FDA Approves Oral Decitabine Plus Cedazuridine for MDS

The FDA has approved an oral combination comprised of decitabine and cedazuridine (Inqovi) for the treatment of adult patients with myelodysplastic syndromes (MDS).

Specifically, the combination is indicated for patients with previously untreated and untreated de novo and secondary MDS with the following subtypes: refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia (CMML). The regimen is also indicated for patients classified as intermediate-1, intermediate-2, and high-risk per the International Prognostic Scoring system (IPSS).

The novel regimen was examined in 2 open-label, randomized, crossover trials. The first trial, Trial ASTX727-01-B (NCT02103478), enrolled a total of 80 patients with MDS, including those with intermediate-1, intermediate-2, or high-risk IPSS scores, or CMML. The second trial, ASTX727-02 (NCT03306264), enrolled 133 patients with either 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 randomized 1:1 to receive 35 mg of oral decitabine plus 100 mg of cedazuridine in cycle 1 and 20 mg/m2 of intravenous (IV) decitabine in cycle 2, or the reverse sequence. Both the oral combination regimen and IV decitabine were given once daily on days 1 through 5 of a 28-day treatment cycle. Starting with cycle 3, all patients received the oral combination regimen once daily on days 1 through 5 of each 28-day cycle until either progressive disease or intolerable toxicity.

Both of the trials provided comparison of exposure and safety between the oral combination and IV decitabine in the first 2 treatment cycles; data regarding disease response with the combination were also collected. Notably, a comparison with regard to disease responses between the oral combination and IV decitabine was not possible, as all patients were administered the combination at the start of cycle 3.

Results from the ASTX727-01-B trial showed that the combination resulted in a complete response (CR) rate of 18% (95% CI, 10-28) and a median duration of CR of 8.7 months. Of 41 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, just under half, or 49% (n = 20) became independent during any consecutive 56-day post-baseline period. Of the 39 patients who had been independent of both RBC and platelet transfusions at baseline,64% (n = 25) remained independent during any consecutive 56-day post-baseline period.

Data from the ASTX727-02 trial demonstrated a 99% geometric mean ratio of the 5-day cumulative decitabine AUC after 5 consecutive once-daily doses of the oral combination versus IV decitabine (90% CI, 93-106). Twenty-one percent of patients experienced a CR with the regimen (95% CI, 15-29) and a median duration of CR of 7.5 months. Of 57 patients who had been dependent on RBC and platelet transfusions at baseline, 53% (n = 30) achieved independence during the 56-day post-baseline period. Among 76 patients who had been independent of both RBC and platelet transfusions at baseline, 62% remained independent during the 56-day post-baseline period.

With regard to safety, the most commonly reported adverse events experienced with the oral combination included fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, reduced appetite, upper-respiratory tract infection, pneumonia, and increased transaminase. The most commonly experienced laboratory abnormalities determined to be grade 3 or 4 were decreased leukocytes, platelet counts, neutrophil counts, and hemoglobin.

Overall, the safety profile with the oral combination was comparable to that of IV decitabine.

The FDA-recommended dose of the regimen is 1 tablet comprised of 35 mg of decitabine and 100 mg of cedazuridine to be received via oral administration on an empty stomach once daily on days 1 through 5 of each 28-day treatment cycle.

Reference

FDA approves oral combination of decitabine and cedazuridine for myelodysplastic syndromes. News release. FDA. July 7, 2020. Accessed July 7, 2020. bit.ly/38DnfZv.