The FDA approved the oral combination of decitabine and cedazuridine (Inqovi, Astex) for the treatment of adults with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).

This combination product is an important advance in treatment options for patients with MDS, who previously needed to visit a health care facility to receive IV therapy, the agency said.

The combination is indicated for MDS patients who: 

• were previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes—refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]), and
• intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System (IPSS) groups.
  

The approval was based on two open-label, randomized, crossover clinical trials that showed similar drug concentrations between IV decitabine and oral decitabine?cedazuridine. Additionally, about half of the patients who were formerly dependent on transfusions no longer required transfusions during an eight-week period. 

Trial ASTX727-01-B included 80 adult patients with MDS (IPSS intermediate-1, intermediate-2 or high-risk) or CMML, and trial ASTX727-02 involved 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 to receive 35 mg of decitabine and 100 mg of cedazuridine orally in cycle 1 and decitabine 20 mg/m2 IV in cycle 2 or the reverse sequence. Both decitabine-cedazuridine and IV decitabine were administered once daily on days 1 through 5 of a 28-day cycle. Starting with cycle 3, all patients received decitabine-cedazuridine orally once daily on days 1 through 5 of each 28-day cycle until disease progression or unacceptable toxicity. 

Both trials provided comparisons of exposure and safety in the first two cycles between oral decitabine-cedazuridine and IV decitabine and a description of disease response to the new medication. Comparison of disease response between decitabine-cedazuridine and IV decitabine was not possible because all patients received decitabine-cedazuridine starting in cycle 3.

The 01-B trial demonstrated a complete response (CR) rate of 18% (95% CI, 10%-28%), and the median duration of CR was 8.7 months (range, 1.1-18.2 months). Among the 41 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 20 (49%) became independent of RBC and platelet transfusions during any consecutive 56-day post-baseline period. Of the 39 patients who were independent of both RBC and platelet transfusions at baseline, 25 (64%) remained transfusion-independent during any consecutive 56-day post-baseline period.

The 02 trial demonstrated a geometric mean ratio of the five-day cumulative decitabine area under the curve following five consecutive once-daily doses of decitabine-cedazuridine compared with IV decitabine of 99% (90% CI, 93%-106%). Efficacy results showed 21% of patients achieved a CR (95% CI, 15%-29%) and the median duration of CR was 7.5 months (range, 1.6-17.5 months). Among the 57 patients who were dependent on RBC and/or platelet transfusions at baseline, 30 (53%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 76 patients who were independent of both RBC and platelet transfusions at baseline, 63% remained transfusion-independent during any 56-day post-baseline period.

The most common adverse reactions were 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 were a decrease in leukocytes, platelet counts, neutrophil counts and hemoglobin. The overall safety profile of oral decitabine-cedazuridine was similar to IV decitabine. The new medication can cause fetal harm, and both male and female patients of reproductive age are advised to use effective contraception.

—Clinical Oncology News Staff

Based on a press release from the FDA.