Recent advances in the frontline treatment of metastatic renal cell carcinoma

Abstract

We aim to describe the most recent advances in the upfront treatment of metastatic renal cell carcinoma, and to provide criteria - though often subjective - which could be used for treatment selection, by means of a critical review of the results of novel trials of immune-based combinations, coupled with personal considerations and experiences. To date, 5 immune-based combinations have been tested within large phase III trials; four of them yielded a significant overall survival benefit (Ipilimumab + Nivolumab, Pembrolizumab + Axitinib, Nivolumab + Cabozantinib and Pembrolizumab + Lenvatinib), while the combination of Avelumab + Axitinib, although reaching study primary endpoint, determined just a significant progression-free survival benefit. In terms of safety, the excess of adverse events is overall counterbalanced to the higher activity of the combinations. Overall, all the discussed immune-based combinations were ultimately approved by different regulatory authorities, and are indeed included in the most important international guidelines. Waiting for longer follow-ups and more mature trial data, as well as for real-world experiences, in the absence of validated biomarkers, our 1st line treatment choice cannot but rely on methodologically incorrect treatment comparisons, personal preferences, and experience.

Keywords

Renal cell carcinoma / immune checkpoint inhibitors / antiangiogenics / survival

References

[1] Motzer RJ,McDermott DF.Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma.N Engl J Med2018;378:1277-90 PMCID:PMC5972549

[2] Rini BI,Stus V.Pembrolizumab plus Axitinib versus Sunitinib for advanced renal-cell carcinoma.N Engl J Med2019;380:1116-27

[3] Choueiri TK,Burotto M.Nivolumab plus Cabozantinib versus Sunitinib for advanced renal-cell carcinoma.N Engl J Med2021;384:829-41

[4] Motzer RJ,Rha SY.Lenvatinib plus Pembrolizumab or Everolimus for advanced renal cell carcinoma.N Engl J Med2021;384:1289-300

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

[6] ESMO Guidelines Committee. eUpdate - renal cell carcinoma treatment recommendations https://www.esmo.org/guidelines/genitourinary-cancers/renal-cell-carcinoma/eupdate-renal-cell-carcinoma-treatment-recommendations-3 [Last accessed on 8 Jul 2021]

[7] Albiges L,Staehler M.Updated European Association of Urology guidelines on renal cell carcinoma: immune checkpoint inhibition is the new backbone in first-line treatment of metastatic clear-cell renal cell carcinoma.Eur Urol2019;76:151-6

[8] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®). Kidney Cancer, Version 3.2021. Available from: https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. [Last accessed on 12 Aug 2021]

[9] 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

[10] Heng DY,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

[11] Motzer RJ,McDermott DF.Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.Lancet Oncol2019;20:1370-85 PMCID:PMC7497870

[12] Motzer RJ,McDermott DF.Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial.J Immunother Cancer2020;8:e000891 PMCID:PMC7359377

[13] 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

[14] 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

[15] 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

[16] Choueiri TK,Rini BI.Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma.Ann Oncol2020;31:1030-9

[17] Rofi E,Arrigoni E.Clinical pharmacology of monoclonal antibodies targeting PD-1 axis in urothelial cancers.Crit Rev Oncol Hematol2020;154:102891

[18] Porta C,Rizzo M.Individualizing renal cell carcinoma treatment through biomarkers discovery in the era of immune checkpoint inhibitors: where do we stand?.Curr Opin Urol2021;31:236-41

[19] Bracarda S,Marrocolo F,del Buono S.GOAL: an inverse toxicity-related algorithm for daily clinical practice decision making in advanced kidney cancer.Crit Rev Oncol Hematol2014;89:386-93