Safety and efficacy of glasdegib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Phase Ib/II GEINO 1602 trial.

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2060 Background: Hedgehog signaling through Smoothened (SMO) protein in gliomas promotes cell cycle progression and leads to glioma stem cells (GSCs) maintenance, which constitutes one of the key hallmarks for glioblastoma (GB) resistance against anticancer therapies. Glasdegib, a SMO inhibitor, may disrupt GSCs and lead to enhanced efficacy of the Stupp scheme. Methods: Newly diagnosed GB pts received glasdegib with standard radiotherapy (RT)/ temozolomide (TMZ) followed by maintenance with glasdegib monotherapy. The primary objective was to determine the recommended phase 2 dose (RP2D) in a 3+3 dose escalation (DE) strategy in phase Ib and overall survival (OS) in phase II. Secondary objectives included progression-free (PFS) according to RANO criteria, safety, changes in performance status, and exploratory biomarker analysis. Results: Between 2018 and 2020, 79 GB pts were enrolled and 78 received at least one dose of glasdegib. In DE, 4 pts received Glasdegib at 100 mg/QD and 6 pts received 75 mg/QD. DLTs were reported in 3/4 pts in 100 mg dose level, and 1/6 pts in 75 mg dose level, declaring 75 mg/QD of glasdegib as RP2D. For phase II, 68 additional pts were treated at 75 mg/QD dose. The median age was 55 years (range: 28-78), 54% were male, 45% were MGMT unmethylated, and 1 pts had an IDH1/2 mutation. Glasdegib treatment lasted a median of 6 m (range: 0.5-21.9). Overall, 72 (97.3%) pts completed concomitant therapy, 65 (87.8%) started adjuvant therapy, 28 (37.8%) completed adjuvant therapy, and 23 (31.1%) continued glasdegib monotherapy. Treatment combination was discontinued due to treatment-related adverse events (TRAEs) in 9 (12.2%) pts. For those pts that received RT/TMZ combined with glasdegib at 75 mg/QD dose, 7 (9.5%) presented grade (G) ≥3 hematological TRAEs during concomitant treatment and 2 (3.1%) during the adjuvant treatment. There were no G≥3 TRAEs of any type during the maintenance phase. Neutrophil count decrease G≥3 was reported in 6 (8.1%) pts and platelet count decrease G≥3 in 7 (9.5%) pts. Cutaneous events G≥3 were reported in 3 (4.1%) pts. ECOG, Minimental and Barthel indexes, were maintained when comparing baseline with end of treatment (p = 0.181, 0.25 and 0.346 respectively). Stabilization was the most common response, reported in 60 (81.1%) pts. After a median follow up of 7.8 m (range 0.7-25.9), median PFS was 6.9 m (95% CI: 6.1-8.5). The 6-m PFS rate was 62.1% (95% CI: 50.9-75.8) and the 18 m OS rate was 63.3% (95% CI: 47.5-84.4). Conclusions: The addition of glasdegib to standard RT and TMZ was safe. Glasdegib monotherapy showed no G ≥3 TRAEs. Most patients had disease stabilization, with a promising preliminary PFS and OS for newly diagnosed GBM. Final survival results are awaited. Clinical trial information: NCT03466450.