Efficacy

Overall survival (OS)

Adding DAURISMO significantly extended OS1

DAURISMO (glasdegib) + LDAC nearly doubled median OS vs LDAC alone with a median follow-up of approximately 20 months1

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​   *HR based on the Cox proportional hazards model stratified by cytogenetic risk.

​   ​​​​​​​1-sided P value from log-rank test stratified by cytogenetic risk.

​     CI=confidence interval; HR=hazard ratio.

reduction in the risk of death with DAURISMO + LDAC vs LDAC alone​​​​​​​1

Improvement in OS was consistent across prespecified cytogenetic risk groups​​​​​​​2

The probability of survival at 1 year was nearly 40% with DAURISMO + LDAC2

OS at 1 year was a prespecified, exploratory endpoint, but there was no prespecified statistical procedure controlling for type 1 error (false positive) rate.

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OS subgroup analyses

OS exploratory subgroup analysis across a range of patients1

These subgroup analyses were not prespecified and not powered to detect statistical significance. There is a slight imbalance toward good/intermediate-risk cytogenetics in the DAURISMO + LDAC arm versus the LDAC arm.
​​​​​​​
The HRs associated with each of these analyses are unreliable due to the very small sample sizes of each subgroup, and the CIs may not be interpretable. HRs and CIs are provided for transparency. These data could represent chance findings and should be interpreted with caution.

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    The sample sizes for the subgroups of baseline age <65 years old, race other than white, and the prognostic risk factor as favorable were too small (n≤10) for analysis.
The HR values presented were based on the unstratified analysis for all subgroups except for the AML population. Prognostic risk factor (good/intermediate vs poor) from interactive voice response system was used as a stratification factor in the stratified analysis for the AML population.

OS exploratory subgroup analysis in patients with sAML1

 
Analyses of OS in the subgroup of patients with sAML and in age-defined subgroups were post hoc and not powered to detect statistical significance. Small patient numbers and lack of multiplicity adjustments can be a limitation of these analyses.
​​​​​​​
The HRs associated with these analyses are unreliable due to the very small sample size. HRs and CIs are provided for transparency. The estimated median OS results in these exploratory subgroups may be biased due to censoring at the time of the analysis.
 

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  • 51% of patients in the DAURISMO + LDAC arm had sAML2
  • Patients with sAML were allowed 1 prior regimen (eg, azacitidine or decitabine) for the treatment of prior hematologic disease1
  • Approximately 28% of patients with sAML in the DAURISMO + LDAC arm were treated with a prior HMA for MDS1

OS exploratory subgroup analyses in patients ≥75 and <75 years1†

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​   *HR based on the Cox proportional hazards model.1

​   ​​​​​​​All patients in the BRIGHT AML 1003 trial were aged ≥55 years. Patients were eligible for the BRIGHT AML 1003 trial if they met at least 1 of the following criteria, which precluded the use of intensive chemotherapy: (a) aged ≥75 years; (b) severe cardiac disease (LVEF <45%); (c) ECOG PS=2; or (d) creatinine >1.3 mg/dL.1,2

  ​   ELN=European LeukemiaNet.
​​​​​​​

Response assessments

With DAURISMO, more patients achieved a CR​​​​​​​1

 
These analyses were not powered to detect statistical significance. Small patient numbers and lack of multiplicity adjustments can be a limitation of these analyses.

CR is the endpoint based on a patient’s hematologic response that is most associated with clinical benefit in AML.
 

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​   *These data do not include stable disease.

​   ​​​​​​​MR=minor response. Protocol definition: 1) Neutrophils: N/A 2) Platelets: N/A, and 3) Bone marrow blasts: >25% decrease from start.

  ​   CR=complete response; CRi=Morphologic CR with incomplete blood count recovery; MLFS=Morphologic leukemia-free state; PR=partial remission; PRi=Partial remission with incomplete blood count recovery.

  • 15.6% of patients in the DAURISMO + LDAC arm (n=12/77; 95% CI, 8.3-25.6) had SD vs 23.7% in the LDAC-alone arm (n=9/38; 95% CI, 11.4-40.2) as their best response1
  • CR was the most common response with DAURISMO + LDAC (18.2% vs 2.6% with LDAC alone)1

Median OS in patients who did and did not achieve a CR1

Analyses of OS in CR-defined subgroups were not prespecified and not powered to detect statistical significance. Small patient numbers and lack of multiplicity adjustments can be a limitation of these analyses. Response status is not a baseline characteristic and, therefore, not subject to randomization or stratification. These data are subject to length-biased sampling, which may lead to an overestimation of median survival.

  • In the 14 patients who achieved a CR, median OS with DAURISMO + LDAC was 26.8 months (95% CI, 12.3-not reached)1
  • In the 63 patients who did not achieve a CR, median OS with DAURISMO + LDAC was 5.0 months (95% CI, 3.5-9.0)1

Time to response

Most responses with DAURISMO + LDAC occurred within the first 6 months on treatment1

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Analyses were not prespecified and not powered to detect statistical significance. Small patient numbers and lack of multiplicity adjustments can be limitations of these analyses.

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​   *Best individual response included CR, CRi, MLFS, PR, PRi, and MR. SD was excluded.

​   Of the patients who achieved their best individual response at cycle 4 or later, 30% (3/10) achieved CR, 40% (4/10) achieved CRi, 10% (1/10) achieved MLFS, 10% (1/10) achieved PR, and 10% (1/10) achieved PRi.

Of patients (9/32) treated with DAURISMO + LDAC achieved their best individual response* at cycle 6 or later1‡

  • In the DAURISMO + LDAC arm, the median time to best individual response* was 1.9 months (range, 0.6-7.6 months; n=32)1†
  • The median duration of treatment in the DAURISMO + LDAC arm was 2.73 months (range, 0.10-31.93 months; n=84) vs 1.54 months (range, 0.20-7.85 months; n=41) in the LDAC-alone arm2
  • Thirty-two patients (38%) were treated with DAURISMO + LDAC for at least 6 months and 14 patients (17%) were treated for at least 1 year (n=84)2

    ‡Best individual response included CR, CRi, MLFS, PR, PRi, and MR. SD was excluded.

In patients without unacceptable toxicity, treat for a minimum of 6 cycles to allow for clinical reponse2

Transfusion independence

Post hoc analyses of transfusion independence1,2

Analyses were post hoc and not powered to detect statistical significance. Small patient numbers and lack of multiplicity adjustments can be limitations of these analyses.

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​   *Transfusion independence was defined as patients who had ≥8 weeks (56 consecutive days) without any type of transfusion at any point in the study. All other patients were considered transfusion dependent. Transfusion independence was not assessed at baseline.

​   ​​​​​​​This post hoc analysis included all patients who received ≥1 study drug dose (N=110).

Post hoc analyses of exposure-adjusted transfusion rates1,2‡§

Analyses were post hoc and not powered to detect statistical significance. Small patient numbers and lack of multiplicity adjustments can be limitations of these analyses.

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   ‡Exposure-adjusted transfusion rates were calculated as the sum of the number of on-study transfusions/total number of patient-days. Number of on-study transfusions includes transfusions from cycle 1, day 1 to the end of treatment. Total number of patient-days was the sum of the total time on treatment for all patients in each treatment arm.

   §This post hoc analysis included all patients who received ≥1 study drug dose (N=110).

​​​​​​​     PRBC=packed red blood cell.

Transfusion independence is an important clinical consideration for patients with AML who are not candidates for intensive chemotherapy


References:
  1. Data on file. Pfizer Inc., New York, NY.
  2. Wang ES, Heuser M, Montesinos P, et al. Glasdegib with LDAC in newly diagnosed patients with acute myeloid leukemia (AML) unsuitable for intensive chemotherapy: effects on transfusions and marrow recovery vs LDAC alone. Poster PF272 presented at: European Hematology Association 24th Congress; June 13-16, 2019; Amsterdam, the Netherlands.

Efficacy & Safety

  • Study Design
  • Efficacy
  • Safety Profile
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Safety Profile

The safety profile of DAURISMO + LDAC was established in older patients not eligible for intensive chemotherapy

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WARNING: EMBRYO-FETAL TOXICITY: DAURISMO can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. DAURISMO is embryotoxic, fetotoxic, and teratogenic in animals. Conduct pregnancy testing in females of reproductive potential prior to initiation of DAURISMO treatment. Advise females of reproductive potential to use effective contraception during treatment with DAURISMO and for at least 30 days after the last dose. Advise males of the potential risk of DAURISMO exposure through semen and to use condoms with a pregnant partner or a female partner of reproductive potential during treatment with DAURISMO and for at least 30 days after the last dose to avoid potential drug exposure.

Blood Donation: Advise patients not to donate blood or blood products while taking DAURISMO and for at least 30 days after the last dose, because their blood or blood products might be given to a female of reproductive potential.

QTc Interval Prolongation: Patients treated with DAURISMO can develop QTc prolongation and ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia. Of the 98 evaluable patients treated with DAURISMO 100 mg in combination with low-dose cytarabine in the clinical trial, 5% were found to have a QTc interval greater than 500 ms and 4% of patients had an increase from baseline QTc greater than 60 ms. The clinical trial excluded patients with baseline QTc of greater than 470 ms or with a history of long QT syndrome or uncontrolled cardiovascular disease. Monitor electrocardiograms (ECGs) and electrolytes. Concomitant use of DAURISMO with drugs known to prolong the QTc interval and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. In patients with congenital long QT syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring is recommended. Interrupt DAURISMO if QTc interval is >500 ms and discontinue permanently for patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

Adverse Reactions: Most common adverse reactions associated with DAURISMO (incidence ≥20%) were anemia (43%), fatigue (36%), hemorrhage (36%), febrile neutropenia (31%), musculoskeletal pain (30%), edema (30%), thrombocytopenia (30%), nausea (29%), dyspnea (23%), decreased appetite (21%), dysgeusia (21%), mucositis (21%), constipation (20%), and rash (20%).

Drug Interactions: Co-administration with strong CYP3A4 inhibitors increased DAURISMO plasma concentrations, which may increase the risk of adverse reactions including QTc interval prolongation. Consider alternative therapies that are not strong CYP3A4 inhibitors during treatment with DAURISMO and monitor patients for increased risk of adverse reactions including QTc interval prolongation. Strong and moderate CYP3A4 inducers should be avoided due to decreased DAURISMO plasma concentrations, which may reduce efficacy. If concomitant use of moderate CYP3A4 inducers cannot be avoided, increase the DAURISMO dosage to 200 mg once daily (if the patient is taking 100 mg) and 100 mg once daily (if the patient is taking 50 mg) as tolerated. Co-administration of DAURISMO with QTc-prolonging drugs may increase the risk of QTc interval prolongation. Avoid co-administration of QTc-prolonging drugs with DAURISMO or replace with alternative therapies. If co-administration of a QTc-prolonging drug is unavoidable, monitor patients for increased risk of QTc interval prolongation.

Lactation: Because of the potential for serious adverse reactions from DAURISMO in a breastfed child, advise women who are taking DAURISMO not to breastfeed or provide breast milk to infants or children during treatment and for at least 30 days after the last dose.

Renal Impairment: No dosage modification is recommended for patients with mild to severe renal impairment. Monitor patients with severe renal impairment (eGFR 15 to 29 mL/min) for increased risk of adverse reactions, including QTc interval prolongation, due to increased glasdegib concentrations.

DAURISMO is a hedgehog pathway inhibitor indicated, in combination with low-dose cytarabine, for the treatment of newly diagnosed acute myeloid leukemia (AML) in adult patients who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

Indication

DAURISMOTM is a hedgehog pathway inhibitor indicated, in combination with low-dose cytarabine, for the treatment of newly diagnosed acute myeloid leukemia (AML) in adult patients who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.