An evaluation of overall survival in patients with newly diagnosed acute myeloid leukemia and the relationship with glasdegib treatment and exposure

Abstract

Purpose: Glasdegib, an oral inhibitor of the Hedgehog signaling pathway, is approved in the United States in combination with low-dose cytarabine (LDAC) to treat patients with newly diagnosed acute myeloid leukemia (AML) ineligible to receive intensive chemotherapy. This population pharmacokinetic/pharmacodynamic analysis characterized the time course of survival with glasdegib + LDAC relative to LDAC alone, and explored whether the differences in glasdegib exposure at the clinical dose of 100 mg once daily (QD) significantly affected overall survival (OS).

Methods: Data from the BRIGHT AML 1003 trial in patients with AML were included in treatment-response (glasdegib + LDAC, n = 78; LDAC alone, n = 38) and exposure-response (glasdegib + LDAC, n = 75) analyses.

Results: The analyses demonstrate that patients treated with glasdegib + LDAC (vs LDAC alone) at any time point during the study period were 58% less likely to die, translating to prolonging of median OS by ~ 5 months (hazard ratio 0.42 [95% confidence interval 0.28-0.66]). Variability in glasdegib exposures did not impact the risk of death. Additionally, potential covariates such as patient demographics, prior treatment with a hypomethylating agent, baseline safety laboratory values, and disease characteristics, did not impact the probability of OS.

Conclusion: Together these results confirm that glasdegib + LDAC treatment (vs. LDAC alone) is associated with a significant survival benefit in patients with newly diagnosed AML, and that variability in glasdegib doses (e.g., for dose reductions) and exposures do not compromise the survival benefit of glasdegib 100 mg QD.

Clinical trial number: NCT01546038.

Keywords: Acute myeloid leukemia; Exposure–response; Hedgehog; Overall survival; Smoothened inhibitor.

Conflict of interest statement

SL, NS, and GC are employees of Pfizer. AR-G was a former Pfizer employee. JEC received research funding to his institution and consulting honoraria from Pfizer, Novartis, Astellas, Daiichi Sankyo, Jazz Pharmaceuticals, Takeda, and Celgene.

Figures

Fig. 1

Treatment–response analysis of overall survival. The black dotted lines represent the survival functions, S(t) a from the base and b in final models with the 95% confidence interval of the predicted survival function in the shaded area by treatment arm. The solid lines are the observed OS data from the glasdegib + LDAC (pink) and LDAC alone (blue) treatment arms. KMMC plots for treatment arm for c the base and d final models. With the inclusion of treatment arm as a covariate in the final model, the KMMC plot was corrected. KMMC Kaplan–Meier mean covariate, LDAC low-dose cytarabine, OS overall survival, S(t) probability of survival, Tx treatment arm

Fig. 2

Kaplan–Meier plots for overall survival by a quartiles of cycle 1 glasdegib Cmin and b quartiles of mean glasdegib daily dose (mg) over the treatment duration. CminQ minimum concentration quartile, MGDQ mean glasdegib dose quartile, OS overall survival

Fig. 3

Exposure–response analysis of overall survival. The black dotted line represents the survival function, S(t) from the final model, with the 95% confidence interval of the predicted survival function in the shaded area. The solid line is the observed OS data from the exposure–response analysis data set. OS overall survival, S(t) probability of survival

Fig. 4

Exploratory treatment–response analysis including glasdegib + decitabine treatment. The black dotted lines represent the survival functions, S(t) from the exploratory treatment–response final model with the 95% confidence interval of the predicted survival function in the shaded area by treatment arm. The solid lines are the observed OS data from the glasdegib + decitabine (pink), glasdegib + LDAC (green), and LDAC alone (blue) treatment arms. LDAC low-dose cytarabine, OS overall survival, S(t) probability of survival