TY - JOUR
T1 - An evaluation of overall survival in patients with newly diagnosed acute myeloid leukemia and the relationship with glasdegib treatment and exposure
AU - Lin, Swan
AU - Shaik, Naveed
AU - Chan, Geoffrey
AU - Cortes, Jorge E.
AU - Ruiz-Garcia, Ana
N1 - Funding Information:
The authors would like to thank all patients who participated in the trial and medical staff of participating centers. Medical writing support was provided by Gemma Shay, PhD, of Engage Scientific Solutions, and was funded by Pfizer.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
KW - Acute myeloid leukemia
KW - Exposure–response
KW - Hedgehog
KW - Overall survival
KW - Smoothened inhibitor
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U2 - 10.1007/s00280-020-04132-x
DO - 10.1007/s00280-020-04132-x
M3 - Article
C2 - 32885274
AN - SCOPUS:85090227366
SN - 0344-5704
VL - 86
SP - 451
EP - 459
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 4
ER -