Glasdegib in combination with temozolomide and radiotherapy in adult patients with newly diagnosed glioblastoma: the phase Ib/II GEINO 1602 trial

Abstract

The hedgehog pathway is implicated in resistance to anticancer therapies in glioblastoma (GB). GEINO1602 (NCT03466450) phase Ib/II study evaluated the safety and efficacy of glasdegib and the Stupp scheme in newly diagnosed GB. Patients received glasdegib with radiotherapy plus concomitant and 6 cycles of adjuvant temozolomide followed by glasdegib monotherapy. The recommended phase 2 dose was 75 mg/day of glasdegib. The primary endpoint was the 15-months overall survival (OS), with a futility threshold of 60% to consider the trial positive; accrual required 70 evaluable patients. 79 patients were enrolled. The 15 m OS rate was 52.1% (95% CI: 41.7-65.2). At 2 years, 29.2% of the patients were still alive. The median progression-free survival (PFS) was 7.1 months (95% CI: 6.2-8.6). Glasdegib plus chemoradiotherapy show preliminary efficacy. Despite not surpassing the futility threshold, 30% lived at the data cutoff. Translational research will help define the molecular traits of long-term survivors.

Fig. 1. Study scheme.

Patient distribution showing the number of patients included in each phase of the trial and according to the glasdegib dose. n refers to patients.

Fig. 2. Overall survival in patients with glioblastoma treated with chemoradiotherapy and glasdegib.

a Kaplan-Meier graph showing overall survival in the treated population. b Kaplan-Meier graph showing overall survival stratified by MGMT promoter methylation status. A Cox hazard model (two sided) was used for statistical comparison between the subgroups (exploratory analysis). The shadowed areas represent the 95% CI. The dotted lines signal the 50% probability of the OS (c) Forest plot showing hazard ratios for death in the analysis of treatment effect in patient subgroups according to baseline characteristics using a Cox hazard model (two sided, exploratory). n indicates the number of patients with events over the total number of patients in each subgroup (N). Whiskers represent 95% CI.

Fig. 3. Progression-free survival in patients with glioblastoma treated with chemoradiotherapy and glasdegib.

a Kaplan-Meier graph showing progression-free survival in the treated population. b Kaplan-Meier graph showing progression-free survival stratified by MGMT promoter methylation status. A Cox hazard model (two sided) was used for the statistical comparison between the subgroups (exploratory analysis). The shadowed areas represent the 95% CI. The dotted lines signal the 50% probability of the PFS. c Forest plot showing hazard ratios for progression or death in the analysis of treatment effect in patient subgroups according to baseline characteristics using a Cox hazard model (two sided, exploratory analysis). n indicates the number of patients with events over the total number of patients in each subgroup (N). Whiskers represent 95% CI.

Fig. 4. Patient cognitive status and corticosteroid requirements.

a Box plots showing the evolution of corticosteroid dependency during the study period. b Barthel index throughout the study period. c Mini-mental index throughout the study period. The box plot shows the median and interquartile ranges 25–75% (box area) and the whiskers represent the 95% CI. The number of patients is depicted below each box. The asterisk indicates time points which showed significant differences from the baseline using the paired Wilcoxon test (two sided); for Barthel maintenance visit 1 (p = 0.03).

Fig. 5. Safety and treatment exposures.

a Most frequent treatment-related adverse events (frequency >5%) in the safety population throughout the study period on the left in red (n = 74) and during the maintenance phase with glasdegib monotherapy on the right in yellow (n = 28). b Treatment duration in the overall population and in patients who discontinued treatment due to toxicity. Each dot represents a patient, and the blue areas along the x axis are proportional to the number of patients with that treatment duration. The gray box plot represents the median and 25–75% interquartile range. The horizontal lines represent 95% CIs. Data is shown for the full dataset for any reason (n = 74 patients) and for the subgroup of 13 patients who discontinued due to toxicity (n = 13). c Pharmacokinetic profile of glasdegib after a course of 14 days of oral administration of 75 mg/day glasdegib in concomitance with 5 mg/m²/day TMZ and 1.8-2 Gy/day RT. The blue line represents the median, and the gray bars represent the standard error for each time point (n = 8 patients).