Phase 1 study of the immunotoxin LMB‐100 in patients with mesothelioma and other solid tumors expressing mesothelin

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-inhuman 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. Cancer 2020;126:4936-4947.

Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

“…LMB-100 monotherapy was also shown to be inefficient in a phase I dose-escalation clinical trial (CTI: NCT02798536) due to the development of anti-LMB-100 antibodies, as well as the lack of durable responses or CRs in patients with different mesothelin-positive cancers ( 138 ). Further clinical evaluation of LMB-100 alone or in combination with nab-paclitaxel in a phase I/II clinical study (CTI: NCT02810418) in pancreatic cancer patients was also underwhelming ( 139 ).…”

Current Management and Future Perspective in Pleural Mesothelioma

“…Mesothelin, a transmembrane tumor antigen, is highly expressed in solid cancers including mesothelioma, pancreatic and ovarian cancers [ 160 ]. It has been investigated as a possible therapeutic target in mesothelioma, including CAR-T therapy and antibody-drug conjugate (ADC) [ 161 , 162 , 163 ]. Anetumab ravtansine, an anti-mesothelin-specific ADC, was reported to show encouraging antitumor activity with manageable safety profile in pre-treated patients with mesothelioma in a phase 1 study [ 164 ].…”

Molecular Pathways in Peritoneal Mesothelioma: A Minireview of New Insights

“…Another well-known inactivation concerns NF2, leading to the loss of merlin protein and the dysregulation of several streams, among which the Hippo-YAP/TAZ pathways (66), potentially blocked by mTOR inhibitors (52,53), warrant further analysis. An attractive target has also been found in mesothelin, a membrane glycoprotein that has been blocked in epithelioid pleural mesothelioma (67)(68)(69). Regarding rare alterations, anecdotal reports about ALK fusions in PM need to be reported in terms of the response to ALK inhibitors, such as in lung cancers (48).…”