AML-043: Glasdegib Plus Low-Dose Cytarabine in Acute Myeloid Leukemia or Myelodysplastic Syndrome: BRIGHT AML 1003 Final Report and 4-Year Overall Survival Follow-Up

Abstract

Context In newly diagnosed AML or high-risk MDS, the randomized phase 2 BRIGHT AML 1003 ( NCT01546038 ) primary analysis showed superior overall survival (OS) for glasdegib (GLAS) + low-dose cytarabine (LDAC) vs LDAC-alone. After the primary cutoff, the trial continued to predefined completion 4 years from randomization of all patients. Objective To assess outcomes at study completion (data cutoff April 2019). Design Beginning January 2014, patients with newly diagnosed AML or high-risk MDS and unsuitable for intensive chemotherapy were randomized 2:1 to open-label GLAS+LDAC or LDAC-alone. Setting Multicenter study at centers in Europe and North America. Patients For the randomized groups (88 GLAS+LDAC vs 44 LDAC-alone), median (range) treatment duration was 83 (3-1575) and 47 (6-239) days; 4/88 vs 1/44 completed ≥4 years' follow-up, and median follow-up was >45 months for both groups. Interventions Glasdegib 100-mg QD; LDAC 20-mg BID×10 days q28 days. Main outcome measures The prespecified primary endpoint was OS (Jan 2017 cutoff: HR 0.51; 80%CI 0.39-0.67 p=0.0004). We compared OS, complete remission (CR), and safety at the final data cutoff. Results Consistent with the primary findings, GLAS+LDAC prolonged OS vs LDAC-alone in the overall ITT population (median OS 8.8 [95%CI 5.0-11.7] vs 4.9 months [2.9-6.5] HR 0.53 [95%CI 0.35-0.80] p=0.001). Results were consistent in patients with AML (HR 0.53 [95%CI 0.35-0.80] p=0.001). Similarly, OS results were consistent for subgroups by cytogenetic risk, patient characteristics, and de novo/secondary AML. GLAS+LDAC induced higher CR rates in the ITT population (16/88 vs 1/44; RR 8.12, 95%CI 1.05-62.78, p=0.010) and across subgroups. Notably, fewer patients discontinued GLAS+LDAC due to AEs (38.1% and 46.3%) and there was no increased sepsis or bleeding vs LDAC-alone despite longer glasdegib treatment. With GLAS+LDAC, SMO-inhibitor-associated AEs included dysgeusia (25.0%), muscle spasms (22.6%), and alopecia (10.7%), with only 1 patient discontinuing due to dysgeusia. Conclusions This BRIGHT AML 1003 analysis showed primary results were maintained after >20 months' additional follow-up. Consistent with primary analyses, GLAS+LDAC continued to have an acceptable safety profile and improved OS vs LDAC-alone. HRs were consistent across cytogenetic risk subgroups and support use of GLAS+LDAC in de novo and secondary AML. Study sponsor Pfizer.