Skip to main content
Top
Published in: Targeted Oncology 2/2024

Open Access 03-02-2024 | Kidney Cancer | Review Article

Planned Discontinuation of Tyrosine Kinase Inhibitor Therapy in Metastatic Renal Cell Carcinoma: Lessons for the Era of Immunotherapy

Authors: Tomas Buchler, Alexandr Poprach

Published in: Targeted Oncology | Issue 2/2024

Login to get access

Abstract

Several regimens combining immunotherapy and tyrosine kinase inhibitors (TKIs) have recently been validated for the first-line treatment of patients with metastatic renal cell carcinoma (mRCC). While immunotherapy is typically discontinued after 2 years in patients who neither progress nor experience limiting toxicity, according to the protocols of most recent phase III clinical trials, TKIs are to be continued until disease progression or the emergence of limiting toxicity. However, the prolonged use of TKIs is associated with significant toxicity and financial costs. This has sparked considerable debate about whether TKIs can be safely discontinued, particularly in mRCC patients who have achieved a verified complete response. This concise review examines the available evidence on TKI discontinuation in the context of mRCC management.
Literature
2.
go back to reference Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378:1277–90.CrossRefPubMedPubMedCentral Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378:1277–90.CrossRefPubMedPubMedCentral
3.
go back to reference Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116–27.CrossRefPubMed Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116–27.CrossRefPubMed
4.
go back to reference Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103–15.CrossRefPubMedPubMedCentral Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103–15.CrossRefPubMedPubMedCentral
5.
go back to reference Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384:829–41.CrossRefPubMedPubMedCentral Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384:829–41.CrossRefPubMedPubMedCentral
6.
go back to reference Motzer R, Alekseev B, Rha S-Y, Porta C, Eto M, Powles T, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384:1289–300.CrossRefPubMed Motzer R, Alekseev B, Rha S-Y, Porta C, Eto M, Powles T, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384:1289–300.CrossRefPubMed
7.
go back to reference Choueiri TK, Powles T, Albiges L, Burotto M, Szczylik C, Zurawski B, et al. Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. N Engl J Med. 2023;388:1767–78.CrossRefPubMedPubMedCentral Choueiri TK, Powles T, Albiges L, Burotto M, Szczylik C, Zurawski B, et al. Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. N Engl J Med. 2023;388:1767–78.CrossRefPubMedPubMedCentral
8.
go back to reference Iacovelli R, Ciccarese C, Bersanelli M, Zucali PA, Fantinel E, Bimbatti D, et al. 1884MO Phase II study of avelumab (Ave) plus intermittent axitinib (Axi) in previously untreated patients (pts) with metastatic renal cell carcinoma (mRCC): the TIDE-A study. Ann Oncol. 2023;34:S1013.CrossRef Iacovelli R, Ciccarese C, Bersanelli M, Zucali PA, Fantinel E, Bimbatti D, et al. 1884MO Phase II study of avelumab (Ave) plus intermittent axitinib (Axi) in previously untreated patients (pts) with metastatic renal cell carcinoma (mRCC): the TIDE-A study. Ann Oncol. 2023;34:S1013.CrossRef
9.
go back to reference Porta C, Gore ME, Rini BI, Escudier B, Hariharan S, Charles LP, et al. Long-term safety of sunitinib in metastatic renal cell carcinoma. Eur Urol. 2016;69:345–51.CrossRefPubMed Porta C, Gore ME, Rini BI, Escudier B, Hariharan S, Charles LP, et al. Long-term safety of sunitinib in metastatic renal cell carcinoma. Eur Urol. 2016;69:345–51.CrossRefPubMed
10.
go back to reference Benjamin DJ, Rezazadeh A. Financial toxicity from first-line TKI plus IO therapies for advanced renal cell carcinoma. J Clin Oncol. 2023;41:634.CrossRef Benjamin DJ, Rezazadeh A. Financial toxicity from first-line TKI plus IO therapies for advanced renal cell carcinoma. J Clin Oncol. 2023;41:634.CrossRef
11.
go back to reference Johannsen M, Staehler M, Ohlmann C-H, Flörcken A, Schmittel A, Otto T, et al. Outcome of treatment discontinuation in patients with metastatic renal cell carcinoma and no evidence of disease following targeted therapy with or without metastasectomy. Ann Oncol. 2011;22:657–63.CrossRefPubMed Johannsen M, Staehler M, Ohlmann C-H, Flörcken A, Schmittel A, Otto T, et al. Outcome of treatment discontinuation in patients with metastatic renal cell carcinoma and no evidence of disease following targeted therapy with or without metastasectomy. Ann Oncol. 2011;22:657–63.CrossRefPubMed
12.
go back to reference Staehler M, Haseke N, Zilinberg E, Stadler T, Karl A, Siebels M, et al. Complete remission achieved with angiogenic therapy in metastatic renal cell carcinoma including surgical intervention. Urol Oncol. 2010;28:139–44.CrossRefPubMed Staehler M, Haseke N, Zilinberg E, Stadler T, Karl A, Siebels M, et al. Complete remission achieved with angiogenic therapy in metastatic renal cell carcinoma including surgical intervention. Urol Oncol. 2010;28:139–44.CrossRefPubMed
13.
go back to reference Albiges L, Oudard S, Negrier S, Caty A, Gravis G, Joly F, et al. Complete remission with tyrosine kinase inhibitors in renal cell carcinoma. J Clin Oncol. 2012;30:482–7.CrossRefPubMed Albiges L, Oudard S, Negrier S, Caty A, Gravis G, Joly F, et al. Complete remission with tyrosine kinase inhibitors in renal cell carcinoma. J Clin Oncol. 2012;30:482–7.CrossRefPubMed
14.
go back to reference Buchler T, Bortlicek Z, Poprach A, Pavlik T, Veskrnova V, Honzirkova M, et al. Outcomes for patients with metastatic renal cell carcinoma achieving a complete response on targeted therapy: a registry-based analysis. Eur Urol. 2016;70(3):469–75.CrossRefPubMed Buchler T, Bortlicek Z, Poprach A, Pavlik T, Veskrnova V, Honzirkova M, et al. Outcomes for patients with metastatic renal cell carcinoma achieving a complete response on targeted therapy: a registry-based analysis. Eur Urol. 2016;70(3):469–75.CrossRefPubMed
15.
go back to reference Sadeghi S, Albiges L, Wood LS, Black SL, Gilligan TD, Dreicer R, et al. Cessation of vascular endothelial growth factor-targeted therapy in patients with metastatic renal cell carcinoma: feasibility and clinical outcome. Cancer. 2012;118:3277–82.CrossRefPubMed Sadeghi S, Albiges L, Wood LS, Black SL, Gilligan TD, Dreicer R, et al. Cessation of vascular endothelial growth factor-targeted therapy in patients with metastatic renal cell carcinoma: feasibility and clinical outcome. Cancer. 2012;118:3277–82.CrossRefPubMed
16.
go back to reference Mittal K, Derosa L, Albiges L, Wood LS, Elson P, Gilligan TD, et al. Outcomes of treatment cessation in select metastatic renal cell carcinoma (mRCC) patients. J Clin Oncol. 2014;32:4521.CrossRef Mittal K, Derosa L, Albiges L, Wood LS, Elson P, Gilligan TD, et al. Outcomes of treatment cessation in select metastatic renal cell carcinoma (mRCC) patients. J Clin Oncol. 2014;32:4521.CrossRef
17.
go back to reference Buchler T, Poprach A, Bortlicek Z, Lakomy R, Chloupková R, Vyzula R, et al. Outcomes of patients with long-term treatment response to vascular endothelial growth factor-targeted therapy for metastatic renal cell cancer. Clin Genitourin Cancer. 2017;15(6):e1047–53.CrossRefPubMed Buchler T, Poprach A, Bortlicek Z, Lakomy R, Chloupková R, Vyzula R, et al. Outcomes of patients with long-term treatment response to vascular endothelial growth factor-targeted therapy for metastatic renal cell cancer. Clin Genitourin Cancer. 2017;15(6):e1047–53.CrossRefPubMed
18.
go back to reference Sbitti Y, Debbagh A, Slimani K, Mahi M, Errihani H, Ichou M. When tyrosine kinase inhibitor sunitinib can be discontinued in metastatic renal cell carcinoma to pancreas: a case report. J Med Case Rep. 2018;12:80.CrossRefPubMedPubMedCentral Sbitti Y, Debbagh A, Slimani K, Mahi M, Errihani H, Ichou M. When tyrosine kinase inhibitor sunitinib can be discontinued in metastatic renal cell carcinoma to pancreas: a case report. J Med Case Rep. 2018;12:80.CrossRefPubMedPubMedCentral
19.
go back to reference Neuhaus T, Luyken J, Stier S. Discontinuation of the tyrosine kinase inhibitor sunitinib in patients with metastatic renal cell carcinoma: a case series. Urol J. 2014;11:1494–8.PubMed Neuhaus T, Luyken J, Stier S. Discontinuation of the tyrosine kinase inhibitor sunitinib in patients with metastatic renal cell carcinoma: a case series. Urol J. 2014;11:1494–8.PubMed
20.
go back to reference Miura Y, Fujii Y, Shimomura A, Sudo N, Ikeda M, Suyama K, et al. O1-5-2-temporal cessation of sunitinib treatment in patients with metastatic renal cell carcinoma: a retrospective study. Ann Oncol. 2014;25: v46.CrossRef Miura Y, Fujii Y, Shimomura A, Sudo N, Ikeda M, Suyama K, et al. O1-5-2-temporal cessation of sunitinib treatment in patients with metastatic renal cell carcinoma: a retrospective study. Ann Oncol. 2014;25: v46.CrossRef
21.
go back to reference Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:2505–12.CrossRefPubMed Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:2505–12.CrossRefPubMed
22.
go back to reference Ornstein MC, Wood LS, Elson P, Allman KD, Beach J, Martin A, et al. A phase II study of intermittent sunitinib in previously untreated patients with metastatic renal cell carcinoma. J Clin Oncol. 2017;35:1764–9.CrossRefPubMed Ornstein MC, Wood LS, Elson P, Allman KD, Beach J, Martin A, et al. A phase II study of intermittent sunitinib in previously untreated patients with metastatic renal cell carcinoma. J Clin Oncol. 2017;35:1764–9.CrossRefPubMed
23.
go back to reference Brown JE, Royle K-L, Gregory W, Ralph C, Maraveyas A, Din O, et al. Temporary treatment cessation versus continuation of first-line tyrosine kinase inhibitor in patients with advanced clear cell renal cell carcinoma (STAR): an open-label, non-inferiority, randomised, controlled, phase 2/3 trial. Lancet Oncol. 2023;24:213–27.CrossRefPubMed Brown JE, Royle K-L, Gregory W, Ralph C, Maraveyas A, Din O, et al. Temporary treatment cessation versus continuation of first-line tyrosine kinase inhibitor in patients with advanced clear cell renal cell carcinoma (STAR): an open-label, non-inferiority, randomised, controlled, phase 2/3 trial. Lancet Oncol. 2023;24:213–27.CrossRefPubMed
24.
go back to reference Choueiri TK, Motzer RJ, Rini BI, Haanen J, Campbell MT, Venugopal B, et al. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020;31:1030–9.CrossRefPubMed Choueiri TK, Motzer RJ, Rini BI, Haanen J, Campbell MT, Venugopal B, et al. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020;31:1030–9.CrossRefPubMed
25.
go back to reference Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23:888–98.CrossRefPubMedPubMedCentral Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23:888–98.CrossRefPubMedPubMedCentral
26.
go back to reference Motzer RJ, McDermott DF, Escudier B, Burotto M, Choueiri TK, Hammers HJ, et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. Cancer. 2022;128:2085–97.CrossRefPubMed Motzer RJ, McDermott DF, Escudier B, Burotto M, Choueiri TK, Hammers HJ, et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. Cancer. 2022;128:2085–97.CrossRefPubMed
27.
go back to reference Rini BI, Plimack ER, Stus V, Gafanov R, Waddell T, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma: 5-year analysis of KEYNOTE-426. J Clin Oncol. 2023;41:LBA4501.CrossRef Rini BI, Plimack ER, Stus V, Gafanov R, Waddell T, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma: 5-year analysis of KEYNOTE-426. J Clin Oncol. 2023;41:LBA4501.CrossRef
28.
go back to reference Motzer RJ, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, et al. Final prespecified overall survival (OS) analysis of CLEAR: 4-year follow-up of lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2023;41:4502.CrossRef Motzer RJ, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, et al. Final prespecified overall survival (OS) analysis of CLEAR: 4-year follow-up of lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2023;41:4502.CrossRef
29.
go back to reference Burotto M, Powles T, Escudier B, Apolo AB, Bourlon MT, Shah AY, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol. 2023;41:603.CrossRef Burotto M, Powles T, Escudier B, Apolo AB, Bourlon MT, Shah AY, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol. 2023;41:603.CrossRef
Metadata
Title
Planned Discontinuation of Tyrosine Kinase Inhibitor Therapy in Metastatic Renal Cell Carcinoma: Lessons for the Era of Immunotherapy
Authors
Tomas Buchler
Alexandr Poprach
Publication date
03-02-2024
Publisher
Springer International Publishing
Published in
Targeted Oncology / Issue 2/2024
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI
https://doi.org/10.1007/s11523-023-01031-y

Other articles of this Issue 2/2024

Targeted Oncology 2/2024 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine