Clinical Activity of Single-Agent Cabozantinib (XL184), a Multi-receptor Tyrosine Kinase Inhibitor, in Patients with Refractory Soft-Tissue Sarcomas.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 01 2022
15 01 2022
Historique:
received:
06
07
2021
revised:
17
09
2021
accepted:
26
10
2021
pubmed:
31
10
2021
medline:
19
2
2022
entrez:
30
10
2021
Statut:
ppublish
Résumé
Soft-tissue sarcomas (STS) are a rare, heterogeneous group of mesenchymal tumors. For decades the mainstay of treatment for advanced, unresectable STS has been palliative chemotherapy. High levels of activated MET receptor have been reported in various sarcoma cell lines, together with elevated vascular endothelial growth factor (VEGF) levels in patients with STS, suggesting that dual targeting of the VEGF and MET pathways with the multi-receptor tyrosine kinase inhibitor cabozantinib would result in clinical benefit in this population. We performed an open-label, multi-institution, single-arm phase II trial of single-agent cabozantinib in adult patients with advanced STS and progressive disease after at least 1 standard line of systemic therapy. Patients received 60 mg oral cabozantinib once daily in 28-day cycles, and dual primary endpoints of overall response rate and 6-month progression-free survival (PFS) were assessed. Changes in several circulating biomarkers were assessed as secondary endpoints. Six (11.1%; 95% CI, 4.2%-22.6%) of the 54 evaluable patients enrolled experienced objective responses (all partial responses). Six-month PFS was 49.3% (95% CI, 36.2%-67.3%), with a median time on study of 4 cycles (range, 1-99). The most common grade 3/4 adverse events were hypertension (7.4%) and neutropenia (16.7%). Patients' levels of circulating hepatocyte growth factor (HGF), soluble MET, and VEGF-A generally increased after a cycle of therapy, while soluble VEGFR2 levels decreased, regardless of clinical outcome. Cabozantinib single-agent antitumor activity was observed in patients with selected STS histologic subtypes (alveolar soft-part sarcoma, undifferentiated pleomorphic sarcoma, extraskeletal myxoid chondrosarcoma, and leiomyosarcoma) highlighting the biomolecular diversity of STS.
Identifiants
pubmed: 34716194
pii: 1078-0432.CCR-21-2480
doi: 10.1158/1078-0432.CCR-21-2480
pmc: PMC8776602
mid: NIHMS1754275
doi:
Substances chimiques
Anilides
0
Protein Kinase Inhibitors
0
Pyridines
0
Vascular Endothelial Growth Factor A
0
cabozantinib
1C39JW444G
Types de publication
Journal Article
Research Support, U.S. Gov't, P.H.S.
Comment
Langues
eng
Sous-ensembles de citation
IM
Pagination
279-288Subventions
Organisme : NCI NIH HHS
ID : HHSN261201500003C
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201500003I
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA186717
Pays : United States
Organisme : Intramural NIH HHS
ID : Z99 CA999999
Pays : United States
Commentaires et corrections
Type : CommentOn
Informations de copyright
©2021 The Authors; Published by the American Association for Cancer Research.
Références
Cancer Res. 2010 Jan 15;70(2):639-45
pubmed: 20068147
J Immunother Cancer. 2020 Nov;8(2):
pubmed: 33203665
Ann Oncol. 2017 Dec 1;28(12):3000-3008
pubmed: 28950372
Lancet Oncol. 2017 Aug;18(8):1089-1103
pubmed: 28651927
Ann Surg Oncol. 2021 Feb;28(2):1142-1150
pubmed: 32572850
Mol Cancer Ther. 2019 Jun;18(6):1168-1178
pubmed: 30962320
J Clin Oncol. 2016 Mar 10;34(8):786-93
pubmed: 26371143
Drug Saf. 2019 Feb;42(2):211-233
pubmed: 30649748
Lancet Oncol. 2017 Oct;18(10):1397-1410
pubmed: 28882536
Ann Oncol. 2012 Mar;23(3):785-790
pubmed: 21746804
Nat Rev Cancer. 2002 Apr;2(4):289-300
pubmed: 12001990
Ann Oncol. 2018 Oct 1;29(Suppl 4):iv268-iv269
pubmed: 30285214
N Engl J Med. 2021 Mar 4;384(9):829-841
pubmed: 33657295
PLoS One. 2015 Apr 06;10(4):e0120079
pubmed: 25844809
Mol Cancer Ther. 2011 Dec;10(12):2298-308
pubmed: 21926191
Eur J Cancer. 2009 Jan;45(2):228-47
pubmed: 19097774
Pediatr Blood Cancer. 2018 Aug;65(8):e27077
pubmed: 29693796
Br J Cancer. 2018 May;118(9):1176-1178
pubmed: 29576624
JAMA. 2020 Apr 7;323(13):1266-1276
pubmed: 32259228
J Clin Oncol. 2016 Nov 10;34(32):3898-3905
pubmed: 27621408
J Cancer Res Clin Oncol. 2004 Jan;130(1):52-6
pubmed: 14600832
Lancet Oncol. 2020 Nov;21(11):1423-1432
pubmed: 33035459
Lancet Oncol. 2019 Jun;20(6):837-848
pubmed: 31078463
Cancer Chemother Pharmacol. 2016 Aug;78(2):313-23
pubmed: 27324022
Lancet Oncol. 2020 Mar;21(3):446-455
pubmed: 32078813
Mol Cancer Ther. 2009 Oct;8(10):2803-10
pubmed: 19825800
Ann Oncol. 2018 Mar 1;29(3):758-765
pubmed: 29216400
Lancet. 2006 Oct 14;368(9544):1329-38
pubmed: 17046465
Lancet Oncol. 2016 Apr;17(4):532-538
pubmed: 26970672
N Engl J Med. 2018 Jul 05;379(1):54-63
pubmed: 29972759
Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4154-62
pubmed: 16857786
JAMA Oncol. 2018 Oct 1;4(10):1398-1404
pubmed: 29801054
J Clin Oncol. 2016 Sep 1;34(25):3005-13
pubmed: 27400947
Curr Opin Oncol. 2020 Jul;32(4):321-331
pubmed: 32541320
JCO Precis Oncol. 2019 Apr 25;3:
pubmed: 32914012
J Clin Oncol. 2013 Jun 20;31(18):2296-302
pubmed: 23630200
Ann Surg Oncol. 2001 Apr;8(3):260-7
pubmed: 11314944
Lancet. 2012 May 19;379(9829):1879-86
pubmed: 22595799
Eur J Cancer. 2014 Jun;50(9):1657-64
pubmed: 24703573
Am J Pathol. 2000 Mar;156(3):821-9
pubmed: 10702398
Eur J Cancer. 2020 Jul;134:62-74
pubmed: 32470848
Lancet. 2016 Apr 16;387(10028):1629-37
pubmed: 26874885
Cancer Lett. 2012 Jul 1;320(1):48-55
pubmed: 22269210
Cancer Res. 1999 Nov 1;59(21):5536-41
pubmed: 10554031
PLoS One. 2017 Sep 25;12(9):e0185321
pubmed: 28945796
J Clin Oncol. 2015 Apr 1;33(10):1180-5
pubmed: 25713428
Nat Immunol. 2006 Oct;7(10):1082-91
pubmed: 16936731
Lancet Oncol. 2020 Jul;21(7):935-946
pubmed: 32615108
Nat Rev Mol Cell Biol. 2003 Dec;4(12):915-25
pubmed: 14685170
BMC Cancer. 2009 Jan 15;9:22
pubmed: 19146682
Cancer Discov. 2012 Mar;2(3):270-87
pubmed: 22585997
Cancer. 2008 Dec 15;113(12):3364-71
pubmed: 18951519
Lancet Oncol. 2014 Apr;15(4):415-23
pubmed: 24618336
Cancer Res. 1993 Nov 15;53(22):5355-60
pubmed: 7693339