NEJM Publishes ASCERTAIN-V Trial Results of First All-Oral Decitabine-Cedazuridine Plus Venetoclax Regimen in AML
Taiho Oncology, Inc., a biopharmaceutical company focused on developing and commercializing innovative therapies for hematologic malignancies and solid tumors, has announced the publication of results from the ASCERTAIN-V Phase 1/2 clinical trial in the New England Journal of Medicine (NEJM). The study evaluated the first fully oral treatment regimen combining decitabine-cedazuridine with venetoclax in patients with newly diagnosed acute myeloid leukemia (AML) who were ineligible for intensive induction chemotherapy.
The findings highlight promising clinical activity, durable responses, and a safety profile consistent with existing hypomethylating agent (HMA)–venetoclax combinations, while introducing a potentially transformative all-oral treatment approach for a high-risk patient population.
Addressing a High-Need Patient Population in AML
Acute myeloid leukemia is an aggressive hematologic cancer characterized by the rapid accumulation of abnormal white blood cells in the bone marrow, leading to impaired blood cell production and severe systemic complications. In the United States, approximately 23,000 patients are expected to be diagnosed with AML in 2026, with a significant proportion of these patients considered unfit for intensive induction chemotherapy due to advanced age, frailty, or comorbid conditions.
More than half of newly diagnosed AML patients fall into this “unfit” category, often defined by age 75 or older or poor performance status. For these patients, current standard-of-care treatment typically involves a combination of oral venetoclax with injectable or intravenous hypomethylating agents such as azacitidine or decitabine.
While effective, these regimens require frequent hospital visits, injections, or infusions, creating a substantial treatment burden. On average, patients spend nearly 13 days per month in healthcare settings, representing a significant logistical, emotional, and financial challenge for patients and caregivers.
The ASCERTAIN-V study was designed to address this unmet need by evaluating whether a fully oral regimen could provide comparable efficacy while reducing treatment burden.
The First All-Oral HMA–Venetoclax Regimen
The ASCERTAIN-V trial evaluated a novel combination of oral decitabine-cedazuridine plus venetoclax, representing the first fully oral hypomethylating agent–based regimen in combination with a BCL-2 inhibitor for AML.
Decitabine-cedazuridine is an oral hypomethylating agent that combines decitabine with cedazuridine, a cytidine deaminase inhibitor that enables oral bioavailability and systemic exposure comparable to intravenous decitabine. Venetoclax, a selective BCL-2 inhibitor, is already established as a backbone therapy in older or unfit AML populations when combined with injectable HMAs.
The ASCERTAIN-V trial enrolled 189 patients across Phase 1, Phase 2a, and Phase 2b cohorts, including:
- Phase 1: n=30
- Phase 2a: n=58
- Phase 2b: n=101
Following an initial dose ramp-up period, patients were treated in 28-day cycles consisting of:
- Decitabine-cedazuridine administered on days 1–5
- Venetoclax administered daily
The study assessed response rates, remission durability, survival outcomes, pharmacokinetics, and safety.
Strong Clinical Activity and Durable Responses
In the Phase 2b portion of the study, ASCERTAIN-V demonstrated meaningful clinical efficacy across multiple endpoints.
Key findings included:
- Complete response (CR) rate: 47% (95% CI: 36–57%)
- CR or CR with incomplete hematologic recovery (CR/CRi): 63% (95% CI: 53–73%)
Responses were observed relatively quickly, with:
- Median time to <5% bone marrow blasts: 28 days (range 22–57 days)
- Median time to CR/CRi: 35 days (range 27–58 days)
Among patients achieving complete remission, durability of response was notable:
- 80% remained in remission at 6 months
- 75% remained in remission at 12 months
Median overall survival was 15.5 months (95% CI: 7.6–not estimable), with a median follow-up of 11.2 months. Early mortality rates were 3% at 30 days and 10% at 60 days, consistent with outcomes observed in similar AML populations treated with standard HMA–venetoclax regimens.
Safety Profile Consistent With Established Regimens
The safety profile of the all-oral combination was generally consistent with known toxicities associated with hypomethylating agents and venetoclax-based therapy.
Serious adverse events occurred in 84% of patients, reflecting the underlying disease severity and treatment intensity in this population. The most common Grade ≥3 treatment-related adverse events included:
- Anemia: 30%
- Neutropenia: 26%
- Febrile neutropenia: 25%
Importantly, no clinically significant drug–drug interactions were observed between decitabine-cedazuridine and venetoclax, supporting the feasibility of combining the two oral agents.
Adaptive Dosing Strategy and Tolerability Improvements
A notable aspect of the ASCERTAIN-V trial was the implementation of a dose-modification strategy following achievement of leukemic blast clearance, as assessed by bone marrow morphology.
As venetoclax dosing duration was reduced in later treatment cycles after remission, investigators observed:
- Decreases in serious adverse events
- Reduction in febrile neutropenia rates
- Improved overall tolerability
These findings suggest that an adaptive dosing approach—starting with induction-level intensity followed by dose-adjusted maintenance cycles—may help optimize the balance between efficacy and safety in patients who achieve remission.
Expert Perspectives on an All-Oral AML Regimen
Lead study author Gail J. Roboz, M.D., Professor of Medicine and Director of the Clinical and Translational Leukemia Program at Weill Cornell Medicine, highlighted the significance of the findings in the context of current AML treatment limitations.
She noted that the combination of response rates, safety, pharmacokinetics, and tolerability supports the potential of a fully oral regimen as a meaningful alternative to existing treatment protocols that rely heavily on intravenous or injectable hypomethylating agents.
According to Dr. Roboz, an oral-only treatment option represents a highly anticipated advancement for patients with AML who are not candidates for intensive chemotherapy, offering the potential to significantly reduce treatment burden while maintaining clinical efficacy.
Potential Impact on AML Treatment Paradigms
If further validated, the ASCERTAIN-V regimen could represent a major shift in AML treatment, particularly for older or medically unfit patients. By eliminating the need for routine infusions or injections, an all-oral approach may improve patient convenience, reduce healthcare utilization, and enhance quality of life.
The findings also reinforce the clinical relevance of combining hypomethylating agents with BCL-2 inhibition, a strategy that has become a cornerstone of modern AML therapy in non-intensive treatment settings.
However, further studies will be required to confirm long-term outcomes, optimize dosing schedules, and compare the regimen directly with existing standard-of-care combinations in larger randomized trials.
The publication of ASCERTAIN-V in the New England Journal of Medicine represents an important milestone in the evolution of AML therapy. The study demonstrates that a fully oral combination of decitabine-cedazuridine and venetoclax can achieve clinically meaningful response rates, durable remissions, and manageable safety outcomes in patients ineligible for intensive chemotherapy.
While additional research is needed, the results support the potential emergence of a new oral treatment paradigm in AML—one that may significantly reduce treatment burden while maintaining therapeutic effectiveness in a high-risk patient population.
About Decitabine and Cedazuridine Fixed-Dose Combination
This product is an orally administered, fixed dose combination of the approved anti-cancer DNA hypomethylating agent, decitabine, together with cedazuridine,6 an inhibitor of cytidine deaminase.7 By inhibiting cytidine deaminase in the gut and the liver, the fixed dose combination is designed to allow for oral delivery of decitabine over five days in a given cycle to achieve comparable systemic exposure to IV decitabine administered over five days.
About Taiho Oncology, Inc.
The mission of Taiho Oncology, Inc. is to improve the lives of patients with cancer, their families and their caregivers. The company specializes in the development and commercialization of orally administered anti-cancer agents for various tumor types. Taiho Oncology has a robust pipeline of small-molecule clinical candidates targeting solid-tumor and hematological malignancies, with additional candidates in pre-clinical development. Taiho Oncology is a subsidiary of Taiho Pharmaceutical Co., Ltd. which is part of Otsuka Holdings Co., Ltd. Taiho Oncology is headquartered in Princeton, New Jersey and oversees its parent company’s European and Canadian operations, which are located in Baar, Switzerland and Oakville, Ontario, Canada.
