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01-07-2021 | Kidney Cancer | Original Research Article

Prognostic Impact of Early Treatment Interruption of Nivolumab Plus Ipilimumab Due to Immune-Related Adverse Events as First-Line Therapy for Metastatic Renal Cell Carcinoma: A Multi-Institution Retrospective Study

Authors: Hiroki Ishihara, Yuki Nemoto, Kazutaka Nakamura, Takashi Ikeda, Hidekazu Tachibana, Hironori Fukuda, Kazuhiko Yoshida, Hirohito Kobayashi, Junpei Iizuka, Hiroaki Shimmura, Yasunobu Hashimoto, Toshio Takagi, Hideki Ishida, Tsunenori Kondo, Kazunari Tanabe

Published in: Targeted Oncology | Issue 4/2021

Abstract

Background

It remains unclear how early treatment interruption of nivolumab plus ipilimumab due to immune-related adverse events affects the outcome of previously untreated metastatic renal cell carcinoma (mRCC).

Objective

To investigate the prognostic impact of the early interruption of nivolumab plus ipilimumab, used as first-line therapy for mRCC.

Patients and Methods

We retrospectively evaluated 59 intermediate- or poor-risk mRCC patients who received nivolumab plus ipilimumab as first-line therapy. Based on whether early treatment interruption was implemented within the initial four treatment cycles (i.e., 3 months) or not, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were compared. The prognostic association was further compared with that of 186 patients treated with tyrosine kinase inhibitors (TKIs) as first-line therapy.

Results

Twenty-three of the 59 patients (39%) experienced interruption of nivolumab plus ipilimumab therapy. The patients with interruption had longer PFS (p = 0.0055), similar OS (p = 0.366), and likely higher ORR (p = 0.0660) than those without interruption. Of the patients treated with TKIs, 60 of 186 (32%) experienced interruption, with shorter PFS (p = 0.0121), similar OS (p = 0.378), and similar ORR (p = 0.738) than those without interruption. In the 23 patients with nivolumab plus ipilimumab interruption, high-dose corticosteroids were administered in seven patients (30%). PFS (p = 0.638), OS (p = 0.968), or ORR (p = 0.760) did not differ based on corticosteroid administration.

Conclusions

Early treatment interruption, which exerted a negative effect for TKIs, was a preferable event for nivolumab plus ipilimumab when considering PFS. Furthermore, early administration of high-dose corticosteroids did not diminish the anti-tumor effect of nivolumab plus ipilimumab.

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Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, Barthélémy P, et al. 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 Open. 2020;5(6): e001079. https://doi.org/10.1136/esmoopen-2020-001079.CrossRefPubMedPubMedCentral

Aeppli S, Schmaus M, Eisen T, Escudier B, Grünwald V, Larkin J, et al. First-line treatment of metastatic clear cell renal cell carcinoma: a decision-making analysis among experts. ESMO Open. 2021;6(1): 100030. https://doi.org/10.1016/j.esmoop.2020.100030.CrossRefPubMedPubMedCentral

Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51–60. https://doi.org/10.1016/j.ctrv.2016.02.001.CrossRefPubMed

Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, et al. 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 Oncol. 2019;20(10):1370–85. https://doi.org/10.1016/s1470-2045(19)30413-9.CrossRefPubMedPubMedCentral

Motzer RJ, Escudier B, McDermott DF, Arén Frontera O, Melichar B, Powles T, et al. 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 Cancer. 2020;8(2): e000891. https://doi.org/10.1136/jitc-2020-000891.CrossRefPubMed

Kawashima A, Takayama H, Arai Y, Tanigawa G, Nin M, Kajikawa J, et al. One-month relative dose intensity of not less than 50% predicts favourable progression-free survival in sorafenib therapy for advanced renal cell carcinoma in Japanese patients. Eur J Cancer. 2011;47(10):1521–6. https://doi.org/10.1016/j.ejca.2011.04.001.CrossRefPubMed

Porta C, Levy A, Hawkins R, Castellano D, Bellmunt J, Nathan P, et al. Impact of adverse events, treatment modifications, and dose intensity on survival among patients with advanced renal cell carcinoma treated with first-line sunitinib: a medical chart review across ten centers in five European countries. Cancer Med. 2014;3(6):1517–26. https://doi.org/10.1002/cam4.302.CrossRefPubMedPubMedCentral

Ishiyama R, Ishihara H, Kondo T, Takagi T, Yoshida K, Iizuka J, et al. Negative effect of immediate sunitinib interruption on survival in patients with metastatic renal cell carcinoma. Vivo. 2019;33(6):2153–60. https://doi.org/10.21873/invivo.11717.CrossRef

Iwamoto K, Ishihara H, Takagi T, Kondo T, Yoshida K, Iizuka J, et al. Evaluation of relative dose intensity during the early phase of first-line sunitinib treatment using a 2-week-on/1-week-off regimen for metastatic renal cell carcinoma. Med Oncol. 2018;35(6):78. https://doi.org/10.1007/s12032-018-1139-y.CrossRefPubMed

10.

Kawashima A, Tsujimura A, Takayama H, Arai Y, Nin M, Tanigawa G, et al. Importance of continuing therapy and maintaining one-month relative dose intensity in sunitinib therapy for metastatic renal cell carcinoma. Med Oncol. 2012;29(5):3298–305. https://doi.org/10.1007/s12032-012-0236-6.CrossRefPubMed

11.

Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol. 2016;2(10):1346–53. https://doi.org/10.1001/jamaoncol.2016.1051.CrossRefPubMed

12.

Maher VE, Fernandes LL, Weinstock C, Tang S, Agarwal S, Brave M, et al. Analysis of the association between adverse events and outcome in patients receiving a programmed death protein 1 or programmed death ligand 1 antibody. J Clin Oncol. 2019;37(30):2730–7. https://doi.org/10.1200/jco.19.00318.CrossRefPubMed

13.

Horvat TZ, Adel NG, Dang TO, Momtaz P, Postow MA, Callahan MK, et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol. 2015;33(28):3193–8. https://doi.org/10.1200/jco.2015.60.8448.CrossRefPubMedPubMedCentral

14.

Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol. 2018;36(28):2872–8. https://doi.org/10.1200/jco.2018.79.0006.CrossRefPubMed

15.

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. https://doi.org/10.1016/j.ejca.2008.10.026.CrossRefPubMed

16.

Kondo T, Takagi T, Kobayashi H, Iizuka J, Nozaki T, Hashimoto Y, et al. Superior tolerability of altered dosing schedule of sunitinib with 2-weeks-on and 1-week-off in patients with metastatic renal cell carcinoma–comparison to standard dosing schedule of 4-weeks-on and 2-weeks-off. Jpn J Clin Oncol. 2014;44(3):270–7. https://doi.org/10.1093/jjco/hyt232.CrossRefPubMed

17.

Ishihara H, Takagi T, Kondo T, Iwamoto K, Tachibana H, Yoshida K, et al. Decreased relative dose intensity during the early phase of treatment impacts the therapeutic efficacy of sunitinib in metastatic renal cell carcinoma. Jpn J Clin Oncol. 2018;48(7):667–72. https://doi.org/10.1093/jjco/hyy078.CrossRefPubMed

18.

Najjar YG, Mittal K, Elson P, Wood L, Garcia JA, Dreicer R, et al. A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. Eur J Cancer. 2014;50(6):1084–9. https://doi.org/10.1016/j.ejca.2014.01.025.CrossRefPubMed

19.

Bracarda S, Iacovelli R, Boni L, Rizzo M, Derosa L, Rossi M, et al. Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis. Ann Oncol. 2015;26(10):2107–13. https://doi.org/10.1093/annonc/mdv315.CrossRefPubMed

20.

Hussaini S, Chehade R, Boldt RG, Raphael J, Blanchette P, Maleki Vareki S, et al. Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors—a systematic review and meta-analysis. Cancer Treat Rev. 2020;92: 102134. https://doi.org/10.1016/j.ctrv.2020.102134.CrossRefPubMed

21.

Ishihara H, Takagi T, Kondo T, Homma C, Tachibana H, Fukuda H, et al. Association between immune-related adverse events and prognosis in patients with metastatic renal cell carcinoma treated with nivolumab. Urol Oncol. 2019;37(6):355.e21-355.e29. https://doi.org/10.1016/j.urolonc.2019.03.003.CrossRef

22.

Kato T, Nagahara A, Kawamura N, Nakata W, Soda T, Matsuzaki K, et al. The prognostic impact of immune-related adverse events in metastatic renal cell carcinoma patients treated with nivolumab: a real-world multi-institutional retrospective study. Int J Clin Oncol. 2021;26(5):954–61. https://doi.org/10.1007/s10147-021-01872-5.CrossRefPubMed

23.

Maillet D, Corbaux P, Stelmes JJ, Dalle S, Locatelli-Sanchez M, Perier-Muzet M, et al. Association between immune-related adverse events and long-term survival outcomes in patients treated with immune checkpoint inhibitors. Eur J Cancer. 2020;132:61–70. https://doi.org/10.1016/j.ejca.2020.03.017.CrossRefPubMed

24.

Vitale MG, Pipitone S, Venturelli M, Baldessari C, Porta C, Iannuzzi F, et al. Correlation between immune-related adverse event (IRAE) occurrence and clinical outcome in patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab: IRAENE Trial, an Italian Multi-institutional Retrospective Study. Clin Genitourin Cancer. 2020;18(6):477–88. https://doi.org/10.1016/j.clgc.2020.05.010.CrossRefPubMed

25.

Heng DY, Choueiri TK, Rini BI, Lee J, Yuasa T, Pal SK, et al. Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials. Ann Oncol. 2014;25(1):149–54. https://doi.org/10.1093/annonc/mdt492.CrossRefPubMedPubMedCentral

26.

Fuentes-Antras J, Provencio M, Diaz-Rubio E. Hyperprogression as a distinct outcome after immunotherapy. Cancer Treat Rev. 2018;70:16–21. https://doi.org/10.1016/j.ctrv.2018.07.006.CrossRefPubMed

27.

Escudier B, Motzer RJ, Sharma P, Wagstaff J, Plimack ER, Hammers HJ, et al. Treatment beyond progression in patients with advanced renal cell carcinoma treated with nivolumab in CheckMate 025. Eur Urol. 2017;72(3):368–76. https://doi.org/10.1016/j.eururo.2017.03.037.CrossRefPubMed

28.

Wang Q, Gao J, Wu X. Pseudoprogression and hyperprogression after checkpoint blockade. Int Immunopharmacol. 2018;58:125–35. https://doi.org/10.1016/j.intimp.2018.03.018.CrossRefPubMed

29.

Libert C, Dejager L. How steroids steer T cells. Cell Rep. 2014;7(4):938–9. https://doi.org/10.1016/j.celrep.2014.04.041.CrossRefPubMed

Title: Prognostic Impact of Early Treatment Interruption of Nivolumab Plus Ipilimumab Due to Immune-Related Adverse Events as First-Line Therapy for Metastatic Renal Cell Carcinoma: A Multi-Institution Retrospective Study
Authors: Hiroki Ishihara
Yuki Nemoto
Kazutaka Nakamura
Takashi Ikeda
Hidekazu Tachibana
Hironori Fukuda
Kazuhiko Yoshida
Hirohito Kobayashi
Junpei Iizuka
Hiroaki Shimmura
Yasunobu Hashimoto
Toshio Takagi
Hideki Ishida
Tsunenori Kondo
Kazunari Tanabe
Publication date: 01-07-2021
Publisher: Springer International Publishing
Keywords: Kidney Cancer
Kidney Cancer
Tyrosine Kinase Inhibitors
Kidney Cancer
Tyrosine Kinase Inhibitors
Checkpoint Inhibitors
Published in: Targeted Oncology / Issue 4/2021
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI: https://doi.org/10.1007/s11523-021-00825-2

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