Prolonged Overall Survival Observed With Oral Decitabine/Cedazuridine in MDS and CMML

Michael R. Savona, MD

Updated data from the phase 3 ASCERTAIN trial (NCT03306264) demonstrated that the oral, fixed-duration combination of decitabine and cedazuridine (Inqovi) induced a median overall survival (OS) of 31.7 months (95% CI, 28.0-not evaluable [NE]) in patients with intermediate- and high-risk myelodysplastic syndrome (MDS), including chronic myelomonocytic leukemia (CMML), according to a news release from Astex Pharmaceuticals, Inc.^1,2

At a median follow-up of approximately 32 months, the results, which were presented during the 16th International Congress on Myelodysplastic Syndromes, also showed an overall response rate (ORR) of 61.7% (95% CI, 52.8%-69.9%) and a complete response (CR) rate of 22% (95% CI, 15.1%-29.8%) among 133 patients treated with the fixed-duration combination. The leukemia-free survival was 29.1 months (95% CI, 22.1-NE).

“Taken together, the ASCERTAIN phase 3 study data support considerable therapeutic utility of oral decitabine and cedazuridine in the treatment of patients with MDS and CMML,” co-principal investigator Michael R. Savona, MD, a professor of medicine and cancer biology at Vanderbilt University, head of Hematology, Cellular Therapy, and Stem Cell Transplant and director of Hematologic Malignancies Research and the Early Therapy Program at Vanderbilt University Medical Center, said in a press release. “The fixed-dose combination of decitabine and cedazuridine is the only available oral DNA methyltransferase inhibitor/hypomethylating agent that has demonstrated equivalent exposure to an IV [intravenous] form. The median [OS] data from this study makes oral decitabine and cedazuridine an alternative option to parenteral administration of decitabine for patients with these diseases.”

Hypomethylating agents (HMAs) are standard treatment options for patients with MDS but are administered parenterally because of limited and variable oral availability. Cedazuridine is a novel inhibitor of cytidine deaminase that when combined with decitabine enables oral availability.

In July 2020, the FDA approved the oral combination for the treatment of adult patients with previously untreated and untreated de novo and secondary MDS, including refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and CMML.³ The combination is indicated for patients with intermediate-1, intermediate-2, and high-risk disease, per the International Prognostic Scoring System.

The ASCERTAIN trial randomized patients with intermediate- or high-risk MDS, CMML, or acute myeloid leukemia (AML) with 20% to 30% blasts 1:1 to sequence A or sequence B.2 Sequence A comprised oral, fixed-dose decitabine (35 mg) plus cedazuridine (100 mg) given as 1 daily tablet for 5 days in cycle 1 and IV decitabine (20 mg/m2) for 5 days in cycle 2 or IV decitabine in cycle 1 and the fixed-dose regimen in cycle 2. All patients received the fixed-duration regimen from cycle 3 onward until progression, toxicity, or withdrawal.

Patients received a median of 9 cycles of treatment.

The primary end point of the study was total 5-day decitabine area under the curve (AUC) equivalence (oral/IV 90% CI between 80% and 125%). Key secondary end points included efficacy (ORR, transfusion independence, duration of response, leukemia-free survival, and OS), safety, and maximum LINE-1 demethylation.

Patients were a median age of 71 years (range, 44-88) and most were male (65%). Twelve percent of patients had CMML; 68% of patients had intermediate-1 or -2 MDS, 16% had high-risk MDS, and 5% had low-risk MDS. Most patients (59%) had an ECOG performance status of 1.

Forty percent of patients were red blood cell transfusion–dependent and 9% were platelet transfusion–dependent.

Additional results showed that the median CR duration was 14 months (range, 2-29) with fixed-duration decitabine and cedazuridine. The median duration of best response was 12.7 months (range, 1-33).

Additionally, 26% of patients who received the combination proceeded to hematopoietic stem cell transplant (HSCT); no survival difference was reported between individuals who underwent HSCT vs those who did not.

“We are encouraged by data from the ASCERTAIN trial that continue to show oral decitabine and cedazuridine is a promising treatment option for patients living with MDS and CMML,” said Timothy Whitten, president and CEO of Taiho Oncology, Inc.1 “Importantly, patients can benefit from the convenience of an at-home [HMA] treatment and potentially reduce the number of office visits and associated travel.”

Pharmacokinetic data showed a 13.7% LINE-1 methylation decrease in cycle 1 of oral decitabine/cedazuridine compared with baseline. The change was less than 1% for both cycles 1 and 2 with overlapping confidence intervals, which suggests similar biologic effects between oral vs IV treatment.²

Moreover, the study met its primary end point with high confidence. The oral/IV 5-day decitabine AUC was approximately 99% (90% CI, approximately 93%-106%).

Regarding safety, all-grade treatment-emergent adverse effects (TRAEs) that were present in at least 10% of patients included neutropenia (51%), thrombocytopenia (53%), anemia (41%), leukopenia (25%), febrile neutropenia (14%), fatigue (24%), diarrhea (17%), nausea (25%), decreased appetite (14%), and constipation (14%). Of these, grade 3 or higher TRAEs included neutropenia (49%), thrombocytopenia (47%), anemia (35%), leukopenia (22%), febrile neutropenia (13%), fatigue (2%), and diarrhea (2%).

Ultimately, the safety profile was consistent with that associated with IV decitabine, and no new safety concerns arose with longer follow-up.

Oral, fixed-duration decitabine and cedazuridine is being evaluated in combination with other agents in various hematologic malignancies based on the encouraging results of the ASCERTAIN trial.¹

“The first of these studies is investigating the all-oral combination of decitabine and cedazuridine with venetoclax [Venclexta] for the treatment of AML,” concluded Harold Keer, MD, PhD, chief medical officer of Astex Pharmaceuticals, Inc.1 “We are extremely grateful to all the patients, caregivers, partner research and manufacturing organizations, as well as the healthcare professionals who have contributed to the clinical development program of oral decitabine and cedazuridine.”

References

1. Astex Pharamceuticals presents overall survival data from ASCERTAIN phase 3 study of oral hypomethylating agent Inqovi (decitabine and cedazuridine) in MDS and CMML at International Congress on Myelodysplastic Syndromes. News release. Astex Pharmaceuticals. September 23, 2021. Accessed September 24, 2021. https://bit.ly/3m0nzJ9
2. Savona MR, McCloskey JK, Griffiths EA, et al. Prolonged survival observed in 133 MDS patients treated with oral decitabine/cedazuridine. Presented at: 16th International Congress on Myelodysplastic Syndromes; September 23-26; virtual poster. Abstract P48. https://bit.ly/3ENe1cV
3. FDA approves oral combination of decitabine and cedazuridine for myelodysplastic syndromes. News release. FDA. July 7, 2020. Accessed September 24, 2021. https://bit.ly/3i35VDg