Immune checkpoint inhibitors in kidney transplant recipients: a multicentre, single-arm, phase 1 study.
Journal
The Lancet. Oncology
ISSN: 1474-5488
Titre abrégé: Lancet Oncol
Pays: England
ID NLM: 100957246
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
06
04
2022
revised:
09
06
2022
accepted:
13
06
2022
pubmed:
10
7
2022
medline:
2
8
2022
entrez:
9
7
2022
Statut:
ppublish
Résumé
Most kidney transplant recipients with cancer stop or reduce immunosuppressive therapy before starting treatment with an immune checkpoint inhibitor, and approximately 40% of such patients will develop allograft rejection. Isolated immunosuppression reduction might be associated with organ rejection. Whether immunosuppression manipulation, immune checkpoint inhibition, or both, induce organ rejection is difficult to ascertain. The aim of this study was to examine the risk of allograft rejection with immune checkpoint inhibitor exposure when baseline immunosuppression was left unchanged. We conducted a multicentre, single-arm, phase 1 study in three hospitals in Australia. Kidney transplant recipients aged 18 years or older with incurable, locally advanced cancer or defined metastatic solid tumours were eligible if they had a creatinine concentration of less than 180 mmol/L, no or low concentrations of donor-specific HLA antibodies, and an Eastern Cooperative Oncology Group status of 0-2. Patients received standard doses of nivolumab (3 mg/kg intravenously every 14 days for five cycles, then 480 mg every 28 days for up to 2 years). The primary endpoint was the proportion of patients with irretrievable allograft rejection and no evidence of tumour response. Primary outcome analyses and safety analyses were done in the modified intention-to-treat population. This trial is registered with the Australian and New Zealand Clinical Trials Register, ANZCTR12617000741381, and is completed. Between May 31, 2017, and Aug 6, 2021, 22 kidney transplant recipients with various solid tumours were screened and enrolled, four of whom chose not to proceed in the study and one of whom had unexpected disease progression. 17 patients (six [35%] women and 11 [65%] men; median age 67 years [IQR 59-71]) were allocated treatment with nivolumab and were included in the analyses. The trial was then stopped due to ongoing difficulties with running clinical trials during COVID-19 health restrictions. Patients were treated with a median of three infusions (IQR 2-10) and median follow-up was 28 months (IQR 16-34). No patients had irretrievable allograft rejection without evidence of tumour response. There were no treatment-related deaths or treatment-related serious adverse events. The most common grade 3 or grade 4 adverse events were decreased lymphocyte count in four (24%) patients, fever or infection in four (24%) patients, decreased haemoglobin in three (18%) patients, and increased creatinine in three (18%) patients. Maintaining baseline immunosuppression before treatment with an immune checkpoint inhibitor in kidney transplant recipients might not affect expected efficacy and might reduce the risk of allograft rejection mediated by immune checkpoint inhibitors. Bristol Myers Squibb.
Sections du résumé
BACKGROUND
Most kidney transplant recipients with cancer stop or reduce immunosuppressive therapy before starting treatment with an immune checkpoint inhibitor, and approximately 40% of such patients will develop allograft rejection. Isolated immunosuppression reduction might be associated with organ rejection. Whether immunosuppression manipulation, immune checkpoint inhibition, or both, induce organ rejection is difficult to ascertain. The aim of this study was to examine the risk of allograft rejection with immune checkpoint inhibitor exposure when baseline immunosuppression was left unchanged.
METHODS
We conducted a multicentre, single-arm, phase 1 study in three hospitals in Australia. Kidney transplant recipients aged 18 years or older with incurable, locally advanced cancer or defined metastatic solid tumours were eligible if they had a creatinine concentration of less than 180 mmol/L, no or low concentrations of donor-specific HLA antibodies, and an Eastern Cooperative Oncology Group status of 0-2. Patients received standard doses of nivolumab (3 mg/kg intravenously every 14 days for five cycles, then 480 mg every 28 days for up to 2 years). The primary endpoint was the proportion of patients with irretrievable allograft rejection and no evidence of tumour response. Primary outcome analyses and safety analyses were done in the modified intention-to-treat population. This trial is registered with the Australian and New Zealand Clinical Trials Register, ANZCTR12617000741381, and is completed.
FINDINGS
Between May 31, 2017, and Aug 6, 2021, 22 kidney transplant recipients with various solid tumours were screened and enrolled, four of whom chose not to proceed in the study and one of whom had unexpected disease progression. 17 patients (six [35%] women and 11 [65%] men; median age 67 years [IQR 59-71]) were allocated treatment with nivolumab and were included in the analyses. The trial was then stopped due to ongoing difficulties with running clinical trials during COVID-19 health restrictions. Patients were treated with a median of three infusions (IQR 2-10) and median follow-up was 28 months (IQR 16-34). No patients had irretrievable allograft rejection without evidence of tumour response. There were no treatment-related deaths or treatment-related serious adverse events. The most common grade 3 or grade 4 adverse events were decreased lymphocyte count in four (24%) patients, fever or infection in four (24%) patients, decreased haemoglobin in three (18%) patients, and increased creatinine in three (18%) patients.
INTERPRETATION
Maintaining baseline immunosuppression before treatment with an immune checkpoint inhibitor in kidney transplant recipients might not affect expected efficacy and might reduce the risk of allograft rejection mediated by immune checkpoint inhibitors.
FUNDING
Bristol Myers Squibb.
Identifiants
pubmed: 35809595
pii: S1470-2045(22)00368-0
doi: 10.1016/S1470-2045(22)00368-0
pii:
doi:
Substances chimiques
Immune Checkpoint Inhibitors
0
Nivolumab
31YO63LBSN
Creatinine
AYI8EX34EU
Banques de données
ANZCTR
['ANZCTR12617000741381']
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1078-1086Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2022 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests MB declares research funding from Bristol Myers Squibb, AstraZeneca, Merck Sharpe & Dohme, Roche, and Amgen; and honoraria from Amgen, AstraZeneca, and Merck Sharpe & Dohme. JRZ declares leadership for ICON group; stock and other ownership interests in Biomarin, Opthea, Amarin Corporation, Concert Pharmaceuticals, Frequency Therapeutics, Gilead Sciences, Madrigal Pharmaceuticals, Uniqure, Zogeniz, Orphazyme, Moderna Therapeutics, Twist Bioscience, and Novovax; honoraria from Specialised Therapeutics, Merck Serono, Targovax, Halozyme, Gilead Sciences, and Deciperha; consulting advisory roles for Merck Serono, Targovax, Merck Sharp & Dohme, Halozyme, Liptoek, Specialised Therapeutics, Center for Emerging and Neglected Diseases, Deciphera, Revolution Medicine, FivePHusion, Genor BioPharma, 1Globe Health Institute, and Novotech; research funding from Merck Serono, Bristol Myers Squibb, AstraZeneca, Pfizer, IQvia, Mylan, Ipsen, Eisai, Medtronic, and MSD Oncology; and travel accommodation and expenses from Merck Serono, AstraZeneca, Merck Sharp & Dohme, Deciphera, and Sanofi. All other authors declare no competing interests.