Abstract CT157: Phase 1 dose-escalation study of linclatamig, a LY6G6D×CD3 T cell-engaging bispecific antibody, in patients with colorectal cancer

Abstract Background: Lymphocyte antigen 6 complex locus G6D (LY6G6D) is a promising target in metastatic colorectal cancer (mCRC) due to its differentiated expression in tumor vs. normal tissues, and higher prevalence in microsatellite-stable CRC. Linclatamig (or BLYG8824A) is a humanized, IgG1, LY6G6D × CD3 T cell-engaging bispecific antibody (TCB), that binds to LY6G6D and CD3+ T cells, forming an immunologic synapse to facilitate T cell-mediated killing of LY6G6D+ cells. This study evaluated the safety, pharmacokinetics (PK), biomarkers, and anti-tumor activity of linclatamig in patients (pts) with LY6G6D+ mCRC. Method: Pts aged ≥18 years with locally advanced or metastatic LY6G6D+ CRC refractory to established therapies, measurable disease by RECIST v1.1 and ECOG 0/1 were enrolled. Escalating doses of intravenous linclatamig were administered in 21-day cycles, beginning with a step-up dose on Cycle 1, Day 1 (C1D1), followed by a (higher) target dose on C1D8 and on D1 of every cycle (C2D1 onward). Results: Pts (n=46) (prior therapy: median 4 lines; range 2-11) received linclatamig (median 3 cycles; range 1-37) at step-up doses 0.2-180 mg and target doses 0.6-1500 mg across 13 dose-escalation cohorts. The maximum tolerated dose was not reached. Dose-limiting toxicities included immune effector cell-associated neurotoxicity syndrome in 2 pts at 180 mg step-up dose, and respiratory distress in the context of CRS and tumor flare in 1 pt at 100 mg step-up dose. Most frequently reported adverse events (AEs) of any grade (Gr) and irrespective of causality were CRS (94%), anemia (48%), diarrhea (50%), fatigue (50%), dry skin (37%), and rash maculopapular (30%). Most frequent treatment-related Gr ≥3 toxicities were reduced lymphocyte count (13%), diarrhea (11%), and anemia (9%). CRS, mainly Gr 1/2, occurred at step-up C1D1 doses ≥5.4 mg and was mostly limited to C1. Skin-related AEs (74%) including alopecia were reported, consistent with LY6G6D expression in hair follicle bulbs. PK data indicated dose proportionality and faster-than-typical IgG1 clearance. Anti-tumor activity was limited, with 1 confirmed and 2 unconfirmed partial responses. Increased blood levels of IFNg, IL6, and T cell activation supported the mechanism of action. Tumor RNA of responders showed CD8B and activated NK cell enrichment, whereas tumors of pts with disease progression had more fibroblasts, TGFb, myeloid inflammation signatures, and KRAS signaling. Conclusion: This first-in-human study (NCT04468607) targeting LY6G6D in mCRC pts demonstrated a tolerable safety profile for linclatamig up to 1500 mg. Step-up dosing mitigated CRS severity, although skin toxicities indicated possible on-target/off-tumor effects. Limited anti-tumor activity of linclatamig was observed in pts with heavily pre-treated mCRC. Citation Format: Marwan Fakih, Jayesh Desai, Iosune Baraibar, Ignacio Melero, David Spigel, Eric Chen, Ben Markman, Arshdeep Pooni, Amy A. Lo, Rosanna S. Kwok, Stephanie Hilz, Zao Li, Pranay Dogra, Neha N. Shah, Andrew G. Polson, Douglas Leipold, Wei Zou, Mengsong Li, Luciana Molinero, Simon Heidegger, Victor Moreno. Phase 1 dose-escalation study of linclatamig, a LY6G6D×CD3 T cell-engaging bispecific antibody, in patients with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT157.