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Myelodysplastic Syndromes: Decitabine/Cedazuridine Approved

Myelodysplastic syndrome cells.

The FDA has approved oral decitabine/cedazuridine (Inqovi®, Astex Pharmaceuticals, Inc.) for the treatment of adult patients with either newly diagnosed or previously treated de novo or secondary myelodysplastic syndrome (MDS) whose disease is classified as one of the following French-American-British subtypes: refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, or chronic myelomonocytic leukemia (CMML). Decitabine/cedazuridine is indicated for patients with intermediate-1, intermediate-2, or high-risk disease according to the International Prognostic Scoring System (IPSS).

The approval was based on two randomized clinical trials. ASTX727-01-B (NCT02103478), a phase 2 trial, enrolled 80 adults with intermediate-1, intermediate-2, or high-risk MDS or CMML. ASTX727-02 (NCT03306264), a phase 3 trial, enrolled 133 adults with intermediate-1, intermediate-2, or high-risk MDS, including all disease subtypes, or CMML. Patients in both trials were randomized in a 1:1 ratio to receive 35 mg oral decitabine in combination with 100 mg oral cedazuridine in Cycle 1 followed by 20 mg/m2 intravenous decitabine in cycle 2, or the reverse sequence. Both treatments were administered once daily on the first five days of each 28-day cycle. All patients received oral decitabine/cedazuridine once daily on Days 1 through 5 of Cycle 3 and subsequent cycles until disease progression or unacceptable toxicity. Upon ending treatment, 15% of patients in ASTX727-01-B and 20% of patients in ASTX727-02 underwent stem cell transplantation.

At a median follow-up of 24 months, oral decitabine/cedazuridine produced a complete response rate of 18% in ASTX727-01-B, with a median time to complete response of 4.8 months. The median treatment duration and median duration of complete response were 6.6 months and 8.7 months, respectively. During any consecutive 56-day period after baseline, red blood cell (RBC) and/or platelet transfusion independence was experienced by 49% of the 41 patients who were transfusion-dependent at the beginning of treatment. Among 39 patients who were independent of transfusions at baseline, continued transfusion independence was seen in 64% of patients during any consecutive 56-day period after baseline.

At a median follow-up of 12.6 months, oral decitabine/cedazuridine produced a complete response of 21% in ASTX727-02, with a median time to complete response of 4.3 months. The median treatment duration was 8.2 months, with a median complete response duration of 7.5 months. During any consecutive 56-day period after baseline, 53% of 57 patients previously dependent on RBC or platelet transfusion achieved transfusion independence. Among 76 patients who were transfusion independent as baseline, 63% retained transfusion independence during any 56-day post-baseline period.

Adverse events experienced by at least 20% of patients in both trials included fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and elevated transaminase. Grade 3/4 adverse laboratory abnormalities occurring in at least 50% of patients included decreased leukocytes (81%), decreased platelet count (76%), decreased neutrophil count (71%), and decreased hemoglobin (55%). Serious adverse events occurred in 68% of patients, with the most frequent including febrile neutropenia (30%), pneumonia (14%), and sepsis (13%). Febrile neutropenia (1%) and pneumonia (1%) were the most frequent adverse events leading to treatment discontinuation. Dose interruptions and reductions occurred in 41% and 19% of patients, respectively, with permanent discontinuation in 5%. Fatal adverse events, including sepsis, septic shock, pneumonia, respiratory failure, cerebral hemorrhage, and sudden death, were seen in 6% of patients. The overall safety profile of oral decitabine/cedazuridine was comparable to that of intravenous decitabine.

"The FDA remains committed to providing additional treatments to patients during the coronavirus pandemic," commented Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and Acting Director of the Office of Oncologic Diseases in the FDA's Center for Drug Evaluation and Research. "In this case, the FDA is making available an oral outpatient treatment option that can reduce the need for frequent visits to health care facilities. At this critical time, we continue to focus on providing options to patients with cancer, including regimens that can be taken at home."

The recommended oral dose of decitabine/cedazuridine is one tablet, consisting of 35 mg decitabine and 100 mg cedazuridine, taken once daily without food on days 1 through 5 of each 28-day cycle.

For More Information

Clinicaltrials.gov (2020). Pharmacokinetic guided dose escalation and dose confirmation with oral decitabine and oral CDAi in patients with MDS. NLM identifier: NCT02103478.

Clinicaltrials.gov (2020). Study of ASTX727 vs IV decitabine in MDS, CMML, and AML. NLM identifier: NCT03306264.

Inqovi® (decitabine/cedazuridine) prescribing information (2020). Astex Pharmaceuticals, Inc. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212576s000lbl.pdf

US Food and Drug Administration (2020). FDA approves oral combination of decitabine and cedazuridine for myelodysplastic syndromes. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-oral-combination-decitabine-and-cedazuridine-myelodysplastic-syndromes

Image credit: TomskiiJA. Licensed under CC BY-SA 3.0

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