ASTX727/Venetoclax Combo Is Safe and Effective in First-Line and Relapsed/Refractory AML

Oral decitabine plus cedazuridine (ASTX727) added to oral venetoclax (Venclexta) demonstrated promising overall response rates in patients with acute myeloid leukemia (AML) who received the combination as a first-line treatment or after relapsing on prior therapies, according to findings from a phase 2 study (NCT04746235) presented at the 10th Annual Meeting of the Society of Hematologic Oncology.¹

Of all patients included in the study (n = 37), 27% (n = 10) achieved a complete response (CR), 24% (n = 9) achieved a CR with incomplete count recovery, and 5% (n = 2) achieved a morphological leukemia-free state. Of the cohort of treatment-naïve patients (n = 28), 57% (n = 16) responded, including 25% (n = 7) who achieved a CR, 29% (n = 8) who achieved a CR with incomplete count recovery, and 1 patient who achieved a morphological leukemia-free state. Of the cohort of patients with relapsed/refractory AML (n = 9), 56% (n = 5) responded, including 33% (n = 3) who achieved a CR, and 1 each who achieved a CR with incomplete count recovery and a morphological leukemia-free state.

Combinations of hypomethylating agents with venetoclax are the standard of care for patients with AML who are unfit for intensive induction chemotherapy because of their age and/or comorbidities.

This trial evaluated the efficacy and safety of ASTX727, an oral formulation of 35 mg of decitabine plus 100 mg of cedazuridine, plus venetoclax in patients with relapsed/refractory AML or previously untreated, elderly patients who were unfit for chemotherapy.

Eligible patients included those at least 18 years of age with relapsed/refractory AML. Patients aged 75 or older or ages 18 to 74 with comorbidities preventing intensive frontline chemotherapy were also included. All patients needed to have adequate organ function.

Patients received oral ASTX727 daily on days 1 through 5 and oral venetoclax on days 1 through 28 of the first cycle, after a venetoclax dose increase from 100 mg to 200 mg to 400 mg in the 3 days preceding the first cycle. Patients underwent bone marrow exams on day 21 ± 3 days, and venetoclax was held if blasts were less than 5% to allow for count recovery. Cycles were repeated every 4 to 8 weeks, and venetoclax was given for 21 days in the second and subsequent cycles.

Dose reductions and dose duration reductions were allowed depending on blast count recovery, and the use of growth factors to enhance count recovery was permitted.

Regarding patient characteristics, men comprised 54% (n = 20) of the overall population, 64% (n = 18) of the frontline cohort and 22% (n = 2) of the relapsed/refractory (R/R) cohort. The median age was 75 years (range, 46-92) in the overall population, and 76.5 years (range, 50-92) and 70 years (range, 46-73) in the frontline and R/R cohorts, respectively. A total of 12 of the patients in the frontline cohort were over 80 years of age.

The overall population had a median ECOG performance score (PS) of 1 (range, 0-3). Specifically, the frontline cohort had a median PS of 2 (range, 0-3), and the R/R cohort had a median PS of 1 (range, 1-2).

The median baseline percentage of bone marrow blasts was 30% (range, 8%-81%) in the overall population, 29% (range, 8%-81%) in the frontline cohort, and 40% (range, 11%-63%) in the R/R cohort. In total, 38% (n = 14) of patients had secondary AML: 43% (n = 12) in the frontline cohort and 22% (n = 2) in the R/R cohort.

Regarding cytogenetics, of the overall population, 30% (n = 11) of patients had diploid, 41% (n = 15) had complex, and 24% (n = 9) had others. In the frontline cohort specifically, 32% (n = 9) had diploid, 39% (n = 11) had complex, and 25% (n = 7) had others. In the R/R cohort, 22% (n = 2) had diploid, 44% (n = 4) had complex, and 22% (n = 2) had others.

In total, 30% (n = 11) of the overall population had ASXL1 mutations, including 32% (n = 9) of the frontline cohort and 22% (n = 2) of the R/R cohort. Eleven percent (n = 4) of the overall population had DNMT3A mutations: 7% (n = 2) of the frontline cohort and 22% (n = 2) of the R/R cohort. Twenty-four percent (n = 9) of the overall population had RUNX1 mutations: 29% (n = 8) of the frontline cohort and 11% (n = 1) of the R/R cohort. Additionally, 35% (n = 13) of the overall population had TET2 mutations, all in the frontline cohort. Furthermore, 16% (n = 6) of the overall population had TP53 mutations: 14% (n = 4) of the frontline cohort and 22% (n = 2) of the R/R cohort.

In the frontline cohort, 36% (n = 10) of patients did not respond to the study treatment, and 2 patients were not evaluable. In the R/R cohort, 44% (n = 4) of patients did not respond.

At a median follow-up of 7 months, the overall survival (OS) in the frontline cohort was not reached, (range, 0.6-13 months), and 11 patients had died. The OS in the R/R cohort was 10.1 months (range, 3.2-13), and 6 patients had died.

Adverse effects of grade 3 or higher in the overall population were mainly related to myelosuppression. They included neutropenic infections (11%; n = 4) and elevation of liver enzymes, which was seen in 1 patient.

“Total oral therapy of ASTX727 plus venetoclax is safe and feasible in the advanced elderly population and demonstrates significant efficacy in patients unfit for chemotherapy in both frontline and relapsed/refractory settings,” the study authors concluded.

Reference

1. Abuasab T, Alvarado Y, Issa G, et al. Phase 2 study of ASTX727 (decitabine/cedazuridine) plus venetoclax in patients with relapsed/refractory acute myeloid leukemia or previously untreated, elderly patients unfit for chemotherapy. Presented at: 2022 SOHO Annual Meeting; September 28-October 1, 2022; Houston, TX. Poster AML-328.