human Interferon Alfa-2a, or Both in Metastatic Renal-Cell Carcinoma , 1998 .

[106]  A. Ravaud,et al.  Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Français d'Immunothérapie. , 1998, The New England journal of medicine.

[107]  E. Tartour,et al.  Variable expression of CD3‐ζ chain in tumor‐infiltrating lymphocytes (TIL) derived from renal‐cell carcinoma: Relationship with til phenotype and function , 1995 .

[108]  R. Fisher,et al.  Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.