Activation of the Hedgehog signalling pathway is associated with the development and progression of acute myeloid leukaemia (AML). The phase 3 BRIGHT AML 1019 study evaluated the efficacy and safety of glasdegib, a potent inhibitor of the Hedgehog signalling pathway, in combination with intensive or non-intensive chemotherapy in patients with untreated AML. Unfortunately, the addition of glasdegib did not improve overall survival. However, this trial confirmed the acceptable safety profile of glasdegib and did not reveal any new safety concerns.
Acute myeloid leukaemia (AML) is an aggressive haematologic malignancy that is most commonly diagnosed in patients aged 65-74 years. Despite recent treatment advances y, survival rates in patients with AML remain low (5-year overall survival [OS] <40%). These patients receive intensive or non-intensive therapy depending on different factors, including age, comorbidities or regional availability of drugs. Activation of the Hedgehog signalling pathway is associated with the development and progression of solid and haematologic malignancies, including AML. The phase 3 BRIGHT AML 1019 trial evaluated the efficacy and safety of glasdegib, a potent inhibitor of the Hedgehog signalling pathway, in combination with intensive chemotherapy (cytarabine and daunorubicin) or non-intensive chemotherapy (azacitidine) in patients with untreated AML. This article reports the primary results of this trial.
BRIGHT AML 1019 comprised two global, double-blind, phase 3 studies, including an intensive and a non-intensive study. Eligible patients included adults with untreated AML and with adequate organ function and QTc interval ≤470 ms. All anti-cancer treatments had to be discontinued ≥2 weeks from study entry. In both studies, patients were randomly assigned (1:1) to receive either glasdegib 100 mg once daily or placebo, combined with cytarabine and daunorubicin in the intensive study, and with azacitidine in the non-intensive one. The primary endpoint of both studies was OS. Secondary efficacy endpoints included response rates and time-to-treatment response (non-intensive study only).
A total of 721 patients received treatment either in the intensive (n=399) or non-intensive study (n=322). In the intensive study, similar percentages of patients in the glasdegib and placebo arms achieved complete response (CR, 49.3% vs. 47.3%, respectively), CR with incomplete count recovery (CRi, 1.5% vs. 5.4%), CR and negative minimal residual disease (CRMRD-neg, 5.0% vs. 5.4%), or partial response (PR, 5.0% vs. 4.4%). Additionally, the incidence of progressive disease was similar between the arms (7.5% vs. 7.4%). After a median follow-up of around 12 months, no significant differences in OS were observed between the two groups (HR[95%CI]: 1.05 [0.782-1.408]; p = 0.749). However, OS was improved in the placebo arm in patients with intermediate European LeukemiaNet (ELN) risk (HR[95%CI]: 1.78 [1.041-3.045]; p = 0.033) and Asian patients (HR[95%CI]: 2.74 [1.365–5.509]; p = 0.003).
In the non-intensive study, CR was achieved by 19.6% of patients in the glasdegib arm and 13.0% in the placebo arm. Few patients in the glasdegib arm achieved CRMRD-neg (1.8% vs. 0.6% in the placebo arm), CRi (2.5% vs. 0.6%), or CRh (3.1% vs. 3.1%). The incidence of progressive disease was similar between arms (5.5% vs. 7.4%). After a median follow-up of around 10 months, OS was similar between the arms (HR[95%CI]: 0.99 [0.768-1.289]; p = 0.969) and no differences were observed across the different subgroups.
The proportion of patients experiencing treatment-emergent adverse events (TEAEs) was comparable between the glasdegib and placebo groups in both the intensive and non-intensive studies (intensive: 99.0% vs. 98.5%; non-intensive: 99.4% vs. 98.8%, in the glasdegib and placebo groups, respectively). The most common TEAEs were nausea, febrile neutropenia, and anaemia in the intensive study, and anaemia, constipation, and nausea in the non-intensive study.
In conclusion, the addition of glasdegib to either cytarabine and daunorubicin or azacitidine therapy did not significantly improve OS, and the primary endpoint for the BRIGHT AML 1019 phase 3 trial was not met. These results contrast with previously favourable outcomes observed with glasdegib in combination with low-dose cytarabine compared to low-dose cytarabine alone. Nonetheless, this trial confirmed the acceptable safety profile of glasdegib and did not reveal any new safety concerns.
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