Phase I Trial of Ipatasertib plus Atezolizumab Enhances PI3K/AKT Pathway Immune Responses in Solid Tumors and Refractory Glioblastoma
Year: 2026
Type: article
Study design: Clinical Trial
Abstract: 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.
Source: Clinical Cancer Research
Authors: Crescens Tiu, Wing Yau, Diogo Silva, Nick Waldron, Malaka Ameratunga, Mariana Scaranti, Andrea Biondo, Liam Welsh, Antonia Creak, Timothy L. Jones, Andrew J. Martin, Leslie Bridges, Anna Zachariou, Mateus Crespo, Ana Ferreira, Ruth Riisnaes, Bora Gurel, Ines Figueiredo, Denisa Bogdan, Wei Yuan, Ricardo Morilla, Karen Swales, Shaun Decordova, Toby Prout, Mona Parmar, Bindu Baikady, Mihaela Rata, Matthew Blackledge, Nina Tunariu, Philip Benjamin, Philip Rich, Robert Daly, Xinjie Hu, Christina Yap, Igor Vivanco, Alec Paschalis, Adam Sharp, Udai Banerji, Anna Minchom, Johann de Bono, Juanita Lopez
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funder: Cancer Research UK
OpenAlex ID: W7156315508