Daurismo (Glasdegib) Approved, in Combination with Low-Dose Cytarabine, for Newly Diagnosed Acute Myeloid Leukemia in Older Adults or Those Unfit for Intensive Chemotherapy

2019 Fourth Annual Oncology Guide to New FDA Approvals

Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow that is characterized by the production of abnormal myeloblasts, red blood cells, or platelets.1 AML originates in the bone marrow, but it often spreads into the blood and to other parts of the body, including the lymph nodes, liver, spleen, and central nervous system.2

An estimated 19,520 individuals were diagnosed with AML in the United States in 2018.3 AML affects more men than women and is more prevalent in older than in younger people. In fact, AML is diagnosed most frequently in patients aged 65 to 74 years; the median age at diagnosis is 68 years. AML accounted for 10,670 deaths in 2018, representing 1.8% of all cancer deaths.3

The treatment of AML typically includes induction therapy, which aims to reduce the leukemic burden and induce disease remission, and consolidation therapy (or maintenance therapy), which aims to further reduce the leukemic burden and reduce the risk for relapse. The treatments for AML include chemotherapy, targeted therapy, other anticancer drugs, and bone marrow transplantation.4

AML treatment considerations include the patient’s age, AML-related adverse biologic factors (ie, cytogenetic risk status), performance status, and comorbidities.5 Older patients have a higher incidence of secondary AML than younger patients, preceded by myelodysplastic syndrome or chemotherapy, and an increased rate of multidrug resistance proteins.5 Furthermore, patients with AML aged ≥60 years have an increased rate of relapse within 2 to 3 years.6 Nearly 50% of adults with AML are not candidates for intensive chemotherapy because of comorbid conditions and chemotherapy-associated adverse effects.7 Therefore, there is a marked need for AML treatments that address the needs of patients with comorbidities and the needs of older patients who are not candidates for intensive induction chemotherapy.8

FDA Approves Daurismo for Certain Patients with AML

On November 21, 2018, the US Food and Drug Administration (FDA) approved glasdegib (Daurismo; Pfizer), in combination with low-dose cytarabine (LDAC), for the treatment of newly diagnosed AML in adults aged ≥75 years or those who have comorbidities that preclude the use of intensive induction chemotherapy.7,9 The FDA granted glasdegib—a selective, small-molecule, oral hedgehog pathway inhibitor—priority review and orphan drug designation.7

“Intensive chemotherapy is usually used to control AML, but many adults with AML are unable to have intensive chemotherapy because of its toxicities. Today’s approval gives health care providers another tool to use in the treatment of AML patients with various, unique needs,” said Richard Pazdur, MD, Director, FDA’s Oncology Center of Excellence. “Clinical trials showed that overall survival was improved using Daurismo in combination with LDAC compared to LDAC alone for patients who would not tolerate intensive chemotherapy,” added Dr Pazdur.7

Dosing and Administration

Glasdegib is available as a 100-mg tablet and a 25-mg tablet.9

The recommended dosage of glasdegib is 100 mg orally, once daily.9

Mechanism of Action

Glasdegib is a potent hedgehog pathway inhibitor that exerts its action by binding to and blocking Smoothened, which is a transmembrane protein involved in hedgehog signal transduction. In preclinical studies, glasdegib combined with LDAC inhibited ­tumor-size growth and reduced the number of CD45+/CD33+ marrow blasts to a greater extent than either glasdegib alone or LDAC alone.9

Bright AML 1003: Pivotal Clinical Trial

The efficacy and safety of glasdegib in combination with LDAC were assessed in the Bright AML 1003 study, an open-label, randomized phase 2 clinical trial with 115 patients (median age, 77 years).8,9 Eligible patients were aged ≥55 years, had newly diagnosed AML, and met ≥1 of the study criteria, including age ≥75 years; severe cardiac disease; baseline Eastern Cooperative Oncology Group performance status of 2; or baseline serum creatinine >1.3 mg/dL.9

Patients were randomized in a 2:1 ratio to glasdegib 10 mg daily with LDAC 20 mg subcutaneously twice daily on days 1 to 10 of a 28-day cycle, or to LDAC alone in 28-day cycles, until disease progression or until unacceptable toxicity.9

In the glasdegib plus LDAC group, the median age was 77 years, 51% of the patients had secondary AML, 66% had severe cardiac disease, 62% had a good or intermediate cytogenetic risk status, and 38% had a poor cytogenetic risk status. In the LDAC-alone group, the median age was 76 years, 53% of the patients had secondary AML, 53% had severe cardiac disease, 55% had a good or intermediate cytogenetic risk status, and 45% had a poor cytogenetic risk status.9

At a median follow-up of approximately 20 months, glasdegib plus LDAC was superior to LDAC alone, demonstrating a 4-month longer median overall survival and a 15.6% greater complete response rate than LDAC alone (Table).9 The improvements in overall survival with glasdegib plus LDAC were consistent across the prespecified cytogenetic risk subgroups.9

Table

Adverse Reactions

The most common (incidence ≥20%) adverse events associated with glasdegib plus LDAC 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%).9

Serious adverse events were reported in 79% of patients receiving glasdegib plus LDAC; the most common (≥5%) events were febrile neutropenia (29%), pneumonia (23%), hemorrhage (12%), anemia (7%), and sepsis (7%). Overall, 36% of patients had side effects that led to permanent treatment discontinuation; the most common of those events were pneumonia (6%), febrile neutropenia (4%), sepsis (4%), sudden death (2%), myocardial infarction (2%), nausea (2%), and renal insufficiency (2%).9

Glasdegib has no contraindications.9

Drug Interactions

The coadministration of glasdegib with strong cytochrome (CY) P3A inhibitors increased glasdegib plasma concentrations, which may increase the risk for adverse events, including corrected QT (QTc) interval prolongation.9

The coadministration of glasdegib with strong CYP3A inducers decreased glasdegib plasma concentrations; glasdegib should not be coadministered with strong CYP3A inducers.9

The coadministration of glasdegib with QTc-prolonging drugs may increase the risk for QTc interval prolongation; glasdegib should not be coadministered with QTc-prolonging drugs, or alternative therapies should be considered. If the coadministration of glasdegib with a QTc-prolonging drug is unavoidable, patients should be monitored for QTc interval prolongation.9

Use in Specific Populations

Glasdegib can cause fetal harm when used by a pregnant woman and is not recommended during pregnancy.9

There are no data on the effect of glasdegib on human milk production or on the breastfed child. Because of the potential risk for serious adverse reactions in the breastfed child, women should not breastfeed infants during treatment with glasdegib and for at least 30 days after the last dose.9

Data on the use of glasdegib in patients aged ≥65 years are insufficient to determine whether these patients respond differently from patients aged ≤65 years.9

Warnings and Precautions

The prescribing information for glasdegib includes a boxed warning about the risk for embryo-fetal death or severe birth defects when glasdegib is used by a pregnant woman. Before initiating glasdegib treatment in women of reproductive potential, a pregnancy test should be conducted; these women should use effective contraception during glasdegib treatment and for at least 30 days after the last dose of glasdegib. Men should use effective contraception, including a condom, to prevent drug exposure through semen to a pregnant partner or to a partner of reproductive potential during glasdegib treatment and for at least 30 days after the last dose.9

In addition, men should not donate semen during glasdegib treatment and for at least 30 days after the last dose.9

Patients should not donate blood or blood products during treatment with glasdegib and for at least 30 days after the last dose of glasdegib.9

Patients receiving glasdegib can have QTc prolongation, including ventricular tachycardia and ventricular fibrillation. If QTc prolongation occurs, glasdegib treatment should be interrupted.9

Conclusion

The FDA approval of glasdegib, for use in combination with LDAC, provides a new oral treatment option for newly diagnosed AML in older patients and for those with comorbidities who are not candidates for intensive induction chemotherapy. At a median follow-up of approximately 20 months, glasdegib plus LDAC demonstrated improvements in overall survival and complete response rates compared with LDAC alone.


References

  1. National Cancer Institute. Adult acute myeloid leukemia treatment (PDQ)–patient version. Updated October 19, 2018. www.cancer.gov/types/leukemia/patient/adult-aml-treatment-pdq#_1. Accessed February 27, 2019.
  2. American Cancer Society. What is acute myeloid leukemia (AML)? Revised August 21, 2018. www.cancer.org/cancer/acute-myeloid-leukemia/about/what-is-aml.html. Accessed February 28, 2019.
  3. National Cancer Institute. SEER cancer stat facts: leukemia – acute myeloid leukemia (AML). https://seer.cancer.gov/statfacts/html/amyl.html. Accessed February 27, 2019.
  4. Mayo Clinic. Acute myelogenous leukemia: diagnosis & treatment. December 27, 2017. www.mayoclinic.org/diseases-conditions/acute-myelogenous-leukemia/diagnosis-treatment/drc-20369115. Accessed February 28, 2019.
  5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Acute Myeloid Leukemia. Version 1.2019. January 18, 2019. www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed March 5, 2019.
  6. Burnett A, Wetzler M, Löwenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29:487-494. Erratum in: J Clin Oncol. 2011;29:2293.
  7. US Food and Drug Administration. FDA approves new treatment for patients with acute myeloid leukemia. November 21, 2018. www.fda.gov/newsevents/newsroom/pressannouncements/ucm626443.htm. Accessed February 25, 2019.
  8. Cortes JE, Heidel FH, Hellmann A, et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019;33:379-389.
  9. Daurismo (glasdegib) tablets, for oral use [prescribing information]. New York, NY: Pfizer; December 2018.

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