Novel standards and emerging therapies for systemically treatment-naïve clear cell renal cell carcinoma - a rapidly changing landscape

Abstract

The last decade has brought about major advances in systemic therapy for patients with advanced clear cell renal cell carcinoma. The introduction of angiogenesis targeting agents, immune checkpoint inhibitors, and combinations thereof has resulted in a multitude of therapeutic standards for patients with newly diagnosed advanced disease. With the rapid adoption and increasing number of available options for patients, selection amongst treatment regimens has become complex. Further, a new balance is also being sought to optimize treatment outcomes and limit treatment-related toxicities. With a rising bar against which novel therapeutics are being measured, the field looks toward an evolved understanding of tumor biology to help pave new ways forward for individualized therapy. Here, we review pivotal studies that led to regulatory approvals and ongoing clinical trials conducted in patients with systemically untreated clear cell renal cell carcinoma and provide perspective on how newly emerging data can be integrated into this rapidly changing landscape.

Keywords

Renal cell carcinoma / combination immunotherapy / clinical trials / first-line

References

[1] Negrier S,Lasset C.Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Français d'Immunothérapie.N Engl J Med1998;338:1272-8

[2] Motzer RJ,Cella D.Pazopanib versus sunitinib in metastatic renal-cell carcinoma.N Engl J Med2013;369:722-31

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

[4] Motzer RJ,McDermott DF.CheckMate 214 InvestigatorsNivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma.N Engl J Med2018;378:1277-90 PMCID:PMC5972549

[5] Rini BI,Stus V.KEYNOTE-426 InvestigatorsPembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.N Engl J Med2019;380:1116-27

[6] Choueiri TK,Burotto M.CheckMate 9ER InvestigatorsNivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.N Engl J Med2021;384:829-41 PMCID:PMC8436591

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

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

[9] Bex A,Jewett M.Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial.JAMA Oncol2019;5:164-70 PMCID:PMC6439568

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

[11] Heng DY,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, multicenter study.J Clin Oncol2009;27:5794-9

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

[13] 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

[14] Hudes G,Tomczak P.Global ARCC TrialTemsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.N Engl J Med2007;356:2271-81

[15] Motzer RJ,Hamidi H.Molecular subsets in renal cancer determine outcome to checkpoint and angiogenesis blockade.Cancer Cell2020;38:803-17.e4 PMCID:PMC8436590

[16] McDermott DF,Atkins MB.Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.Nat Med2018;24:749-57 PMCID:PMC6721896

[17] Hakimi AA,Kuo F.Transcriptomic profiling of the tumor microenvironment reveals distinct subgroups of clear cell renal cell cancer: data from a randomized phase III trial.Cancer Discov2019;9:510-25 PMCID:PMC6697163

[18] Motzer R,Mcdermott D.661P Conditional survival and 5-year follow-up in CheckMate 214: First-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in advanced renal cell carcinoma (aRCC).Ann Oncol2021;32:S685-7

[19] Albiges L,Burotto M.Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial.ESMO Open2020;5:e001079 PMCID:PMC7703447

[20] Tannir NM,Choueiri TK.Efficacy and safety of nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma.Clin Cancer Res2021;27:78-86

[21] Escudier B,Koralewski P.Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial.Lancet2007;370:2103-11

[22] Amin A,Ernstoff MS.Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study.J Immunother Cancer2018;6:109 PMCID:PMC6196426

[23] Chowdhury S,Voss MH.A phase I/II study to assess the safety and efficacy of pazopanib (PAZ) and pembrolizumab (PEM) in patients (pts) with advanced renal cell carcinoma (aRCC).J Clin Oncol2017;35:4506

[24] 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

[25] Powles T,Soulières D.Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial.Lancet Oncol2020;21:1563-73

[26] Rini BI,Stus V.Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): results from 42-month follow-up of KEYNOTE-426.J Clin Oncol2021;39:4500

[27] Plimack ER,Bedke J.Outcomes for patients in the pembrolizumab+axitinib arm with advanced renal cell carcinoma (RCC) who completed two years of treatment in the phase III KEYNOTE-426 study.J Clin Oncol2021;39:327

[28] Motzer RJ,Powles T.Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): Outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER.J Clin Oncol2021;39:308

[29] Alhalabi O,Wilson NR.Outcomes of patients with intermediate-risk or poor-risk metastatic renal cell carcinoma who received their first cycle of nivolumab and ipilimumab in the hospital because of symptomatic disease: The MD Anderson Cancer Center experience.Int J Cancer2021;149:387-93

[30] McDermott DF,Bjarnason GA.Open-label, single-arm phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced clear cell renal cell carcinoma.J Clin Oncol2021;39:1020-8 PMCID:PMC8078336

[31] Grimm MO,Martinez ID.Tailored immunotherapy approach with nivolumab in advanced renal cell carcinoma (TITAN-RCC).Ann Oncol2019;30:v892

[32] McKay RR,Xie W.Optimized management of nivolumab and ipilimumab in advanced renal cell carcinoma: a response-based phase II study (OMNIVORE).J Clin Oncol2020;38:4240-8 PMCID:PMC7768333

[33] Atkins MB,Haas NB.Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced renal cell carcinoma (RCC) (HCRN GU16-260).J Clin Oncol2020;38:5006

[34] Lee C,Hsieh JJ.Phase II trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) for disease progression after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell renal cell carcinoma (mccRCC).J Clin Oncol2020;38:5008

[35] Epaillard N,Elaidi R.BIONIKK: A phase 2 biomarker driven trial with nivolumab and ipilimumab or VEGFR tyrosine kinase inhibitor (TKI) in naïve metastatic kidney cancer.Bulletin du Cancer2020;107:eS22-7

[36] Beuselinck B,Becht E.Molecular subtypes of clear cell renal cell carcinoma are associated with sunitinib response in the metastatic setting.Clin Cancer Res2015;21:1329-39

[37] Choueiri TK,Powles T,Wang F.A phase III study (COSMIC-313) of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in patients (pts) with previously untreated advanced renal cell carcinoma (aRCC) of intermediate or poor risk.J Clin Oncol2020;38:TPS767

[38] Apolo AB,Girardi DM.Phase I study of cabozantinib and nivolumab alone or with ipilimumab for advanced or metastatic urothelial carcinoma and other genitourinary tumors.J Clin Oncol2020;38:3672-84 PMCID:PMC7605393

[39] 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

[40] Charych DH,Langowski JL.NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models.Clin Cancer Res2016;22:680-90

[41] Diab A,Bentebibel SE.Bempegaldesleukin (NKTR-214) plus nivolumab in patients with advanced solid tumors: phase I dose-escalation study of safety, efficacy, and immune activation (PIVOT-02).Cancer Discov2020;10:1158-73

[42] Tannir NM,Pal SK.A phase III randomized open label study comparing bempegaldesleukin (NKTR-214) plus nivolumab to sunitinib or cabozantinib (investigator's choice) in patients with previously untreated advanced renal cell carcinoma.J Clin Oncol2019;37:TPS4595

[43] Dovedi SJ,Yang C.Design and efficacy of a monovalent bispecific PD-1/CTLA4 antibody that enhances CTLA4 blockade on PD-1⁺ activated T cells.Cancer Discov2021;11:1100-17