Phase 1 study of the immunotoxin LMB-100 in patients with mesothelioma and other solid tumors expressing mesothelin.
LMB-100
immunotoxin
mesothelin
mesothelioma
Journal
Cancer
ISSN: 1097-0142
Titre abrégé: Cancer
Pays: United States
ID NLM: 0374236
Informations de publication
Date de publication:
15 11 2020
15 11 2020
Historique:
received:
01
06
2020
revised:
30
06
2020
accepted:
02
07
2020
pubmed:
2
9
2020
medline:
9
6
2021
entrez:
2
9
2020
Statut:
ppublish
Résumé
LMB-100 is an antibody-toxin conjugate with an antimesothelin Fab linked to a 24-kilodalton portion of Pseudomonas exotoxin A with mutations that decrease immunogenicity. The objective of the current first-in-human phase 1 study was to determine the maximum tolerated dose (MTD) and safety in patients with advanced solid tumors expressing mesothelin. Cohorts of 1 to 7 patients received intravenous LMB-100 at 7 dose levels from 40 µg/kg to 250 µg/kg intravenously on days 1, 3, and 5 of a 21-day cycle. Of the 25 patients accrued, 17 had mesothelioma, 3 each had ovarian or pancreatic cancer, and 2 patients had gastric cancer. Dose-limiting toxicities occurred in 2 of 4 patients treated at a dose of 250 µg/kg (capillary leak syndrome) and in 3 of 7 patients treated at a dose of 170 µg/kg (creatinine increase). The MTD of LMB-100 was 140 µg/kg. Of the 10 patients with mesothelioma who were treated at doses of 170 µg/kg or 140 µg/kg, 8 had stable disease and 2 developed progressive disease. Peak LMB-100 plasma concentrations were dose-dependent during cycle 1. The development of antidrug antibodies decreased LMB-100 blood levels in 8 of 21 patients (38%) who received cycle 2 and 9 of 11 patients (81.8%) who received cycle 3. The MTD for single-agent LMB-100 was found to be 140 µg/kg given on a schedule of every other day for 3 doses every 3 weeks. Although less immunogenic than the first-generation antimesothelin immunotoxin SS1P, the majority of patients developed antidrug antibodies after 2 cycles, indicating that LMB-100 has limited antitumor efficacy as a single agent. Phase 2 studies of LMB-100 plus pembrolizumab currently are ongoing for patients with mesothelioma and lung cancer. Mesothelin, a cell surface antigen, is an attractive target for cancer therapy given its limited expression in normal human tissues and high expression in many human cancers. LMB-100 is a recombinant antimesothelin immunotoxin consisting of a humanized antimesothelin antibody fragment fused to a truncated Pseudomonas exotoxin A. In the current study, the authors determined the safety, maximum tolerated dose, and pharmacokinetics of LMB-100, as well as the generation of antidrug antibodies. Ongoing phase 2 clinical trials are evaluating the combination of LMB-100 plus pembrolizumab in patients with treatment-refractory mesothelioma and non-small cell lung cancer.
Sections du résumé
BACKGROUND
LMB-100 is an antibody-toxin conjugate with an antimesothelin Fab linked to a 24-kilodalton portion of Pseudomonas exotoxin A with mutations that decrease immunogenicity. The objective of the current first-in-human phase 1 study was to determine the maximum tolerated dose (MTD) and safety in patients with advanced solid tumors expressing mesothelin.
METHODS
Cohorts of 1 to 7 patients received intravenous LMB-100 at 7 dose levels from 40 µg/kg to 250 µg/kg intravenously on days 1, 3, and 5 of a 21-day cycle.
RESULTS
Of the 25 patients accrued, 17 had mesothelioma, 3 each had ovarian or pancreatic cancer, and 2 patients had gastric cancer. Dose-limiting toxicities occurred in 2 of 4 patients treated at a dose of 250 µg/kg (capillary leak syndrome) and in 3 of 7 patients treated at a dose of 170 µg/kg (creatinine increase). The MTD of LMB-100 was 140 µg/kg. Of the 10 patients with mesothelioma who were treated at doses of 170 µg/kg or 140 µg/kg, 8 had stable disease and 2 developed progressive disease. Peak LMB-100 plasma concentrations were dose-dependent during cycle 1. The development of antidrug antibodies decreased LMB-100 blood levels in 8 of 21 patients (38%) who received cycle 2 and 9 of 11 patients (81.8%) who received cycle 3.
CONCLUSIONS
The MTD for single-agent LMB-100 was found to be 140 µg/kg given on a schedule of every other day for 3 doses every 3 weeks. Although less immunogenic than the first-generation antimesothelin immunotoxin SS1P, the majority of patients developed antidrug antibodies after 2 cycles, indicating that LMB-100 has limited antitumor efficacy as a single agent. Phase 2 studies of LMB-100 plus pembrolizumab currently are ongoing for patients with mesothelioma and lung cancer.
LAY SUMMARY
Mesothelin, a cell surface antigen, is an attractive target for cancer therapy given its limited expression in normal human tissues and high expression in many human cancers. LMB-100 is a recombinant antimesothelin immunotoxin consisting of a humanized antimesothelin antibody fragment fused to a truncated Pseudomonas exotoxin A. In the current study, the authors determined the safety, maximum tolerated dose, and pharmacokinetics of LMB-100, as well as the generation of antidrug antibodies. Ongoing phase 2 clinical trials are evaluating the combination of LMB-100 plus pembrolizumab in patients with treatment-refractory mesothelioma and non-small cell lung cancer.
Identifiants
pubmed: 32870522
doi: 10.1002/cncr.33145
pmc: PMC8552963
mid: NIHMS1628021
doi:
Substances chimiques
GPI-Linked Proteins
0
Immunoconjugates
0
Immunotoxins
0
LMB-100
D6AT024T4P
Mesothelin
J27WDC343N
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
4936-4947Subventions
Organisme : Intramural NIH HHS
ID : Z01 BC006150
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 BC010816
Pays : United States
Organisme : Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research
ID : Z01-BC-006150
Informations de copyright
© 2020 American Cancer Society.
Références
Sci Transl Med. 2020 Jul 1;12(550):
pubmed: 32611684
Am J Pathol. 2018 Aug;188(8):1736-1743
pubmed: 29870741
J Thorac Oncol. 2018 Sep;13(9):1269-1283
pubmed: 29966799
Mol Oncol. 2016 Oct;10(8):1317-29
pubmed: 27507537
Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):3937-42
pubmed: 15217923
Clin Cancer Res. 2007 Sep 1;13(17):5144-9
pubmed: 17785569
Clin Cancer Res. 2001 Dec;7(12):3862-8
pubmed: 11751476
Mol Cancer Ther. 2014 Nov;13(11):2653-61
pubmed: 25239937
Mod Pathol. 2003 Mar;16(3):192-7
pubmed: 12640097
Int J Cancer. 1992 Feb 1;50(3):373-81
pubmed: 1735605
Clin Breast Cancer. 2013 Oct;13(5):378-84
pubmed: 23810431
Eur J Cancer. 2009 Jan;45(2):228-47
pubmed: 19097774
Oncotarget. 2015 May 10;6(13):11694-703
pubmed: 26028668
Sci Transl Med. 2013 Oct 23;5(208):208ra147
pubmed: 24154601
J Natl Cancer Inst. 2009 May 20;101(10):708-20
pubmed: 19436029
Toxins (Basel). 2018 Nov 14;10(11):
pubmed: 30441807
Leukemia. 2018 Aug;32(8):1768-1777
pubmed: 30030507
J Clin Oncol. 2016 Dec;34(34):4171-4179
pubmed: 27863199
Am J Clin Pathol. 2005 Dec;124(6):838-45
pubmed: 16416732
Appl Immunohistochem Mol Morphol. 2016 Apr;24(4):246-52
pubmed: 26894650
Stat Med. 1998 May 30;17(10):1103-20
pubmed: 9618772
Cancer. 2014 Nov 1;120(21):3311-9
pubmed: 24989332
Oncotarget. 2017 Apr 18;8(16):26744-26754
pubmed: 28460459
Cancer Immunol Res. 2017 Aug;5(8):685-694
pubmed: 28674083
Oncotarget. 2017 Feb 7;8(6):9189-9199
pubmed: 27999204
Nat Rev Cancer. 2006 Jul;6(7):559-65
pubmed: 16794638
Clin Cancer Res. 2009 Aug 15;15(16):5274-9
pubmed: 19671873
Clin Cancer Res. 2014 Feb 15;20(4):1020-8
pubmed: 24334761
Clin Cancer Res. 2007 Mar 1;13(5):1571-5
pubmed: 17332303
J Immunol. 2014 Jul 1;193(1):48-55
pubmed: 24890727
Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):136-40
pubmed: 8552591
Clin Cancer Res. 2017 Mar 15;23(6):1564-1574
pubmed: 27635089
Ann Oncol. 2004 Feb;15(2):257-60
pubmed: 14760119
FEBS J. 2011 Dec;278(23):4683-700
pubmed: 21585657
Mol Cancer Ther. 2014 Aug;13(8):2040-9
pubmed: 24928849