Expert Review: DAURISMO™ (glasdegib) for the Treatment of Adults With Newly Diagnosed Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy Clinical Synopsis For many years, nonintensive acute myeloid leukemia (AML) treatment options have been limited to single-agent low-dose cytarabine (LDAC) or hypomethylating agent (HMA) therapy.1 The emergence of targeted agents and combination approaches has the potential to improve outcomes for patients ineligible for intensive chemotherapy.2-4 The Hedgehog (Hh) pathway, implicated preclinically in the maintenance of leukemic stem cells (LSCs), has emerged as a promising therapeutic target in AML.5 In November 2018, the Hh pathway inhibitor glasdegib, in combination with LDAC, received US Food and Drug Administration (FDA) approval for the JORGE E. CORTES, MD treatment of newly diagnosed AML in adult patients aged ≥ 75 years or who have comorbidities that preclude the use of intensive induction chemotherapy.4 In a randomized trial, glasdegib combined with LDAC demonstrated superior overall survival (OS) compared with LDAC alone, significantly extending median OS (8.3 versus 4.3 months; hazard ratio [HR] = 0.46 [95% confidence interval {CI}, 0.30-0.71], P = 0.0002).4 Serious adverse reactions (ARs) were reported in 79% of patients who received glasdegib plus LDAC compared with 78% of patients who received LDAC alone, and dose reductions associated with ARs in the glasdegib plus LDAC arm were reported in 26% of patients.4,6 With the emergence of new therapies, including mutation-targeted agents,7 the AML treatment landscape is becoming increasingly complex, placing greater importance on a detailed patient workup to guide personalized treatment decisions. Appropriate candidates for nonintensive treatment may be selected based on many criteria, such as age ≥ 75 years and specific comorbidities.8,9 Furthermore, patient choice and personal circumstance inform treatment decisions in the nonintensive setting. Glasdegib tablets plus subcutaneous LDAC can be administered at home, thereby providing a therapeutic option for patients who do not wish to be treated in an inpatient or clinic setting. Glasdegib in combination with LDAC is a category 2A treatment option in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for certain adults with newly diagnosed AML who are not candidates for or decline intensive induction therapy.10 Pfizer developed this manuscript in conjunction with Dr Cortes. The discussion of glasdegib plus LDAC administration in clinical practice, therapy management, and patient cases reflects Dr Cortes’ opinion on AML management in these specific situations. SELECTED SAFETY INFORMATION 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. Please see additional Important Safety Information on page 11 and full Prescribing Information, including BOXED WARNING and Medication Guide, here. 1 EXPERT REVIEW The Hh pathway plays a role in maintaining LSC quiescence and self-renewal.5,25-27 These key Part 1. Introduction characteristics of LSCs are theorized to contribute to chemoresistance and disease relapse.5,27-29 AML is most frequently diagnosed among older Preclinical data suggest that glasdegib inhibits patients (median age 68 years).11 Advanced age is Smoothened, a transmembrane protein involved a predictor of poor outcomes,12 and Surveillance, in Hh signal transduction, and may contribute to Epidemiology, and End Results (SEER) data from the chemosensitization of LSCs by blocking LSC 2009-2015 indicate that patients aged ≥ 65 years quiescence.5,26 In a preclinical model of human AML, have a 5-year relative survival rate of 7.9%.13 glasdegib plus LDAC inhibited tumor growth and It has been reported that of AML patients who receive reduced the percentage of AML blasts in the bone front-line induction therapy, approximately 40% do not marrow (BM) to a greater extent than glasdegib or 14 receive intensive chemotherapy. Selecting treatments LDAC alone.4 These results suggest that the 2 agents for older adults involves consideration of performance work synergistically, with glasdegib sensitizing status, comorbid conditions, cytogenetic and molecular dormant LSCs to the chemotherapeutic effects 15 profiles, and history of antecedent hematologic of LDAC.4,26 It is important to note that preclinical 16 disorder (AHD), as well as patient choice, personal and in vitro data may not necessarily correlate with circumstance, and the balance between disease clinical outcomes. control and quality of life (QoL).12,17 New therapies for older patients remain a significant BRIGHT AML 1003 Trial 12,16,18 unmet need. Until recently, treatment options for Trial Design patients who decline or are ineligible for intensive The BRIGHT AML 1003 trial was an open-label, chemotherapy have been limited to HMAs, such as multicenter, Phase II trial that evaluated the safety decitabine or azacitidine, or LDAC.1 Since 2017, 8 and efficacy of glasdegib in combination with LDAC. therapeutic agents have been approved by the FDA The trial enrolled 115 patients aged ≥ 55 years with for the treatment of AML, but only 3 are indicated newly diagnosed de novo AML or secondary acute for this underserved population.2-4,19-23 DAURISMO myeloid leukemia (sAML) who were not eligible for (glasdegib) and venetoclax were approved in intensive chemotherapy.4 sAML was defined in the trial November 2018 and ivosidenib was approved in as AML evolving from myelodysplastic syndrome May 2019 for IDH1-mutated cases.2-4 (MDS) or another AHD and AML occurring after previous cytotoxic therapy or radiation.6 Part 2. Glasdegib Mechanism of Action Patients were required to meet at least 1 of the and Clinical Data following criteria demonstrating ineligibility for intensive chemotherapy: age ≥ 75 years, severe Mechanism of Action baseline cardiac disease (left ventricular ejection Glasdegib is a Hh pathway inhibitor that is indicated, fraction [LVEF] < 45%), baseline Eastern Cooperative in combination with LDAC, for the treatment of newly Oncology Group performance status (ECOG PS) of 2, diagnosed AML in adult patients who are ≥ 75 years or baseline serum creatinine > 1.3 mg/dL.4,6 Patients old or who have comorbidities that preclude the use were stratified by cytogenetic risk (good/intermediate of intensive induction chemotherapy.4 The Hh signaling or poor) and randomized (2:1) to receive glasdegib pathway regulates self-renewal and differentiation of plus LDAC (n = 77) or LDAC alone (n = 38) until cells. It is highly active during embryogenesis, during disease progression or unacceptable toxicity.4 In each which it guides organ and tissue development. In 28-day cycle, glasdegib 100 mg was administered adults, the role of Hh signaling is limited to germ cell orally once daily on days 1-28 and LDAC 20 mg was maturation in the reproductive system.24,25 Preclinical administered subcutaneously twice daily on days 1-10.4 research has suggested that inappropriate activation The primary endpoint was OS and key secondary of the Hh pathway is associated with a variety of endpoints included response assessments.6 cancers, including AML.25,26 SELECTED SAFETY INFORMATION 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