608 Synergistic effect of the combination of ATG-017, an ERK1/2 inhibitor, and immune checkpoint inhibitor in preclinical cancer models

Background The RAS/MAPK pathway has emerged as a critical for therapeutic targeting in spectrum of solid tumor and hematological malignances. Inhibitors MAPK targets, such RAS, BRAF, or MEK have been approved the treatment cancer either monotherapy combination. However, there no drug ERK1/2, terminal kinases Ras-Raf-MEK-ERK signal transduction cascade. combination ERK1/2 inhibitor checkpoint inhibitors strategy not explored clinic. ATG-017 is an oral, potent, highly selective which under Phase 1 clinical investigation. ATG-012 novel KRAS G12C. In this study, we tested anti-tumor effect induced by ATG-017, ATG-012, anti-PDL1 antibody preclinical models. Methods We assessed anti-cancer effects G12C PD1/PDL1 inhibition monotherapy, combinations. Anti-PDL1 (atezolizumab), atezolizumab, triple were PD(L)1 blockade insensitive syngeneic lung model,LL/2. ATG-017-atezolizumab was also evaluated G13C-mutant,PD(L)1 lymphoma model, EL4. To further investigate if could enhance efficacy atezolizumab aberration-independent manner, wild type A20. As well assessment impact on growth, drugs infiltrating leukocytes analyzed flow cytometry. Results showed enhanced mouse EL4 neither nor single agent activity, while significant growth (TGI=22%) day 9. No body weight loss observed. percentage CD8+ T cells, NK cells CD8:CD4 ratio found increased group. mean CD8+T among CD45+ from 4.17% (IgG +Vehicle control), 3.81% (ATG-017), 3.23% to 12.92% 0.25 (IgG+Vehicle), 0.32(ATG-017), 0.17 (atezolizumab) 0.67 (combination), respectively (Figure 1). More data LL/2 A20 model are being generated. Conclusions Synergism observed vivo, suggesting promising strategies patients that warrants Ethics Approval protocol any amendment(s) procedures involving care use animals study reviewed Institutional Animal Care Use Committee (IACUC) CrownBio prior execution. During conducted accordance with regulations Association Assessment Accreditation Laboratory (AAALAC).All studies following IACUC protocol. AUP NO.: AN-2004-09-309 Abstract 608 Figure ATG-017-Atezolizumab vivo synergism(A) Tumor curve (B) model; N=8 each (C) (left), CD8+/CD4+ (middle), (right). TILs isolated samples shown (A). N=3