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

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. 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. 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). 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.