Efficacy, safety and biomarker analysis of durvalumab in patients with mismatch-repair deficient or microsatellite instability-high solid tumours.
Durvalumab
Immunotherapy
Microsatellite instability
Mismatch repair deficiency
Precision medicine
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
04 Mar 2023
04 Mar 2023
Historique:
received:
20
12
2022
accepted:
20
02
2023
entrez:
4
3
2023
pubmed:
5
3
2023
medline:
8
3
2023
Statut:
epublish
Résumé
In this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based on their tumour molecular profile. Patients with dMMR/MSI-H solid tumours who had exhausted all standard of care options were eligible. Patients were treated with durvalumab. The primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease ≥16 weeks) and safety. Patients were enrolled using a Simon like 2-stage model, with 8 patients in stage 1, up to 24 patients in stage 2 if at least 1/8 patients had CB in stage 1. At baseline, fresh frozen biopsies were obtained for biomarker analyses. Twenty-six patients with 10 different cancer types were included. Two patients (2/26, 8%) were considered as non-evaluable for the primary endpoint. CB was observed in 13 patients (13/26, 50%) with an OR in 7 patients (7/26, 27%). The remaining 11 patients (11/26, 42%) had progressive disease. Median progression-free survival and median overall survival were 5 months (95% CI, 2-not reached) and 14 months (95% CI, 5-not reached), respectively. No unexpected toxicity was observed. We found a significantly higher structural variant (SV) burden in patients without CB. Additionally, we observed a significant enrichment of JAK1 frameshift mutations and a significantly lower IFN-γ expression in patients without CB. Durvalumab was generally well-tolerated and provided durable responses in pre-treated patients with dMMR/MSI-H solid tumours. High SV burden, JAK1 frameshift mutations and low IFN-γ expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings. Clinical trial registration: NCT02925234. First registration date: 05/10/2016.
Sections du résumé
BACKGROUND
BACKGROUND
In this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based on their tumour molecular profile.
PATIENTS AND METHODS
METHODS
Patients with dMMR/MSI-H solid tumours who had exhausted all standard of care options were eligible. Patients were treated with durvalumab. The primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease ≥16 weeks) and safety. Patients were enrolled using a Simon like 2-stage model, with 8 patients in stage 1, up to 24 patients in stage 2 if at least 1/8 patients had CB in stage 1. At baseline, fresh frozen biopsies were obtained for biomarker analyses.
RESULTS
RESULTS
Twenty-six patients with 10 different cancer types were included. Two patients (2/26, 8%) were considered as non-evaluable for the primary endpoint. CB was observed in 13 patients (13/26, 50%) with an OR in 7 patients (7/26, 27%). The remaining 11 patients (11/26, 42%) had progressive disease. Median progression-free survival and median overall survival were 5 months (95% CI, 2-not reached) and 14 months (95% CI, 5-not reached), respectively. No unexpected toxicity was observed. We found a significantly higher structural variant (SV) burden in patients without CB. Additionally, we observed a significant enrichment of JAK1 frameshift mutations and a significantly lower IFN-γ expression in patients without CB.
CONCLUSION
CONCLUSIONS
Durvalumab was generally well-tolerated and provided durable responses in pre-treated patients with dMMR/MSI-H solid tumours. High SV burden, JAK1 frameshift mutations and low IFN-γ expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings.
TRIAL REGISTRATION
BACKGROUND
Clinical trial registration: NCT02925234. First registration date: 05/10/2016.
Identifiants
pubmed: 36870947
doi: 10.1186/s12885-023-10663-2
pii: 10.1186/s12885-023-10663-2
pmc: PMC9985217
doi:
Substances chimiques
durvalumab
28X28X9OKV
Biomarkers
0
Banques de données
ClinicalTrials.gov
['NCT02925234']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
205Informations de copyright
© 2023. The Author(s).
Références
Eur J Cancer. 2009 Jan;45(2):228-47
pubmed: 19097774
J Clin Oncol. 2017 Jul 20;35(21):2439-2449
pubmed: 28640707
Cancers (Basel). 2019 Oct 15;11(10):
pubmed: 31618962
Sci Rep. 2017 Jul 17;7(1):5532
pubmed: 28717238
PLoS One. 2017 Nov 9;12(11):e0176181
pubmed: 29121062
Ann Oncol. 2017 Jan 1;28(1):96-102
pubmed: 27742654
Nature. 2019 Nov;575(7781):210-216
pubmed: 31645765
Mol Cancer. 2018 Aug 23;17(1):129
pubmed: 30139382
Lancet Oncol. 2017 Mar;18(3):e143-e152
pubmed: 28271869
Nat Med. 2019 Mar;25(3):389-402
pubmed: 30842677
Clin Cancer Res. 2016 Feb 15;22(4):813-20
pubmed: 26880610
Lancet Oncol. 2022 May;23(5):659-670
pubmed: 35427471
PLoS One. 2010 Dec 22;5(12):e15661
pubmed: 21203531
J Clin Invest. 2017 Aug 1;127(8):2930-2940
pubmed: 28650338
Clin Cancer Res. 2021 Jul 1;27(13):3714-3724
pubmed: 33926917
Clin Cancer Res. 2021 Nov 15;27(22):6106-6114
pubmed: 34475104
Ann Oncol. 2019 Jul 1;30(7):1096-1103
pubmed: 31038663
Nat Rev Immunol. 2020 Jan;20(1):25-39
pubmed: 31570880
Science. 2019 May 3;364(6439):485-491
pubmed: 31048490
Genome Med. 2017 May 24;9(1):46
pubmed: 28539123
Dig Liver Dis. 2021 Mar;53(3):318-323
pubmed: 33359404
N Engl J Med. 2020 Dec 3;383(23):2207-2218
pubmed: 33264544
JCO Precis Oncol. 2017;2017:
pubmed: 29850653
Oncologist. 2020 Jun;25(6):481-487
pubmed: 31967692
Diagn Pathol. 2014 Jun 26;9:126
pubmed: 24968821
Stat Med. 2004 Feb 28;23(4):561-9
pubmed: 14755389
J Clin Oncol. 2020 Jan 1;38(1):1-10
pubmed: 31682550
Cold Spring Harb Mol Case Stud. 2020 Oct 7;6(5):
pubmed: 33028646
Cancer Discov. 2017 Feb;7(2):188-201
pubmed: 27903500
Drug Des Devel Ther. 2018 Jan 23;12:209-215
pubmed: 29416316
J Mol Diagn. 2021 Jul;23(7):816-833
pubmed: 33964451
J Immunother Cancer. 2021 Jun;9(6):
pubmed: 34103352
Cancer Cell. 2022 Jan 10;40(1):88-102.e7
pubmed: 34951955
Eur J Cancer. 2022 Aug;171:114-123
pubmed: 35716537
Clin Cancer Res. 2019 Jul 1;25(13):3753-3758
pubmed: 30787022
JCO Precis Oncol. 2020;4:492-497
pubmed: 32494760
J Clin Oncol. 2017 Aug 1;35(22):2535-2541
pubmed: 28489510
Nat Genet. 2013 Oct;45(10):1113-20
pubmed: 24071849
Nature. 2012 Jul 18;487(7407):330-7
pubmed: 22810696
J Cancer Res Clin Oncol. 2019 Dec;145(12):2891-2899
pubmed: 31617076
Lancet Oncol. 2017 Sep;18(9):1182-1191
pubmed: 28734759
NPJ Precis Oncol. 2021 Mar 2;5(1):15
pubmed: 33654267
Nat Commun. 2017 Jun 06;8:15180
pubmed: 28585546
J Pathol. 2018 Oct;246(2):129-133
pubmed: 30027543
Methods Mol Biol. 2020;2120:1-9
pubmed: 32124308
Int J Cancer. 2022 Jun 15;150(12):2038-2045
pubmed: 35179785
Nat Genet. 2019 Feb;51(2):202-206
pubmed: 30643254
Nature. 2019 Oct;574(7776):127-131
pubmed: 31570881
Ann Oncol. 2019 May 1;30(5):663-665
pubmed: 31038154
Sci Rep. 2013 Oct 24;3:3042
pubmed: 24154688
JAMA Oncol. 2020 Nov 01;6(11):1766-1772
pubmed: 33001143