NCCN Grants Category 2A Recommendation to Decitabine/Cedazuridine Combo for MDS

November 23, 2020 - The National Comprehensive Cancer Network has updated its Clinical Practice Guidelines in Oncology for Myelodysplastic Syndromes (MDS) to include the combination of decitabine and cedazuridine (Inqovi) as a category 2a recommendation for the treatment of adult patients with intermediate- and high-risk MDS.¹

Oral decitabine and cedazuridine, given at 35-mg and 100-mg tablets, can be considered a substitution for intravenous decitabine in the treatment of adult patients with MDS who are experiencing clinically significant cytopenias or increased marrow blasts, significant anemia, or are transplant candidates.

"The addition of Inqovi to the Clinical Practice Guidelines in Oncology for Myelodysplastic Syndromes will further inform health care providers of a new oral treatment option," said Karin Blakolmer, senior vice president and head of medical affairs, Taiho Oncology, Inc., the developer of the regimen. "As the first orally administered hypomethylating agent for MDS, and an important alternative to multiple monthly intravenous infusions, Taiho Oncology believes that Inqovi will help address unmet treatment needs for patients who may currently have limited access to in-office intravenous therapy. We look forward to working with healthcare professionals to bring this therapy to appropriate patients."

The regimen is now commercialized by Taiho Oncology, which previously announced it has assumed the responsibility from Astex Pharmaceuticals, Inc. and its parent company, Otsuka Pharmaceutical Co., Ltd.

Inqovi is an orally administered, fixed-dose combination of the approved anti-cancer DNA hypomethylating agent, decitabine, together with cedazuridine, which is an inhibitor of cytidine deaminase.

The regimen garnered FDA approval in July 2020 for the treatment of adult patients with MDS.²

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.

Findings 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.

Regarding 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, of grade 3/4, 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 incidence of MDS in the United States is estimated to be 10,000 cases annually.

References

1. National Comprehensive Cancer Network® Adds INQOVI® (decitabine and cedazuridine) Tablets to its Clinical Practice Guidelines in Oncology for Myelodysplastic Syndromes. News release. Taiho Oncology, Inc. November 23, 2020. Accessed November 23, 2020. https://yhoo.it/3mci4Gh
2. FDA approves oral combination of decitabine and cedazuridine for myelodysplastic syndromes. News release. FDA. July 7, 2020. Accessed July 7, 2020. bit.ly/38DnfZv