Randomized confirmatory trial
The VIALE-A study was a randomized, placebo-controlled trial designed to put the early promise of the combination to the test.
Investigators enrolled 433 adults with newly diagnosed AML who were ineligible for induction therapy either because they were 75 or older or were younger than 75 but had one or more of the following comorbidities: heart failure requiring treatment or a left ventricular ejection fraction of 50% or less, chronic stable angina, diffusion lung capacity for carbon monoxide of 65% or less or forced expiratory volume in 1 second of 65% or less, or Eastern Cooperative Oncology Group performance status score of 2-3.
After stratification by age, cytogenetic risk, and geographic region, the patients were randomized in a 2:1 fashion to receive azacitidine 75 mg/m2 either subcutaneously or intravenously on days 1-7 of each 28-day cycle, plus either oral venetoclax 400 mg daily following a 3-day ramp up in the first cycle (286 patients) or placebo (145 patients).
The median age in each arm was 76 years. Approximately 75% of patients in each arm had de novo AML.
Approximately half of all patients in each arm has bone marrow blast counts of 50% or greater. Two-thirds of patients had intermediate cytogenetic risk and one-third had poor risk disease. Somatic mutation rates, including mutations in IDH1/2, FLT3, NPM1 and TP53, were roughly comparable between the arms.
As noted before, median overall survival, the primary endpoint, was significantly longer with venetoclax, at 14.7 versus 9.6 months, translating into a hazard ratio for death with venetoclax of 0.66 (P < .001).
Although the numbers were relatively small, an analysis of overall survival by subgroups showed either a significant advantage or trend favoring venetoclax in all subgroups, notably among patients with difficult-to-treat disease, including patients 75 years and older and those with secondary AML, Dr. DiNardo said.
The combined complete response and CR with incomplete recovery (CRi) response rate was 66.4% with venetoclax, compared with 28.3% with azacitidine alone. The median time to a CR/CRi was shorter with the combination at 1.3 versus 2.8 months for azacitidine plus placebo, and the median duration of a CR/CRi response was longer, at 17.5 versus 13.4 months, respectively.
Response rates were also notably higher with venetoclax in all cytogenetic risk, AML subtype, molecular mutation, age, ECOG score, and bone marrow blast subgroups.
Additionally, significantly more patients treated with venetoclax/azacitidine were transfusion independent for a minimum of 8 weeks for platelets or combined red cells and platelets, Dr. DiNardo noted.
Median event-free survival – time from randomization to relapse, death, or treatment failure – was 9.8 months in the venetoclax arm versus 7 months in the placebo arm (HR, 0.63; P < .001).
All patients experienced at least one treatment-emergent adverse event. Grade 3 or greater hematologic adverse events were seen 82% of patients in the venetoclax arm and 68% in the placebo arm. The respective rates of grade 3 or greater neutropenia were 42% versus 29%, and febrile neutropenia were 42% versus 19%. Thrombocytopenia, anemia, and leukopenia rates were also higher among patients who received venetoclax.
Grade 1-2 gastrointestinal events were the most frequent nonhematologic adverse events. There was no increase in early deaths seen with the study combination.
The study was supported by AbbVie and Genentech. Dr. DiNardo disclosed research funding from and advisory board activities for those companies and from others. Dr. Zeidner disclosed serving on an independent review committee for AbbVie and advisory board activity for Genentech and others.
SOURCE: DiNardo C et al. EHA25, Abstract LB2601.