Phase I trial of Ipatasertib plus Atezolizumab enhances PI3K/AKT pathway immune responses in solid tumors and refractory glioblastoma
PURPOSE: Activation of the phosphatodylinositol-3-kinase/AKT (PI3K/AKT) signalling pathway promotes tumor immune evasion by suppressing effector T-cell infiltration and enhancing regulatory T-cell activity contributing to resistance to immune checkpoint inhibitors. Preclinical studies have demonstrated that inhibition of this pathway can restore anti-tumor 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 and advanced solid tumors. EXPERIMENTAL DESIGN: Phase 1b, 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 glioblastoma onto Cohort A2. Part B enrolled patients into 6 exploratory cohorts. 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 2 dose of ipatasertib 400 mg/daily plus atezolizumab 1200mg every 3 weeks. Pharmacodynamic analysis demonstrated depletion of FOXP3+ regulatory T cells and increased infiltration of CD8+ effector T cells within the tumor microenvironment. Durable exceptional responses were seen in some patients with treatment-refractory or recurrent glioblastoma. CONCLUSION: This is the first report in clinical samples showing that ipatasertib efficiently depletes FOXP3+ regulatory T cells and results in increased infiltration of effector CD8+ T cells in the tumor microenvironment. This was associated with preliminary efficacy in a subset of patients with treatment-refractory glioblastoma (GBM).
Authors
- Anna Zachariou (ORCID: https://orcid.org/0000-0002-7867-8327)
- Karen E. Swales (ORCID: https://orcid.org/0000-0002-6572-1293)
- Juanita Lopez
- Igor Vivanco (ORCID: https://orcid.org/0000-0001-6347-9416)
- Mona Parmar (ORCID: https://orcid.org/0000-0001-7818-4100)
- Mariana Scaranti (ORCID: https://orcid.org/0000-0001-7713-0100)
- Bora Gürel (ORCID: https://orcid.org/0000-0002-5018-8078)
- Philip Benjamin (ORCID: https://orcid.org/0000-0002-7361-9571)
- Malaka Ameratunga (ORCID: https://orcid.org/0000-0002-7171-6781)
- Christina Gertrude Yap (ORCID: https://orcid.org/0000-0002-6715-2514)
- Philip Rich
- Udai Banerji (ORCID: https://orcid.org/0000-0003-1503-3123)
- Ines Figueiredo (ORCID: https://orcid.org/0009-0007-2754-5608)
- Ana Ferreira
- Mateus Crespo (ORCID: https://orcid.org/0000-0003-4043-8296)
- Shaun Decordova (ORCID: https://orcid.org/0000-0002-0091-0587)
- Denisa Bogdan (ORCID: https://orcid.org/0000-0002-3017-4832)
- Liam Welsh (ORCID: https://orcid.org/0000-0001-9150-0737)
- Wing Yau (ORCID: https://orcid.org/0000-0003-3550-4420)
- Timothy L. Jones (ORCID: https://orcid.org/0000-0003-2037-7334)
- Antonia Creak (ORCID: https://orcid.org/0000-0002-9426-2989)
- Toby Prout (ORCID: https://orcid.org/0000-0002-6465-4578)
- Nina Tunariu (ORCID: https://orcid.org/0000-0001-6656-3699)
- Wei Yuan (ORCID: https://orcid.org/0000-0001-8004-1846)
- Adam Sharp (ORCID: https://orcid.org/0000-0002-3740-1612)
- Crescens Tiu (ORCID: https://orcid.org/0000-0002-0515-6130)
- Johann Sebastian De Bono (ORCID: https://orcid.org/0000-0002-2034-595X)
- Mihaela Rata (ORCID: https://orcid.org/0000-0003-4999-8038)
- Anna Rachel Minchom (ORCID: https://orcid.org/0000-0002-9339-7101)
- Andrea Biondo (ORCID: https://orcid.org/0000-0002-8625-1489)
- Alec Paschalis (ORCID: https://orcid.org/0000-0001-9566-5096)
- Ruth Riisnaes
- Nick Waldron
- Dr Matthew Blackledge
- Xinjie Hu
- Diogo Da Silva
- Bindu Baikady (ORCID: https://orcid.org/0000-0002-2655-4752)
- Robert Daly (ORCID: https://orcid.org/0009-0006-8403-8509)
- Ricardo Morilla (ORCID: https://orcid.org/0009-0007-3147-9308)
- Leslie Bridges (ORCID: https://orcid.org/0000-0002-0333-8272)
- Andrew J. Martin (ORCID: https://orcid.org/0009-0006-3232-7819)
Institutions
- Royal Marsden NHS Foundation Trust (GB)
- Institute of Cancer Research (GB)
- St George's, University of London (GB)
- King's College London (GB)
- St George’s University Hospitals NHS Foundation Trust (GB)
- Institute of Cancer Research (CA)
- Sutton Hospital (GB)
- King's College School (GB)
- Royal Marsden Hospital (GB)
- St George's Park (GB)
- CRUK Lung Cancer Centre of Excellence (GB)
- Monash University (AU)
Publication Details
- Journal
- Clinical Cancer Research
- Published
- 2026-04-27
- DOI
- https://doi.org/10.1158/1078-0432.ccr-25-4364
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00