An all-oral regimen of decitabine-cedazuridine (DEC-C) plus venetoclax (VEN) in patients (pts) with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive induction chemotherapy: Results from a phase 2 cohort of 101 pts.

Abstract

6504 Background: In pts with AML aged ≥75 years and ineligible for induction chemotherapy, the combination of the Bcl-2 inhibitor VEN plus azacitidine (AZA) was approved based on the Phase 3 VIALE-A trial (complete remission [CR] rate, 36.7%; median CR duration, 17.5 months; median overall survival [OS], 14.7 months). However, monthly seven-day clinic injections of parenteral AZA until progression impose a significant burden on pts. Further, multiple adjusted comparisons have demonstrated similar clinical efficacy between AZA and decitabine. Oral DEC-C (decitabine 35 mg and cedazuridine 100 mg) has equivalent pharmacokinetic (PK) area under the curve exposure to intravenous decitabine. This Phase 1/2 trial was designed to evaluate the all-oral regimen of DEC-C plus VEN in pts with AML aged ≥75 years or with comorbidities precluding first-line intensive induction chemotherapy (NCT04657081). Here, we report results from the pivotal Phase 2 part of the trial. Methods: Eligible pts received oral DEC-C on Days 1–5 plus VEN 400 mg daily in 28-day cycles after Cycle 1 VEN ramp up (100 mg Day 1, 200 mg Day 2, 400 mg Day ≥3). Bone marrow examination during Cycle 1 was optional, with VEN and/or DEC-C dose adjustments based on response and count recovery. The primary endpoint was CR rate, based on European LeukemiaNet (ELN) 2017 response criteria. The sample size was calculated based on the lower limit of the 95% confidence interval (CI) of the target CR rate exceeding the clinically meaningful historical rate of 17.9%, with a one-sided α of 0.025, which required ~100 pts to ensure ≥95% power. Results: As of September 30, 2024, 101 pts were enrolled and had completed a median of 4 (range, 1–15) cycles. Median age was 78 years. ELN 2017 classification was favorable, intermediate, and adverse in 31.7%, 33.7%, and 29.7% of pts, respectively. Median follow-up was 11.2 months. The CR and CR/CR with incomplete hematologic recovery rates were 46.5% (95% CI, 36.5%–56.7%) and 63.4% (95% CI, 53.2%–72.7%), respectively. Median time to CR was 2.4 months. Median CR duration was not reached; among pts who achieved CR, 80.0% remained so at 6 months and 75.3% at 12 months. Median OS was 15.5 (95% CI, 7.6–not estimable) months. Grade ≥3 treatment-emergent adverse events were reported in 98.0% of pts, most commonly febrile neutropenia (49.5%), anemia (38.6%), and neutropenia (35.6%). The 30- and 60-day mortality rates were 3.0% and 9.9%, respectively. PK data confirmed no drug-drug interactions between oral DEC-C and VEN. Conclusions: The all-oral regimen of DEC-C plus VEN resulted in comparable safety, response, and survival rates to parenteral AZA plus VEN in pts with newly diagnosed AML ineligible for intensive induction chemotherapy. These data support the potential use of DEC-C plus VEN as a treatment option for these pts. Clinical trial information: NCT04657081 .