Eganelisib combined with immune checkpoint inhibitor therapy and chemotherapy in frontline metastatic triple-negative breast cancer triggers macrophage reprogramming, immune activation and extracellular matrix reorganization in the tumor microenvironment

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis particularly in the metastatic setting. Treatments with anti-programmed cell death protein-1/programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICI) in combination with chemotherapies have demonstrated promising clinical benefit in metastatic TNBC (mTNBC) but there is still an unmet need, particularly for patients with PD-L1 negative tumors. Mechanisms of resistance to ICIs in mTNBC include the presence of immunosuppressive tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Eganelisib is a potent and selective, small molecule PI3K-γ inhibitor that was shown in preclinical studies to reshape the TME by reducing myeloid cell recruitment to tumors and reprogramming TAMs from an immune-suppressive to an immune-activating phenotype and enhancing activity of ICIs. These studies provided rationale for the clinical evaluation of eganelisib in combination with the anti-PD-L1 atezolizumab and nab-paclitaxel in firstline mTNBC in the phase 2 clinical trial MAcrophage Reprogramming in Immuno-Oncology-3 (MARIO-3, NCT03961698). We present here for the first time, in-depth translational analyses from the MARIO-3 study and supplemental data from eganelisib monotherapy Ph1/b study in solid tumors (MARIO-1, NCT02637531).