GALLANT-1: Galectin-3 (Gal-3) inhibitor GB1211 plus atezolizumab (atezo) in patients with non-small cell lung cancer (NSCLC)?A randomized, double-blind trial

ABSTRACT

Background: Gal-3 is a protein that binds specifically to N-acetylglucosamine-expressing carbohydrates, which are upregulated on key tumorigenic cell surface proteins. Gal-3 is widely over-expressed in the tumor microenvironment and is generally linked to poor outcomes. Gal-3 regulates immune cell function of T cells and macrophages, and promotes neovascularization and fibrosis [Peng Cancer Res 2008;Markowska J Biol Chem 2011;Kouo Cancer Immunol Res 2015]. Gal-3 sequesters interferon gamma, reduces T-cell influx, and contributes to tumor cell evasion of the immune system via LAG-3 activation [Chen PNAS 2009;Gordon-Alonso Nat Commun 2017]. Gal-3 has been identified as a marker of resistance to checkpoint inhibitors (CPIs);patients with stage IV NSCLC with high Gal-3 levels (> 70% Gal-3 immunohistochemical staining) have been shown to be resistant to the CPI pembrolizumab [Capalbo Int J Mol Sci 2019]. Animal data indicate synergy between CPI therapy and Gal-3 inhibition [Vuong Cancer Res 2019;Zhang FEBS Open Bio 2021]. Thus, inhibiting Gal-3 together with CPI-based immunotherapy may enhance tumor-specific immune responses, and overcome CPI resistance. Methods: GALLANT-1 (NCT05240131) is a 3-part, placebo-controlled phase Ib/IIa trial that will investigate safety and efficacy of GB1211 (a Gal-3 inhibitor) + atezo vs placebo + atezo in patients with advanced NSCLC. Part A will include 8-12 patients and study safety and tolerability of 200 mg and 400 mg GB1211 twice-daily + atezo (open-label). Primary endpoint is number of adverse events (AEs) after 12 weeks' treatment and will determine the dosage for Part B. Part B will include 75-94 patients, and is a randomized, double-blind study of GB1211 + atezo or placebo + atezo. Primary endpoints are safety (number of AEs) and efficacy (percentage change from baseline in the sum of longest diameter of target lesions after 12 weeks' treatment). Part C is an expansion study including patients from Parts A and B, with safety and efficacy assessments. Eligibility criteria advanced or metastatic stage IIIB or IV NSCLC adenocarcinoma;measurable disease per RECIST v1.1;expression of programmed death ligand-1 on ≥50% of tumor cells;eligible for 1200 mg atezo every 3 weeks. Exclusion criteria symptomatic, untreated, or actively progressing central nervous system metastases;prior systemic chemotherapy for treatment of recurrent advanced or metastatic disease, except if part of neoadjuvant/ adjuvant therapy;prior treatment with immune CPIs and/or GB1211;presence of EGFR mutation and ALK, ROS1, and RET alterations;treatment with antineoplastic or systemic immunotherapeutic agents prior to first GB1211 dose;severe infectious disease < 4 weeks prior to first GB1211 dose;active hepatitis B or C, HIV, or COVID-19. The study is being initiated;updated enrollment status will be presented at the meeting.