On July 7, 2020, an oral combination of the nucleoside metabolic inhibitor decitabine and the cytidine deaminase inhibitor cedazuridine was approved for treatment of adult patients with myelodysplastic syndromes (MDS), including:

Previously treated and untreated, de novo, and secondary MDS with the following French-American-British (FAB) subtypes: refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia (CMML)

Intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System (IPSS) groups.^1,2

Supporting Efficacy Data

Approval was supported by findings in two open-label, randomized, crossover trials.² Trial ASTX727-01-B (ClinicalTrials.gov identifier NCT02103478) consisted of 80 adults with MDS (IPSS intermediate-1, intermediate-2, or high-risk) or CMML. Trial ASTX727-02 (NCT03306264) comprised 133 adults with MDS or CMML, including all FAB 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 alone at 20 mg/m² intravenously (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 comparison of exposure and safety in the first two cycles between oral decitabine/cedazuridine and IV decitabine and description of disease response with the combination of agents. Comparison of disease response between decitabine/cedazuridine and IV decitabine was not possible because all patients received the former starting from cycle 3.

Among the 80 patients in the ASTX727-01-B trial, a complete response was observed in 18% (95% confidence interval [CI] = 10%–28%), and the median duration of complete response was 8.7 months (range = 1.1–18.2 months). The median time to complete response was 4.8 months (range = 1.7–10.0 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 postbaseline 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 postbaseline period.

The ASTX727-02 trial showed that the geometric mean ratio of the 5-day cumulative decitabine area under the concentration time curve following five consecutive once-daily doses of decitabine/cedazuridine compared with that of IV decitabine was 99%. Among the 133 patients in the trial, a complete response was observed in 21% (95% CI = 15%–29%), and the median duration of complete response was 7.5 months (range = 1.6–17.5 months). Median time to complete response was 4.3 months (range = 2.1–15.2 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 postbaseline period. Of the 76 patients who were independent of both RBC and platelet transfusions at baseline, 63% remained transfusion-independent during any 56-day postbaseline period.

How It Works

Decitabine is a nucleoside metabolic inhibitor that is believed to exert its effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation and/or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in cancer cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA. Nonproliferating cells are relatively insensitive to decitabine.

Cytidine deaminase (CDA) is an enzyme that catalyzes the degradation of cytidine, including the cytidine analog decitabine. High levels of CDA in the gastrointestinal tract and liver degrade decitabine and limit its oral bioavailability. Cedazuridine is a CDA inhibitor. Administration of cedazuridine with decitabine increases systemic exposure of decitabine.

How It Is Used

The recommended dosage of decitabine plus cedazuridine is one tablet containing 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 for a minimum of four cycles until disease progression or unacceptable toxicity. A complete or partial response may take longer than four cycles. Decitabine/cedazuridine must not be substituted for an IV decitabine product within a treatment cycle. Administration of antiemetics prior to each dose should be considered to minimize nausea and vomiting.

Product labeling provides detailed instructions on monitoring patients for and management of hematologic adverse reactions, including cycle delay and dose reduction. Recommended dose reductions for hematologic adverse reactions are sequentially to one tablet on days 1 to 4, one tablet on days 1 to 3, and one tablet on days 1, 3, and 5. Dosage modification for nonhematologic adverse events including increased bilirubin, increased aspartate aminotransferase or alanine aminotransferase, and active or uncontrolled controlled infection include cycle delay and dose reduction. Concomitant administration with drugs metabolized by cytidine deaminase should be avoided.

Safety Profile

Safety data are from a pooled population of 208 patients who received decitabine/cedazuridine in the ASTX727-01-B and ASTX727-02 trials and include adverse events observed during the cycle of IV decitabine. Treatment exposure was at least 6 months in 61% of patients and at least 1 year in 24%.

The most common adverse events of any grade (incidence ≥ 20%) were fatigue (55%), constipation (44%), hemorrhage (43%), myalgia (42%), mucositis (41%), arthralgia (40%), nausea (40%), dyspnea (38%), diarrhea (37%), rash (33%), dizziness (33%), febrile neutropenia (33%), edema (30%), headache (30%), cough (28%), decreased appetite (24%), upper respiratory tract infection (23%), pneumonia (21%), and increased transaminase (21%). The most common grade 3 or 4 adverse events included febrile neutropenia (32%), pneumonia (15%), sepsis (11%), and dyspnea (6%). The most common grade 3 or 4 laboratory abnormalities (≥ 50%) were decreased leukocytes (81%), decreased platelet count (76%), decreased neutrophil count (71%), and decreased hemoglobin (55%). The overall safety profile of decitabine/cedazuridine was similar to that of IV decitabine.

Serious adverse events occurred in 68% of patients, the most common being febrile neutropenia (30%), pneumonia (14%), and sepsis (13%). Adverse events led to dose interruption in 41% of patients, most commonly due to neutropenia (18%) and febrile neutropenia (8%), and dose reduction in 19%, most commonly due to neutropenia (12%). Adverse events led to permanent discontinuation of treatment in 5% of patients, most commonly due to febrile neutropenia (1%) and pneumonia (1%). Fatal adverse events occurred in 6% of patients, including sepsis (1%), septic shock (1%), pneumonia (1%), respiratory failure (1%), and one incidence each of cerebral hemorrhage and sudden death.

Decitabine/cedazuridine has warnings and precautions for myelosuppression, including fatal and serious myelosuppression and infectious complications, and embryofetal toxicity. Complete blood cell counts should be obtained prior to initiation of treatment, prior to each cycle, and as clinically indicated to monitor for response and toxicity. Patients should be advised not to breastfeed while receiving decitabine/cedazuridine and that the agents can impair fertility. 

REFERENCES

1. U.S. Food and Drug Administration: 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. Accessed August 26, 2020.

2. Inqovi (decitabine and cedazuridine) tablets, for oral use, Otsuka Pharmaceuticals, July 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212576s000lbl.pdf. Accessed August 26, 2020.