Abstract C114: Dose escalation results from a first-in-human, phase I/II study of GB263T, a novel EGFR/cMET/cMET trispecific antibody, in patients with advanced EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC)
Authors: Yang Jin-Ji , Pavlakis Nick , Xie Fan , Li Tong , Wu Yi-Long 
Published: December 2023

Abstract
Background: GB263T, a novel trispecific antibody directed against EGFR and cMET, adopts the design of two humanized VHH antibodies that recognize two different cMET epitopes, in which a conformational change induced by the first VHH binding exposes the second epitope for the second VHH to bind. Sequential binding of the two VHH antibodies to cMET increases tumor specificity, which results in widening of the safety window. In vitro studies show that GB263T induces better antigen-antibody molecular endocytosis, more completely blocks the signal transduction pathway, and has better ADCC activity compared to a benchmark. In addition, GB263T has demonstrated promising pre-clinical activity in models with various EGFR/cMET alterations, including those with high medical need. Here, we report updated dose escalation results of the first-in-human phase I/II study of GB263T in patients (pts) with advanced EGFRm NSCLC (NCT05332574).
Methods: This multicenter (China and Australia), phase I/II study was conducted using an accelerated titration method followed by a traditional 3+3 design for dose escalation. Pts with EGFRm NSCLC with prior EGFR TKI and platinum-based chemotherapy were enrolled. GB263T was given at 140-1680 mg (5 dose cohorts) IV weekly for the first two 28-day cycles and biweekly thereafter. Objectives were to evaluate the safety and tolerability, determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D), assess the pharmacokinetics, immunogenicity, and preliminary efficacy of GB263T.
Results: As of July 5, 2023, 13 pts were treated: 140mg (n=1), 420mg (n=1), 840mg (n=3), 1260mg (n=3), 1680mg (n=5). The enrolment of the 1680mg cohort is ongoing. All pts had received previous third-generation EGFR-TKI and platinum-based chemotherapy. Median number of prior lines of systemic therapy was 3 (range 1-7). One patient at 1680mg experienced DLT (grade 3 oral mucositis, which has resolved after symptomatic treatment). The most common treatment-related adverse events (TRAEs) were rash (61.5%), infusion related reaction (38.5%), fatigue (30.8%) and myalgia (23.1%), and all are mild (grade 1/2). Only one patient developed ≥grade 3 TRAE (grade 3 oral mucositis). There were no treatment-related discontinuations. Among 10 response-evaluable pts, two achieved partial response (PR) and four achieved stable disease (SD) with tumor shrinkage observed in 3/4 SD pts. The disease control rate (DCR) is 60%. The objective response rate (ORR) at the therapeutic dose range (1260-1680mg) is 40% (2/5). Two PR pts and 2/4 SD pts remained on treatment at data cutoff.
Conclusions: Results to date demonstrate a good safety profile with promising efficacy at the therapeutic dose range (1260-1680mg). Continued dose escalation and clinical investigation of GB263T is ongoing.Clinical trial information: NCT05332574. Research Sponsor: Genor Biopharma Co. Ltd.
Citation Format: Jin-Ji Yang, Nick Pavlakis, Fan Xie, Tong Li, Yi-Long Wu. Dose escalation results from a first-in-human, phase I/II study of GB263T, a novel EGFR/cMET/cMET trispecific antibody, in patients with advanced EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C114.