The combination of venetoclax (Venclexta) and azacitidine led to a 34% reduction in the risk of death versus azacitidine alone in treatment-naïve patients with acute myeloid leukemia who are ineligible for intensive therapy.
The combination of venetoclax (Venclexta) and azacitidine led to a 34% reduction in the risk of death versus azacitidine alone in treatment-naïve patients with acute myeloid leukemia (AML) who are ineligible for intensive therapy, according to findings from the phase 3 VIALE-A trial that were presented during the 2020 European Hematology Association Congress.1
At a median follow-up of 20.5 months, the median overall survival (OS) was 14.7 months (range, 11.9-18.7) with venetoclax/azacitidine versus 9.6 months with azacitidine/placebo (HR, 0.66; 95% CI, 0.52-0.85; P <.001).
“VIALE-A is the first phase 3 study in older unfit patients with newly diagnosed AML to show a demonstrable survival benefit,” lead study investigator, Courtney D. DiNardo, MD, MSCE, a clinical researcher in the Department of Leukemia of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, said in an interview with OncLive. “The combination of venetoclax and azacitidine should be considered a new standard of care for our older patients who are not eligible for standard intensive chemotherapy.”
The majority of patients with AML have an average age of 70 years at diagnosis and medical comorbidities that limit their ability to undergo intensive induction chemotherapy. Lower intensity treatments, such as azacitidine, decitabine, and low-dose cytarabine, have modest activity and result in poor survival. In a phase 1b trial (NCT02203773), the combination of venetoclax, a selective small-molecule inhibitor of BCL-2, and azacitidine showed promising activity and safety in this patient population.
In November 2018, the FDA granted an accelerated approval to venetoclax for use in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of adult patients with newly diagnosed AML who are aged 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.
The randomized, double-blind, multicenter, placebo-controlled VIALE-A trial enrolled patients with confirmed AML who were ineligible for intensive induction therapy because of medical comorbidities and/or who were 75 years of age or older. Patients who had been previously exposed to a hypomethylating agent were excluded from the trial.
Patients were randomized 2:1 to receive venetoclax/azacitidine (n = 286) or azacitidine/placebo (n = 145). Patients in the investigational arm received 75 mg/m2 of azacitidine subcutaneously or intravenously on days 1-7 every 28 days and 400 mg of oral venetoclax once daily on days 1-28 with a 3-day ramp up in cycle 1. Patients in the control arm received 75 mg/m2 of azacitidine on days 1-7 every 28 days and oral placebo once daily on days 1-28.
The primary end point of the study was OS. Key secondary end points included composite complete remission [complete remission (CR) plus CR with incomplete count recovery (CRi)], CR/CRi by the start of cycle 2, CR, transfusion independence [TI; red blood cells (RBC) or platelets], CR/CRi and OS by molecular subgroups, and event-free survival (EFS).
A sample size of 400 was established to detect a hazard ratio of 0.7 in OS with a 2-sided alpha of 4% and power of 87%.
Patients enrolled on the trial had a median age of 76 years (range, 49-91). Participants received a median of 7.0 (range, 1-30) and 4.5 (range, 1-26) lines of treatment in the venetoclax/azacitidine and azacitidine/placebo arms, respectively.
The CR/CRi rates were 66.4% (95% CI, 60.6%-71.9%) and 28.3% (95% CI, 21.1%-36.3%) in the venetoclax/azacitidine and azacitidine/placebo arms, respectively (P <.001). The CR/CRi rates by the start of cycle 2 were 43.4% (95% CI, 37.5%-49.3%) and 7.6% (95% CI, 3.8%-13.2%), respectively (P <.001).
The CR rate with venetoclax/azacitidine was more than double that of azacitidine/placebo, at 36.7% (95% CI, 31.1%-42.6%) and 17.9% (95% CI, 12.1%-25.2%), respectively (P <.001).
The median time to first CR/CRi response was 1.3 months (95% CI, 0.6-9.9) in the venetoclax/azacitidine arm and 2.8 months (95% CI, 0.8-13.2) in the azacitidine/placebo arm. The duration of CR/CRi was 17.5 months and 13.4 months, respectively.
Moreover, responses favored the addition of venetoclax, irrespective of cytogenetic risk or molecular subgroup. The response rates in patients with poor cytogenetic risk were 53% and 23% in the venetoclax/azacitidine and azacitidine/placebo arms, respectively. Patients with intermediate cytogenetic risk had response rates of 74% and 32%, respectively. The response rates in patients with de novo AML were 66% and 30%, respectively. Patients with secondary AML had response rates of 67% and 23%, respectively.
The CR/CRi rates were also significantly higher among patients with IDH1/2 (75.4%; 10.7%), FLT3 (72.4%; 36.4%), NPM1 (66.7%; 23.5%), and TP53 mutations (55.3%; 0%) in the venetoclax/azacitidine and azacitidine/placebo arms, respectively.
The duration of EFS was 9.8 months (95% CI, 8.4-11.8) and 7.0 months (95% CI, 5.6-9.5) in the venetoclax/azacitidine and azacitidine/placebo arms, respectively (P <.001).
The safety profile was consistent with the known safety profiles of the combination of venetoclax and azacitidine and the known safety profiles of each agent alone. The most common all-grade gastrointestinal adverse effects (AEs) in the venetoclax/azacitidine and azacytidine/placebo arms, respectively, included nausea (44% vs 35%), constipation (43% vs 39%), diarrhea (41% vs 33%), and vomiting (30% vs 23%).
Serious AEs (grade ≥3) in the venetoclax/azacitidine and azacitidine/placebo arms, respectively, consisted of febrile neutropenia (30% vs 10%) and pneumonia (16% vs 22%). Laboratory tumor lysis syndrome was rare, occurring in 1% of patients in the venetoclax/azacitidine arm. The 30-day mortality rates were 7% (n = 21) and 6% (n = 9), respectively.
Grade 3 or higher hematological AEs occurring in at least 10% of patients in the venetoclax/azacitidine and azacitidine/placebo arms, respectively, consisted of thrombocytopenia (45% vs 38%), neutropenia (42% vs 29%), febrile neutropenia (42% vs 19%), anemia (26% vs 20%), and leukopenia (21% vs 12%).
DiNardo added that with the combination, bone marrow biopsies should be performed at the end of cycle 1 as opposed to 3 or 4 months into treatment with azacitidine alone.
“Patients living with AML may be too sick to endure chemotherapy, and they face one of the most aggressive types of blood cancer,” Neil Gallagher, MD, PhD, chief medical officer of AbbVie, said in the press release.2 “The positive results from the VIALE-A study underscore the significant impact venetoclax plus azacitidine can have on improved survival and complete response in a previously-untreated patient population.”