451MO - Final results of glasdegib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Phase Ib/II GEINO 1602 trial

Background

Hedgehog pathway has been implicated in resistance against anticancer therapies in glioblastoma (GB). A phase I/II trial was developed with glasdegib (GLG), a SMO inhibitor, in patients with recent diagnosis of GB to improve the efficacy of Stupp scheme. A biomarker study is underway.

Methods

These are the final survival results of the GEINOGLAS phase I/II trial presented at ESMO 2023, with longer follow-up. Newly diagnosed GB patients (pts) received GLG with standard STSC, radiotherapy (RT)/ temozolomide (TMZ) followed by maintenance with GLG monotherapy. The recommended phase II dose (RP2D) was established at 75 mg/QD of GLG. The primary objective in phase II was 15m overall survival (OS) rate. The study established a futility threshold of 60% for 15m OS to consider the trial positive; accrual required: 70 evaluable pts in Phase II. Biomarkers of Hedgehog pathway, Sonic Hedgehog signaling molecule, GLI1, SMO and the stem cell marker CD133 have been validated in samples of 65 pts. Translational research will be presented.

Results

Between 2018 and 2021, 79 GB pts were enrolled, and 74 pts received GLG at 75mg/QD. The median age was 55 years (range: 28-78), 54% were male, 43.2% were MGMT methylated. At data cutoff (Feb 2024), 58 (78.4%) pts were dead. The 15m OS rate was 52.1% (95% CI: 41.7-65.2), with a median OS of 15.3 m (95%CI: 14-20). At 2 years, 29.2% of pts were still alive. Risk of death was lower for pts with MGMT methylation (hazard ratio [HR]: 0.38; 95% CI: 0.21-0.67) and complete resection (HR: 0.16; 95% CI: 0.06-0.41) at multivariable analysis. The mPFS was 7.1 m (95% CI: 6.2-8.6). Performance and neurological status were maintained throughout the study. No new safety alerts were reported. Biomarkers are needed to identify those subgroups of patients with longer survival and also to understand the role of the hedgehog pathway and cancer stem cells in this disease.

Conclusions

The addition of GLG to standard STSC was administered safely and showed preliminary efficacy for newly diagnosed GBM, with almost 30% pts still alive at data cutoff despite the futility threshold not being surpassed. Translational research will help to define the molecular traits of long-term survivors.

Clinical trial identification

NCT03466450 / EudraCT 2017-002410-31.

Editorial acknowledgement

We acknowledge MFAR Clinical Research staff for their assistance in the development of this abstract.

Legal entity responsible for the study

Grupo Español de Investigación en NeuroOncología (GEINO).

Funding

Grupo Español de Investigación en NeuroOncología (GEINO) as Sponsor, Pfizer as industry partner.

Disclosure

S. del Barco: Financial Interests, Personal, Other, Breast Cancer: Novartis. J.M. Sepúlveda: Financial Interests, Personal, Speaker, Consultant, Advisor: Cantex Pharma, BMS, GSK, GW Pharma; Financial Interests, Personal, Advisory Board: Servier, Novocure, BMS, MSD, GSK; Financial Interests, Personal, Speaker’s Bureau: Novocure, GSK; Financial Interests, Personal, Project Lead, Experimental treatment in clinical trial: Tilray Pharma, Pfizer. E. Pineda: Financial Interests, Personal, Advisory Role: Novocure, Novartis; Financial Interests, Personal, Speaker’s Bureau: Novocure; Non-Financial Interests, Personal, Leadership Role, President of GEINO (Spanish group of Neuro-Oncology) group.: GEINO; Non-Financial Interests, Personal, Membership or affiliation: EANO, SEOM, GEINO. C. Balana: Financial Interests, Personal, Other, Honoraria as Speaker: Servier; Financial Interests, Personal, Other, DSMB member role of several trials: LAMINARPHARMA; Financial Interests, Personal, Licencing Fees, For the edition of the book: New Insights into Glioblastoma/ Diagnosis, Therapeutics and Theranostics; ISBN :9780323998734: ELSERVIER. M. Martínez-García: Financial Interests, Personal, Advisory Role: Novocure, Boehringer Ingelheim, Eli Lilly, Gilead, Seagen; Financial Interests, Personal, Speaker’s Bureau: Novocure; Financial Interests, Personal, Other, Honoraria: Eli Lilly; Financial Interests, Personal, Other, Honoraria, Travel accommodation expenses: AstraZeneca, Pfizer; Financial Interests, Personal, Other, travel/accommodation expenses: Gilead, Daiichi Sankyo; Financial Interests, Personal, Other, Honoraria (public speaking): Reddy Pharma. R. Gironés: Financial Interests, Personal, Advisory Board: BMS, Ipsen, Janssen; Financial Interests, Personal, Invited Speaker: PFIZER; Financial Interests, Advisory Board: SIOG, SEOM. All other authors have declared no conflicts of interest.