TIG-007: Study of EOS884448/GSK4428859A Alone, and in Combination with Iberdomide with or without Dexamethasone, in Participants with Relapsed or Refractory Multiple Myeloma

Background: T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory immune checkpoint receptor expressed on subsets of T cells and NK cells. In multiple myeloma (MM), TIGIT expression increases as the disease progresses and correlates with defective T cell effector functions. Higher TIGIT expression was observed in MM bone marrow CD8+ T cells in mice and patients compared to other immune checkpoint inhibitors, including PD-1, TIM-3, LAG-3, or CTLA-4 (Guillerey, C. et al, Blood 2018; Minnie, S. A. et al . Blood 2018). EOS884448/GSK4428859A (EOS-448) is a potent and highly selective fully human antagonist IgG1 antibody targeting TIGIT. Preclinically, anti-TIGIT Ab elicits superior anti-tumor immune responses compared to anti-PD1 mAbs (Guillerey, C. et al, Blood 2018). In murine Vk*Myc MM models, Fc-enabled a-TIGIT Ab elicits effective control of MM disease progression after autologous stem-cell transplant (ASCT), while Fc-disabled version is inactive. Anti-tumor activity is seen with monotherapy after ASCT at high T cell doses and provides significant synergistic activity when combined with an Immunomodulatory imide drug (IMiD) if T cell doses are suboptimal (Minnie, S. A. et al, Abstract submitted ASH 2021). Iberdomide (also known as CC-220) is a novel potent cereblon (CRBN) E3 ligase modulatory compound (CELMoD) that regulates multiple transcription factors within immune cells (Gandhi, A. K. et al . Brit J Haematol 2014). Iberdomide has shown notable clinical activity and acceptable tolerability in heavily pre-treated patients with relapsed or refractory multiple myeloma (RRMM), including those refractory to prior IMiDs (Lonial, S. et al. J Clin Oncol 2019). Given the dominant role of TIGIT in the immune suppression associated with MM, we hypothesize that TIGIT represents an ideal checkpoint to target clinically. EOS-448 alone or the synergistic combination of EOS-448 with iberdomide may provide a therapeutic opportunity to amplify myeloma-specific T-cell anti-tumor responses in difficult to treat RRMM patients previously exposed to IMiD, proteasome inhibitors (PIs) and anti-CD38.