Safety and preliminary efficacy of MIL93 in patients with advanced solid tumors: The monotherapy part of a phase 1 trial.
Authors: Huang Jing , Zhang Bo , Wang Ying , Wang Feng , Yu Zhuang , Wu Shikai , Zheng Yi , Cao Yu , Xu Jianping , Lan Dongmei , Wei Min , Liu Sijun 
Published: January 2023

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Background: Claudin18.2 (CLDN18.2) is specifically expressed in the tight junction of gastric epithelial cells, and has been identified as a promising target in gastric and pancreatic cancer as well as several other malignancies. MIL93 is a humanized afucosylated IgG1 monoclonal antibody targeting CLDN18.2 with enhanced ADCC function, which demonstrated superior activity compared with zolbetuximab in vitro and in vivo, respectively. We conducted a multicenter, dose escalation and expansion phase 1 study of MIL93 for advanced solid tumors. Methods: We enrolled pts aged 18 years or older with advanced solid tumors whose disease had progressed after standard systemic treatments in the monotherapy part of this study. Pts were required to have measurable lesion as per RECIST v1.1; ECOG PS score of 0-1 and adequate organ functions. In the dose escalation phase, 6 dose levels (0.3mg/kg, 1mg/kg, 3mg/kg, 10mg/kg, 20mg/kg and 30mg/kg, Q3W) of MIL93 were conducted for assessment. Accelerated titration was adopted for the first 2 dose levels, and the 3+3 design was used afterwards. In the dose expansion phase, pts with CLDN18.2-positive cancers received the selected RP2D. The primary objectives were the safety and tolerability, dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MIL93. Secondary objectives included pharmacokinetics, immunogenicity and preliminary efficacy. Results: At the data cut-off date (August 9, 2022), 30 pts were enrolled from 6 centers in China. MIL93 was well-tolerated for the dosages tested (0.3mg/kg through 30mg/kg Q3W). DLT was observed in one pt during the 3-week window at 30mg/kg. However, none of the three additional patients at 30mg/kg had DLT, and MTD has not been reached. In further expansion study 9 additional pts were enrolled into the expansion phase at the 20 mg/kg Q3W dose and 3 pts were enrolled into the dose escalation at the 10mg/kg Q2W. The most common TEAE occurring in ≥20% of pts were nausea (60%), hypoalbuminemia (46.7%), vomiting (43.3%), anemia (36.7%), hyponatremia (33.3%), hypocalcemia (23.3%), decreased appetite (23.3%), asthenia (23.3%), aspartate aminotransferase increased (20.0%). Serious adverse events (SAEs) were observed in 9 (30%) pts, and MIL93-related SAEs occurred in 6 (20%) pts including hypoalbuminemia/hypoproteinemia, malnutrition, anorexia and vomiting. No treatment related Grade 4 or 5 event was reported. Among the 25 pts who had at least one post-treatment radiological evaluation, 2 gastric cancer pts who progressed on multiple lines of therapies achieved partial response (PR). The disease control rate (DCR) reached 44%. Conclusions: MIL93 had a manageable and tolerable safety profile in patients with advanced solid tumors and preliminary anti-tumor activity in 2 heavily pretreated gastric cancer pts. Combination of MIL93 and standard treatment in selected tumor types is currently underway. Clinical trial information: NCT04671875 .