A Phase Ib/II Study of WNT974 + Encorafenib + Cetuximab in Patients With BRAF V600E-Mutant KRAS Wild-Type Metastatic Colorectal Cancer.
WNT974
cetuximab
colorectal cancer
encorafenib
metastatic
Journal
The oncologist
ISSN: 1549-490X
Titre abrégé: Oncologist
Pays: England
ID NLM: 9607837
Informations de publication
Date de publication:
17 03 2023
17 03 2023
Historique:
received:
07
02
2022
accepted:
01
12
2022
pubmed:
23
2
2023
medline:
22
3
2023
entrez:
22
2
2023
Statut:
ppublish
Résumé
WNT974 is a small molecule inhibitor of Wnt signaling that specifically inhibits porcupine O-acyltransferase. This phase Ib dose--escalation study evaluated the maximum tolerated dose of WNT974 in combination with encorafenib and cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer with RNF43 mutations or RSPO fusions. Patients received once-daily encorafenib and weekly cetuximab, in addition to once-daily WNT974, in sequential dosing cohorts. In the first cohort, patients received 10-mg WNT974 (COMBO10), which was reduced in subsequent cohorts to 7.5-mg (COMBO7.5) or 5-mg (COMBO5) after dose-limiting toxicities (DLTs) were observed. Primary endpoints were incidence of DLTs and exposure to WNT974 and encorafenib. Secondary endpoints were anti-tumor activity and safety. Twenty patients were enrolled (COMBO10, n = 4; COMBO7.5, n = 6; COMBO5, n = 10). DLTs were observed in 4 patients, including grade 3 hypercalcemia (COMBO10, n = 1; COMBO7.5, n = 1), grade 2 dysgeusia (COMBO10, n = 1), and lipase increased (COMBO10, n = 1). A high incidence of bone toxicities (n = 9) was reported, including rib fracture, spinal compression fracture, pathological fracture, foot fracture, hip fracture, and lumbar vertebral fracture. Serious adverse events were reported in 15 patients, most frequently bone fracture, hypercalcemia, and pleural effusion. The overall response rate was 10% and disease control rate 85%; most patients achieved stable disease as their best response. Concerns surrounding the safety and lack of preliminary evidence of improved anti-tumor activity of WNT974 + encorafenib + cetuximab, compared with previous encorafenib + cetuximab data, ultimately led to study discontinuation. Phase II was not initiated. ClinicalTrials.gov, NCT02278133.
Sections du résumé
BACKGROUND
WNT974 is a small molecule inhibitor of Wnt signaling that specifically inhibits porcupine O-acyltransferase. This phase Ib dose--escalation study evaluated the maximum tolerated dose of WNT974 in combination with encorafenib and cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer with RNF43 mutations or RSPO fusions.
PATIENTS AND METHODS
Patients received once-daily encorafenib and weekly cetuximab, in addition to once-daily WNT974, in sequential dosing cohorts. In the first cohort, patients received 10-mg WNT974 (COMBO10), which was reduced in subsequent cohorts to 7.5-mg (COMBO7.5) or 5-mg (COMBO5) after dose-limiting toxicities (DLTs) were observed. Primary endpoints were incidence of DLTs and exposure to WNT974 and encorafenib. Secondary endpoints were anti-tumor activity and safety.
RESULTS
Twenty patients were enrolled (COMBO10, n = 4; COMBO7.5, n = 6; COMBO5, n = 10). DLTs were observed in 4 patients, including grade 3 hypercalcemia (COMBO10, n = 1; COMBO7.5, n = 1), grade 2 dysgeusia (COMBO10, n = 1), and lipase increased (COMBO10, n = 1). A high incidence of bone toxicities (n = 9) was reported, including rib fracture, spinal compression fracture, pathological fracture, foot fracture, hip fracture, and lumbar vertebral fracture. Serious adverse events were reported in 15 patients, most frequently bone fracture, hypercalcemia, and pleural effusion. The overall response rate was 10% and disease control rate 85%; most patients achieved stable disease as their best response.
CONCLUSION
Concerns surrounding the safety and lack of preliminary evidence of improved anti-tumor activity of WNT974 + encorafenib + cetuximab, compared with previous encorafenib + cetuximab data, ultimately led to study discontinuation. Phase II was not initiated.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT02278133.
Identifiants
pubmed: 36811382
pii: 7051060
doi: 10.1093/oncolo/oyad007
pmc: PMC10020809
doi:
Substances chimiques
encorafenib
8L7891MRB6
Cetuximab
PQX0D8J21J
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
LGK974
U27F40013Q
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
KRAS protein, human
0
BRAF protein, human
EC 2.7.11.1
Banques de données
ClinicalTrials.gov
['NCT02278133']
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
230-238Subventions
Organisme : NCI NIH HHS
ID : K12 CA088084
Pays : United States
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press.
Références
PLoS One. 2012;7(4):e35826
pubmed: 22558232
Nature. 2012 Aug 30;488(7413):660-4
pubmed: 22895193
Int J Mol Sci. 2020 Nov 26;21(23):
pubmed: 33256240
Nature. 2012 Jan 26;483(7387):100-3
pubmed: 22281684
Bone Res. 2018 May 25;6:17
pubmed: 29844946
Cancers (Basel). 2021 Jan 04;13(1):
pubmed: 33406649
Cancer Discov. 2021 Oct;11(10):2413-2429
pubmed: 34518209
Curr Colorectal Cancer Rep. 2017 Apr;13(2):101-110
pubmed: 28413363
Nature. 2012 Jul 18;487(7407):330-7
pubmed: 22810696
Clin Cancer Res. 2017 Dec 15;23(24):7490-7497
pubmed: 28954784
Sci Rep. 2017 Nov 10;7(1):15270
pubmed: 29127379
Breast Cancer Res Treat. 2020 Nov;184(1):53-62
pubmed: 32803633
Cancer Discov. 2017 Jun;7(6):610-619
pubmed: 28363909
J Clin Oncol. 2021 Feb 1;39(4):273-284
pubmed: 33503393
Nat Rev Clin Oncol. 2017 Apr;14(4):235-246
pubmed: 27922044
Fundam Clin Pharmacol. 2020 Feb;34(1):51-64
pubmed: 31233627
Invest New Drugs. 2020 Jun;38(3):821-830
pubmed: 31338636
Front Cell Dev Biol. 2019 Jan 07;6:170
pubmed: 30666305
J Clin Oncol. 2015 Dec 1;33(34):4032-8
pubmed: 26460303
Nat Commun. 2017 Jul 11;8:15945
pubmed: 28695896
N Engl J Med. 2019 Oct 24;381(17):1632-1643
pubmed: 31566309
ESMO Open. 2020 Mar;5(2):
pubmed: 32188714
Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):12649-54
pubmed: 23847203
Br J Cancer. 2021 Jul;125(1):28-37
pubmed: 33941878
Nature. 2002 Jun 27;417(6892):949-54
pubmed: 12068308
Oncotarget. 2016 Oct 25;7(43):70589-70600
pubmed: 27661107
Cancer Discov. 2012 Mar;2(3):227-35
pubmed: 22448344
Nat Genet. 2014 Dec;46(12):1264-6
pubmed: 25344691
Cancers (Basel). 2016 Jun 08;8(6):
pubmed: 27338477
Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20224-9
pubmed: 24277854