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Ref Type Abstract
Authors Crescens Tiu; Wing Hing Yau; Liam C. Welsh; Timothy L. Jones; Anna Zachariou; Toby Prout; Mona Parmar; Alison J. Turner; Robert W. Daly; Christina Yap; Mateus Crespo; Bora Gurel; Ruth M. Riisnaes; Shaun A. DeCordova; Karen E. Swales; Udai Banerji; Anna R. Minchom; Adam Sharp; Johann S. de Bono; Juanita S. Lopez
Title Abstract CT093: Preliminary evidence of antitumor activity of Ipatasertib (Ipat) and Atezolizumab (A) in glioblastoma (GBM) patients (pts) with PTEN loss in the Phase 1 Ice-CAP trial (NCT03673787)
Abstract Text Background PTEN loss of function is frequent in GBM correlating with poor prognosis, impaired antitumor responses and reduced efficacy of Immune Checkpoint Inhibitors (ICI). Ipat is a potent, selective, small-molecule inhibitor of Akt. Ipat efficiently depletes FOXP3+ regulatory T cells from the tumor microenvironment (TME) resulting in increased infiltration of effector T cells in solid tumors (Lopez 2020, AACR). We hypothesize that Akt inhibition in PTEN loss glioblastomas may deplete the TME of suppressive immune cells, and render malignant brain tumors more responsive to ICIs. Methods Relapsed WHO grade IV GBM pts with stable neurological symptoms ≥5 days prior to enrollment, requiring <3mg Dexamethasone were recruited into a dose determination cohort (A2; n=12) and an expansion cohort (B3; n=11) of this early phase, open-label trial studying the combination of Ipat and A. Primary objectives were to determine the safety and tolerability of the combination (A2) and preliminary efficacy (B3). Results 23 recurrent GBM pts (median age 55 yrs (25-71 yrs; 74% male) were enrolled. Median ECOG PS 1. All pts had surgery followed by radical-chemoradiotherapy. Median prior lines of therapy 1 (range 1-4). 15 pts had PTEN loss by IHC (H<30) indicative of biallelic loss of function, 1 had deleterious PTEN mutations detected by next generation sequencing. No DLTs, no significant treatment-related (TR) serious adverse events (SAEs), or immune-related AEs were observed. Most common TR AEs were G1-2 diarrhea (61%), rash (26%) and mucositis (22%). Clinical benefit rate (CR, PR and SD> 6 cycles) in 19 efficacy evaluable pts was 32% (6/19 overall) and 28.6% (4/14) for pts with PTEN loss. Multiplex IHC of archival samples (n=19) showed PTEN loss tumors had significantly greater numbers of CD3+ infiltrating T-lymphocytes within the TME compared to PTEN wild type tumors (median 53.64/mm2 vs 1.94/mm2; p=0.0021). Within the PTEN loss cohort (n=13), pts with clinical benefit had significantly higher baseline number of CD8+ effector T cells as compared to non-responders (median 46.50/mm2 vs 8.21/mm2; p=0.0336). Two pts with PTEN loss proceeded to re-resection on trial. One exceptional responder, a 58yr male refractory to radical chemo-radiotherapy and Bevacizumab had a resection of enhancing disease after 5 cycles that showed >70% depletion of CD4+ T regulatory cells with an increase in CD8+ lymphocyte infiltration and no residual evidence of tumor (pathological CR). In contrast, a non-responding patient who proceeded to debulking surgery had no change in infiltration of CD8+ lymphocytes, but a marked increase (>27-fold) in CD4+ regulatory T cells. Conclusion The RP2D of 400mg Ipa OD + 1200mg A Q3W was well tolerated in GBM pts. Early efficacy signals were detected with PTEN loss being a promising predictive biomarker for response to combination.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN loss glioblastoma predicted - sensitive Atezolizumab + Ipatasertib Phase I Actionable In a Phase I trial (Ice-CAP), the combination of Ipatasertib (GDC-0068) and Tecentriq (atezolizumab) resulted in a clinical benefit rate (CBR) of 32% (6/19) in patients with glioblastoma, and CBR was 28.6% (4/14) in patients with PTEN loss as determined by IHC (H<30) (Cancer Res (2023) 83 (8_Supplement): CT093; NCT03673787). detail...