Phase I dose escalation of IMC-C103C, a CD33MAGE-A4 T-cell receptor (TCR) bispecific protein

Abstract

Background: TCR bispecific proteins (bsp) redirect polyclonal T cells to target intra/ extracellular proteins in cancer, as validated by tebentafusp (CD3gp100 TCR) with a survival benefit in metastatic uveal melanoma (HR 0.51). IMC-C103C is a TCR bsp against MAGE-A4, a cancer-testis antigen expressed in several tumor types (eg, lung, ovarian, HNSCC, GEJ) but minimally in normal tissue. Methods: HLA-A*02:01+ pts with selected advanced tumors are eligible; prospective MAGE-A4 testing is required in indications with lower MAGE-A4 prevalence. The Ph1 primary objective is to identify the expansion dose. Other objectives: adverse events (AE), clinical activity (RECIST v1.1), biomarkers. IMC-C103C is dosed IV weekly, with step-dosing at > 15 mg (full dose at Day 15). Results: As of 20 Aug 2021, 42 pts were treated in 9 cohorts. 18 pts (78% 3L+ ovarian) were treated at 90 mg, doses consistently showing robust evidence of T cell activity (Table). Median MAGE-A4 H-score was low, 19. Paired tumor biopsies (n¼6) showed substantial increases in CD3, CD8 T cell infiltration on treatment. Most common related AEs (n¼42) were pyrexia 50%, chills 50%, cytokine release syndrome 36%, headache 31%, and nausea 31%. These were typically Gr1/2, occurred in first 3 weeks and rapidly resolved. Reversible neutropenia (19%), the most common Gr3 related AE, typically occurred at 90 mg. No related AE led to discontinuation or death. Clinical activity is seen in platinum-resistant ovarian cancer: 2 confirmed PRs (15 mg, duration 8.3mo; 90 mg, response ongoing); 2 pts at 140 mg had overall reduction in target lesions (-44%, -81%) but had new lesions; all 4 pts had MAGE-A4 H-score