We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Phase 1 study of the immunotoxin LMB‐100 in patients with mesothelioma and other solid tumors expressing mesothelin.
- Authors
Hassan, Raffit; Alewine, Christine; Mian, Idrees; Spreafico, Anna; Siu, Lillian L.; Gomez‐Roca, Carlos; Delord, Jean‐Pierre; Italiano, Antoine; Lassen, Ulrik; Soria, Jean‐Charles; Bahleda, Rastilav; Thomas, Anish; Steinberg, Seth M.; Peer, Cody J.; Figg, William D.; Niederfellner, Gerhard; Méresse Naegelen, Valérie; Pastan, Ira
- Abstract
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. The mesothelin‐targeting immunotoxin LMB‐100 is well tolerated with manageable adverse effects. Based on the antitumor efficacy observed in preclinical studies, the combination of LMB‐100 plus pembrolizumab currently is being evaluated in the clinic.
- Subjects
CELL surface antigens; NON-small-cell lung carcinoma; CAPILLARY leak syndrome; ANTIBODY-toxin conjugates; PATIENT safety
- Publication
Cancer (0008543X), 2020, Vol 126, Issue 22, p4936
- ISSN
0008-543X
- Publication type
Article
- DOI
10.1002/cncr.33145