Individualized therapy for metastatic renal cell carcinoma

Abstract

Metastatic Renal Cell Carcinoma (mRCC) is a highly heterogeneous disease that is notoriously difficult to treat successfully. However, the discovery of novel, targeted therapies over the last decade has revolutionized its management. As the therapeutic options continue to evolve, developing a more individualized treatment strategy is of paramount importance. The International mRCC Database Consortium (IMDC) is a prognostic model that is commonly used in trials and clinical settings to risk stratify patients. This allows for optimal therapy selection on a more individual basis. However, the distinct lack of validated predictive biomarkers in mRCC renders it difficult to assess therapy response. An improved understanding of tumor biology and genetics has prompted a shift from cytokine therapy to the use of vascular endothelial growth factor (VEGF) inhibitors, tyrosine kinase Inhibitors, immune checkpoint inhibitors or combination strategies. Studies have identified some putative markers and genetic mutations as potential predictors of therapy response. Early results are promising, and there are many ongoing trials further assessing their suitability for clinical use. This review will evaluate the current treatment landscape and molecular biology of mRCC, with a specific focus on the prognostic and predictive markers available to guide treatment options and further improve patient outcomes.

Keywords

Metastatic renal cell carcinoma / IMDC / predictive biomarker / individualized therapy / immunotherapy / VEGF / prognosis

References

[1] Global Cancer Observatory: Cancer Today. Lyon, France: international agency for research on cancer. Available from: https://gco.iarc.fr/today [Last accessed on 3 Jun 2021]

[2] Bray F,Soerjomataram I,Torre LA.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin2018;68:394-424

[3] Cancer research UK (2020) kidney cancer statistics. Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/kidney-cancer [Last accessed on 3 Jun 2021]

[4] Hsieh JJ,Signoretti S.Renal cell carcinoma.Nat Rev Dis Primers2017;3:17009 PMCID:PMC5936048

[5] Haddad AQ.Tumour and patient factors in renal cell carcinoma towards personalised therapy.Nat Rev Urol2015;12:253-62

[6] Heng DYC,Regan MM.Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicentre study.J Clin Oncol2009;27:5794-9

[7] Motzer RJ,Murphy BA.Interferon-alpha as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma.J Clin Oncol2002;20:289-96

[8] Heng DYC,Regan MM.External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model :a population-based study.Lancet Oncol2013;14:141-8 PMCID:PMC4144042

[9] Ko JJ,Kroeger N.The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study.Lancet Oncol2015;16:293-300

[10] Wells JC,Norton C.Third-line targeted therapy in metastatic renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium.Eur Urol2017;71:204-9

[11] Kroeger N,Lee JL.Metastatic non-clear cell renal cell carcinoma treated with targeted therapy agents: characterization of survival outcome and application of the International mRCC Database Consortium criteria.Cancer2013;119:2999-3006 PMCID:PMC3934562

[12] Yip S,Moreira RB,Heng DYC.Real world experience of immuno-oncology agents in metastatic renal cell carcinoma: results from the IMDC.J Clin Oncol2017;35:492

[13] Cella D,Escudier B.Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial.Lancet Oncol2019;20:297-310 PMCID:PMC6701190

[14] Srigley JR,Eble JN.ISUP renal tumor panel. The International Society of Urological Pathology (ISUP) vancouver classification of renal neoplasia.Am J Surg Pathol2013;37:1469-89

[15] Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma.Nature2013;499:43-9 PMCID:PMC3771322

[16] Patard J-J,Fergelot P.Understanding the importance of smart drugs in renal cell carcinoma.Eur Urol2006;49:633-43

[17] Sternberg CN,Bracarda S.Safety and efficacy of sunitinib in patients from Italy with metastatic renal cell carcinoma: final results form an expanded-access trial.Oncology2015;8:273-80

[18] Chowdhury B,Stewart JC.PBRM1 regulates the expression of genes involved in metabolism and cell adhesion in renal clear cell carcinoma.PLoS One2016;11:e0153718 PMCID:PMC4839679

[19] Hsieh JJ,Wang PI.Genomic biomarkers of a randomized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma.Eur Urol2017;71:405-14 PMCID:PMC5431298

[20] Carlo M,Patil S.Genomic alterations and outcomes with VEGF-targeted therapy in patients with clear cell renal cell carcinoma.Kidney Cancer2017;1:49-56 PMCID:PMC6179122

[21] Creighton CJ.A gene transcription signature of the Akt/mTOR pathway in clinical breast tumors.Oncogene2007;26:4648-55

[22] Cao G,Wang Z.What is the optimum systemic treatment for advanced/metastatic renal cell carcinoma of favourable, intermediate and poor risk, respectively?.BMJ Open2020;10:eo34626 PMCID:PMC7454197

[23] Loewth R,Wullschleger S.Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control.Mol Cell2002;10:457-68

[24] Inoki K.Complexity of the TOR signalling network.Trends Cell Biol2006;16:206-12

[25] Kwiatkowski DJ,Fay AP.Mutations in TSC1, TSC2, and MTOR are associated with response to rapalogs in patients with metastatic renal cell carcinoma.Clin Cancer Res2016;22:2445-52 PMCID:PMC4976069

[26] Motzer RJ,McDermott DF.Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma.N Engl J Med2018;378:1277-90 PMCID:PMC5972549

[27] Motzer RJ,McDermott DF.CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma.N Engl J Med2015;373:1803-13 PMCID:PMC5719487

[28] Escudier B,McDermott DF.CheckMate 214: efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups.Ann Oncol2017;28:V621-2

[29] Mazza C,Albiges L.Nivolumab in renal cell carcinoma: latest evidence and clinical potential.Ther Adv Med Oncol2017;9:171-81 PMCID:PMC5349425

[30] Iacovelli ,Nole F.Prognostic role of PD-L1 expression in renal cell carcinoma. A systematic review and meta-analysis.Target Oncol2016;11:143-48

[31] RH, Dong H, Kwon ED. Implications of B7-H1 expression in clear cell carcinoma of the kidney for prognostication and therapy.Clin Cancer Res2007;13:709s-15s

[32] Miao D,Gao W.Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma.Science2018;59:801-6 PMCID:PMC6035749

[33] Brannon AR,Seiler M.Molecular stratification of clear cell renal cell carcinoma by consensus clustering reveals distinct subtypes and survival patterns.Genes Cancer2010;1:152-63 PMCID:PMC2943630

[34] de Velasco G,Fay AP.Molecular subtypes improve prognostic value of International Metastatic Renal Cell Carcinoma Database Consortium prognostic model.Oncol2017;22:286-92 PMCID:PMC5344647

[35] Durinck S,Pavia-Jimenez A.Spectrum of diverse genomic alterations define non-clear cell renal carcinoma subtypes.Nat Genet2015;47:13-21 PMCID:PMC4489427

[36] Linehan WM,Ricketts CJ.Cancer genome atlas research network. Comprehensive molecular characterization of papillary renal-cell carcinoma.N Engl J Med2016;374:135-45 PMCID:PMC4775252

[37] Choueiri TK,Rosenberg JE.Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma.J Clin Oncol2013;31:181-6 PMCID:PMC3532390

[38] Choueiri TK,Arkenau HT.Biomarker-based phase II trial of savolitinib in patients with advanced papillary renal cell cancer.J Clin Oncol2017;35:2993-3001

[39] Choueiri TK,Sanford BL.Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial.J Clin Oncol2017;35:591-7 PMCID:PMC5455807

[40] Choueiri TK,Powles T.METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma.N Engl J Med2015;373:1814-23 PMCID:PMC5024539

[41] Gad S,Khoo SK.Mutations in BHD and TP53 genes, but not in HNF1beta gene, in a large series of sporadic chromophobe renal cell carcinoma.Br J Cancer2007;96:336-40 PMCID:PMC2360004

[42] Higgins JP,Gill H.Gene expression patterns in renal cell carcinoma assessed by complementary DNA microarray.Am J Pathol2003;162:925-32 PMCID:PMC1868114

[43] Yamazaki K,Ohta T.Overexpression of KIT in chromophobe renal cell carcinoma.Oncogene2003;22:847-52

[44] Haitel A,Wick N.c-kit overexpression in chromophobe renal cell carcinoma is not associated with c-kit mutation of exons 9 and 11.Am J Surg Pathol2005;29:842

[45] Polascik TJ,Epstein JI.Distal nephron renal tumors: microsatellite allelotype.Cancer Res1996;56:1892-15

[46] Choueiri TK.Systemic therapy for metastatic renal-cell carcinoma.N Engl J Med2017;376:354-66

[47] Gerlinger M,Horswell S.Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.N Engl J Med2012;366:883-92 PMCID:PMC4878653

[48] Pal SK,Agarwal N.Evolution of circulating tumor DNA profile from first-line to subsequent therapy in metastatic renal cell carcinoma.Eur Urol2017;72:557-64

[49] Park I,Ahn JH.Active surveillance for metastatic or recurrent renal cell carcinoma.J Cancer Res Clin Oncol2014;140:1421-8

[50] Rini BI,Elson P.Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial.Lancet Oncol2016;17:1317-24

[51] Heng DYC,Rini BI.Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium.Eur Urol2014;66:704-10

[52] Bex A,Jewett MAS.Immediate versus deferred cytoreductive nephrectomy (CN) in patients with synchronous metastatic renal cell carcinoma (mRCC) receiving sunitinib (EORTC 30073 SURTIME).Ann Oncol2017;28:V622

[53] Méjean A,Thezenas S.Sunitinib alone or after Nephrectomy in metastatic renal-cell carcinoma.N Engl J Med2018;379:417-27

[54] Méjean A,Chevreau C.Cytoreductive nephrectomy (CN) in metastatic renal cancer (mRCC): Update on Carmena trial with focus on intermediate IMDC-risk population.J Clin Oncol2019;37:4508-8

[55] Motzer RJ,Tomczak P.Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma.J Clin Oncol2009;27:3584-90 PMCID:PMC3646307

[56] Pal SK,Vogelzang N.Disease-specific survival in de novo metastatic renal cell carcinoma in the cytokine and targeted therapy era.PLoS One2013;8:e63341 PMCID:PMC3643924

[57] Escudier B,Koralewski P.Bevacizumanb plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomized, double-blind phase III trial.Lancet2007;370(9605):2103-11

[58] Ribas A.Cancer immunotherapy using checkpoint blockade.Science2018;359:1350-5 PMCID:PMC7391259

[59] Hodi FS,McDermott DF.Improved survival with ipilimumab in patients with metastatic melanoma.N Eng J Med2010;363711-23 PMCID:PMC3549297

[60] Antonia SJ,Bendell J.Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial.Lancet Oncol2016;17:883-95

[61] Rini BI,Stus V.Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.N Engl J Med2019;380:1103-15

[62] Motzer RJ,Haanen J.Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.N Engl J Med2019;380:1103-15 PMCID:PMC6716603

[63] Choueiri TK,Burotto M.CheckMate 9ER InvestigatorsNivolumab plus Cabozantinib versus Sunitinib for advanced renal-cell carcinoma.N Engl J Med2021;384:829-41

[64] Motzer RJ,Gannon A.Sunitinib: ten years of successful clinical use and study in advanced renal cell carcinoma.Oncologist2017;22:41-52 PMCID:PMC5313263

[65] Gee MS,Makonnen S.Tumor vessel development and maturation impose limits on the effectiveness of anti-vascular therapy.Am J Pathol2003;162:183-93 PMCID:PMC1851112

[66] Kotecha RR,Voss MH.Towards individualized therapy for metastatic renal cell carcinoma.Nature2019;16:621-33

[67] Gao W,Xiao T,Kaelin WG Jr.Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL-/- clear cell renal carcinoma.Proc Natl Acad Sci U S A2017;114:1027-32 PMCID:PMC5293026

[68] Motzer R,Rha SY.CLEAR Trial InvestigatorsLenvatinib plus Pembrolizumab or Everolimus for advanced renal cell carcinoma.N Engl J Med2021;384:1289-300

[69] Grunwald V,Choueiri TK.Lenvatinib plus everolimus or pembrolizumab versus sunitinib in advanced renal cell carcinoma: study design and rationale.Future Oncol2019;15:929-41

[70] Rini BI,Atkins MB.Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial.Lancet2019;393:2404-15

[71] Al-Marrawi MY,Harshman LC.International mRCC Database Consortium. The association of clinical outcome to first-line VEGF-targeted therapy with clinical outcome to second-line VEGF-targeted therapy in metastatic renal cell carcinoma patients.Target Oncol2013;8:203-9 PMCID:PMC4144038

[72] Rini BI,Escudier BJ.Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study.Lancet2020;21:95-104

[73] Zakharia Y,Ross R,Alva AS.Phase Ib/II study of durvalumab and guadecitabine in advanced kidney cancer Big Ten Cancer Research Consortium BTCRC GU16-043.JCO2021;39:328

[74] Choueiri TK,Mcdermott DF.Phase 2 study of the oral hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 in combination with cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC).J Clin Oncol2021;39:272

[75] Kollmannsberger C.Sunitinib side effects as surrogate biomarkers of efficacy.Can Urol Assoc J2016;10:S245-7 PMCID:PMC5215302

[76] Rini BI,Lu DR.Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib.J Natl Cancer Inst2011;103:763-73 PMCID:PMC3086879

[77] Wasserstrum Y,Raanani P,Pasvolsky O.Hypertension in cancer patients treated with anti-angiogenic based regimens.Cardiooncology2015;7;1-6 PMCID:PMC7837153

[78] Bianchi M,Jeldres C.Distribution of metastatic sites in renal cell carcinoma: a population-based analysis.Ann Oncol2012;23:973-80

[79] Kavolius JP,Pavlovich C.Resection of metastatic renal cell carcinoma.J Clin Oncol1998;16:2261-6

[80] Wang CJ,Lin MH.Safety and efficacy of stereotactic ablative radiation therapy for renal cell carcinoma extracranial metastases.Int J Radiat Oncol Biol Phys2017;98:91-100 PMCID:PMC5555369

[81] Aoun HD,Jaber M.Percutaneous cryoablation of renal tumors: is it time for a new paradigm shift?.J Vasc Interv Radiol2017;28:1363-70

[82] Mehta S,Choudhury A.Immunotherapy with radiotherapy in urological malignancies.Curr Opin Urol2016;26:514-22

[83] EurekAlert! AAAS. No benefit from Pazopanib in advanced kidney cancer after surgery to remove metastases. Available from: https://www.eurekalert.org/pub_releases/2019-06/ecrg-nbf053119.php [Last accessed on 3 Jun 2021]