Glasdegib receives approval from the European Commission for the treatment of adult patients with newly diagnosed AML

On June 30, 2020, the European Commission approved glasdegib, an oral smoothened inhibitor, in combination with low-dose cytarabine (LDAC) for the treatment of newly diagnosed de novo or secondary acute myeloid leukemia (AML) in patients ineligible for standard chemotherapy. This approval follows the positive opinion received from the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use and the approval by the U.S. Food and Drug Administration (FDA). The European Commission’s approval was based on the results from the phase II BRIGHT 1003 trial (NCT01546038).¹ Follow-up data and 4-year overall survival from this trial were recently presented as an e-poster at the 25th European Hematology Association Annual Congress.

Study design^1–3

• Randomized, open-label phase II trial in patients with previously untreated de novo or secondary AML who were not eligible to receive intensive chemotherapy
• 116 patients with AML were randomized 2:1 to receive glasdegib + LDAC (n = 78) or LDAC alone (n = 38)
• Glasdegib was administered at 100 mg, once daily, continuously for 28 days
• LDAC was administered at 20 mg/m², twice daily, on Days 1–10 of a 28-day cycle
• Outcome measures: Overall survival (OS), complete response (CR), tolerability, and toxicities

Results^1,3

• Treatment with glasdegib approximately doubled the median OS compared with LDAC alone (8.3 vs 4.3 months, respectively; HR, 0.53; 95% CI, 0.35–0.80; p = 0.002)
  • This trend was also true whether patients had de novo AML (6.6 vs 4.3 months, respectively; HR, 0.75; 95% CI, 0.41–1.36; p = 0.337) or secondary AML (9.1 vs 4.1 months, respectively; HR, 0.29; 95% CI, 0.15–0.55; p < 0.001) and across subgroups of cytogenetic risk
• Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were higher in the glasdegib + LDAC cohort vs the LDAC alone cohort (22.4% vs 5.3%, respectively)
  • The median time to CR/CRi in the respective cohorts was 60 days vs 162 days
• The most frequently reported adverse events in patients receiving glasdegib can be seen in Table 1
  • Those that led to dose reductions included muscle spasms (4.7%), fatigue (3.5%), febrile neutropenia (3.5%), anemia (2.3%), thrombocytopenia (2.3%), and prolonged QT electrocardiogram (2.3%)
  • Those that led to permanent discontinuation included pneumonia (5.9%), febrile neutropenia (3.5%), and nausea (2.3%)

 Table 1. Most frequently reported hematological and non-hematological adverse events in patients receiving glasdegib

Adverse event	% of patients (n = 78)
Hematological
Anemia	45.2
Hemorrhages	45.2
Febrile neutropenia	35.7
Thrombocytopenia	30.9
Non-hematological
Nausea	35.7
Decreased appetite	33.3
Fatigue	30.9
Muscle spasms	30.9
Pyrexia	29.7
Diarrhea	28.5
Pneumonia	28.5
Dysgeusia	26.1
Peripheral edema	26.1
Constipation	25.0
Abdominal pain	25.0
Rash	25.0
Dyspnea	25.0
Vomiting	21.4
Decreased weight	20.2

 

Glasdegib is currently being assessed in the phase III BRIGHT AML1019 trial (NCT03416179) in combination with intensive chemotherapy or in combination with azacitidine in patients with previously untreated AML.⁴