Phase I Trial of Ipatasertib plus Atezolizumab Enhances PI3K/AKT Pathway Immune Responses in Solid Tumors and Refractory Glioblastoma.

PURPOSE: Activation of the phosphoinositide 3-kinase/AKT (PI3K/AKT) signaling pathway promotes tumor immune evasion by suppressing effector T-cell infiltration and enhancing regulatory T-cell (Treg) activity, contributing to resistance to immune checkpoint inhibitors (ICI). Preclinical studies have demonstrated that inhibition of this pathway can restore antitumor immunity and synergize with PD-1/PD-L1 blockade. We explore the synergistic clinical potential of targeting the PI3K/AKT pathway in combination with atezolizumab to overcome immunotherapy resistance in recurrent glioblastoma (GBM) and advanced solid tumors.

PATIENTS AND METHODS: Phase Ib, investigator-initiated, open-label study (NCT03673787) composed of a proof-of-concept dose escalation part A of ipatasertib plus atezolizumab in a 3 + 3 design. Adult patients with treatment-refractory advanced cancers were enrolled into cohort A1 and recurrent GBM into cohort A2. Part B enrolled patients into six exploratory cohorts. The study aims to evaluate the safety, immune-modulatory effects, and preliminary efficacy of the combination of ipatasertib with atezolizumab.

RESULTS: The combination was well tolerated, with no dose-limiting toxicities at the recommended phase II dose of ipatasertib 400 mg daily plus atezolizumab 1,200 mg every 3 weeks. Pharmacodynamic analysis demonstrated depletion of FOXP3+ Tregs and increased infiltration of CD8+ effector T cells within the tumor microenvironment (TME). Durable exceptional responses were seen in some patients with treatment-refractory or recurrent GBM.

CONCLUSIONS: This is the first report in clinical samples showing that ipatasertib efficiently depletes FOXP3+ Tregs and results in increased infiltration of effector CD8+ T cells in the TME. This was associated with preliminary efficacy in a subset of patients with treatment-refractory GBM.