501O - Glasdegib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Phase Ib/II GEINO 1602 trial

Background

Glioblastoma (GB) resistance against anticancer therapies is enhanced by Smoothened (SMO) signaling. Glasdegib (GLG), a SMO inhibitor, may lead to improved efficacy of the Stupp scheme.

Methods

Newly diagnosed GB patients (pts) received GLG with standard radiotherapy (RT)/ temozolomide (TMZ) followed by maintenance with GLG monotherapy. The study was carried out in two phases. In phase Ib the primary objective was the recommended phase 2 dose (RP2D) in a 3+3 dose escalation strategy. The dose of 75 mg/QD of GLG was declared the RP2D. The primary objective in phase II was 15-m overall survival (OS) rate. The study established a futility threshold of 60% for 15-m OS to consider the trial positive; accrual required: 70 evaluable pts in phase II. Secondary objectives included progression-free survival (PFS) according to RANO criteria, safety, changes in performance status, pharmacokinetic and exploratory biomarker analysis.

Results

Between 2018 and 2020, 79 GB pts were enrolled, and 74 (98.7%) pts received GLG at 75mg/QD. The median age was 55 years (range: 28-78), 54% were male, 58.1% were ECOG 1, 39.2% were MGMT methylated, and 1 pts had an IDH1/2 mutation. Complete surgical resection was achieved in 35 (47.3%) pts. GLG treatment lasted a median of 6.9 m (range 0.7-24). 68 (91.9%) finalized concomitant period with RT/TMZ, 64 (86.5%) started adjuvant therapy with TMZ, 33 (51.6%) finalized adjuvant period, and 28 (37.8%) continued GLG monotherapy. 53 pts (71.6%) presented stable disease. After a median follow up of 14.8 m (range 0.7-36.4), mPFS was 7 m (95% CI: 6.1-8.6), and the 12-m PFS rate was 22.2% (95% CI: 14.4-34.2). The mPFS based on MGMT status was 8.4 m (95% CI: 6.5-16.9) and 7.3 m (95% CI: 4.9-9.1) for MGMT methylated and unmethylated respectively (p= 0.044). The mOS was 15.3 m (95% CI: 14-21.2). At data cut-off, 22 (29.7%) pts alive. The mOS was 25.6 m (95% CI: 16-NR) and 14.3 m (95% CI: 11.7-19) for MGMT methylated and unmethylated respectively (p= 0.005).

Conclusions

The addition of GLG to standard RT and TMZ showed preliminary efficacy for newly diagnosed GBM, with almost 30% pts still alive at data cutoff. Long-term survival will be updated. No new safety alerts were reported.

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

Disclosure

J.M. Sepúlveda: Financial Interests, Personal, Advisory Board: Cantex, CeCaVa, MSD, Novocure; Financial Interests, Personal, Invited Speaker: GSK; Non-Financial Interests, Personal and Institutional, Research Grant: Cantex, Pfizer. M. Martínez-García: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Novocure, Pierre Fabre, Seagen, Takeda; Financial Interests, Personal, Other, Travel, Accomodation, Expenses: Daiichi Sankyo, AstraZeneca, Gilead, Pfizer; Non-Financial Interests, Personal, Principal Investigator, Clinical Trials: Bristol Myers Squibb, Gelgene, Cantargia; Non-Financial Interests, Personal, Leadership Role, Member of the board: Geino; Non-Financial Interests, Personal, Principal Investigator, Clinical trial: Incyte, Laminar Pharma, Roche. R. Gironés: Financial Interests, Personal, Speaker, Consultant, Advisor: Bristol Myers Squibb, Astellas, Janssen, Pfizer, Merck; Financial Interests, Personal, Advisory Board: Ipsen, Novocure; Financial Interests, Personal, Other, Travel: MSD. All other authors have declared no conflicts of interest.