On July 7, the U.S. Food and Drug Administration (FDA) approved an oral combination of decitabine and cedazuridine (Inqovi) for adult patients with myelodysplastic syndromes (MDS), including the following:
ASTX727-01-B and ASTX727-02
The combination was investigated in two open-label, randomized, crossover trials: ASTX727-01-B included 80 adult patients with MDS (classified as IPSS intermediate-1, intermediate-2, or high-risk) or CMML; and ASTX727-02 included 133 adult patients with MDS or CMML, including all French/American/British classification criteria and IPSS intermediate-1, intermediate-2, or high-risk prognostic scores.
In both trials, patients were randomly assigned 1:1 to receive decitabine and cedazuridine (35 mg of decitabine and 100 mg of cedazuridine) orally in cycle 1 and decitabine at 20 mg/m2 intravenously in cycle 2 or the reverse sequence. Both the combination and intravenous decitabine were administered once daily on days 1 through 5 of a 28-day cycle. Starting with cycle 3, all patients received decitabine and cedazuridine orally once daily on days 1 through 5 of each 28-day cycle until disease progression or unacceptable toxicity.
Both trials compared exposure and safety in the first two cycles between oral decitabine and cedazuridine and intravenous decitabine and described disease response with the combination. Comparison of disease response between oral and intravenous decitabine was not possible because all patients received the combination starting from cycle 3.
The 01-B trial demonstrated a complete response rate of 18% (95% confidence interval [CI] = 10%–28%); median duration of complete response was 8.7 months (range = 1.1–18.2). Among the 41 patients who were dependent on red blood cell and/or platelet transfusions at baseline, 20 (49%) became independent of red blood cell and platelet transfusions during any consecutive 56-day postbaseline period. Of the 39 patients who were independent of both red blood cell and platelet transfusions at baseline, 25 (64%) remained transfusion-independent during any consecutive 56-day postbaseline period.
The 02 trial demonstrated a geometric mean ratio of the 5-day cumulative decitabine area under the curve following five consecutive once-daily doses of the combination compared to that of intravenous decitabine was 99% (90% CI = 93%–106%). Efficacy results demonstrated that 21% of patients achieved complete response (95% CI =15%–29%) and median duration of complete response was 7.5 months (range = 1.6–17.5).
Among the 57 patients who were dependent on red blood cell and/or platelet transfusions at baseline, 30 (53%) became independent of red blood cell and platelet transfusions during any 56-day postbaseline period. Of the 76 patients who were independent of both red blood cell and platelet transfusions at baseline, 63% remained transfusion-independent during any 56-day postbaseline period.
The most common adverse reactions (incidence ≥ 20%) associated with decitabine and cedazuridine are fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and increased transaminase. The most common grade 3 or 4 laboratory abnormalities (≥ 50%) were decreased leukocytes, platelet count, neutrophil count, and hemoglobin. The overall safety profile of oral decitabine and cedazuridine was similar to intravenous decitabine.
The recommended dose of the combination is one tablet (consisting of 35 mg of decitabine and 100 mg of cedazuridine) taken orally on an empty stomach once daily on days 1 through 5 of each 28‑day cycle.