Venetoclax Plus Azacitidine Significantly Prolongs OS, Incidence of Remission in AML

Courtney D. DiNardo, MD, MSCE

Venetoclax (Venclexta) plus azacitidine led to a statistically significant prolongation of overall survival (OS) with a higher incidence of remission in treatment-naïve older patients with acute myeloid leukemia (AML), according to updated results from the phase 3 VIALE-A trial (NCT02993523) published in the New England Journal of Medicine.¹

Results showed that at a median follow-up of 20.5 months, the median OS was 14.7 months in the venetoclax/azacitidine arm and 9.6 months in the azacitidine/placebo arm (HR for death, 0.66; 95% CI, 0.52-0.85; P <.001). Notably a higher incidence of complete remission (CR) was observed in the experimental arm versus the control arm, at 36.7% versus 17.9% (P <.001); this also proved true with regard to the composite CR, at 66.4% versus 28.3%, respectively (P < .001).

“A large portion of patients with AML, including those older than 75 [years] or those who have medical comorbidities, cannot tolerate existing treatment strategies. The patients with AML who are ineligible for intensive chemotherapy often experience poor prognoses,” lead investigator of the study 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, stated in a press release.² “We launched the VIALE-A trial to evaluate whether we could safely use a combination therapy to treat this critical patient population.”

In the multicenter, randomized, double-blind, placebo-controlled phase 3 trial, investigators set out to examine the safety and efficacy of venetoclax plus azacitidine versus azacitidine plus placebo in previously untreated patients with confirmed AML who were not candidates for standard induction therapy due to coexisting conditions, because they were aged 75 years or older, or both.

A total of 431 were included in the intent-to-treat population. The median age of participants in both arms was 76 years, and the majority, or 60%, were male. Twenty-five percent of patients in the venetoclax/azacitidine arm had secondary AML versus 24% in the azacitidine/placebo arm; poor-risk cytogenetics were observed in 36% and 39%, respectively. After undergoing randomization in a 2:1 fashion, a total of 286 were included in the venetoclax/azacitidine arm and 145 were enrolled to the azacitidine/placebo arm.

Venetoclax was given to patients orally, once daily, and with food. To mitigate tumor lysis syndrome during cycle 1, venetoclax was administered at a dose of 100 mg on day 1 and 200 mg on day 2. On day 3, patients received the 400-mg target dose of the agent. Patients continued on treatment until day 28. In all subsequent 28-day cycles, venetoclax was administered at a daily dose of 400 mg.

Participants in both arms were given azacitidine at a dose of 75 mg per square meter of body-surface area, either subcutaneously or intravenously, on days 1 through 7 of each 28-day treatment cycle. Venetoclax was interrupted between cycles to mitigate cytopenia and related clinical consequences. Moreover, dose modifications associated with prophylactic anti-infective drugs for venetoclax dose equivalency were also initiated.

The primary end point of the trial was OS. Secondary end points included composite CR, CR with or without partial hematologic recovery, complete remission by the initiation of cycle 2, red-cell and platelet transfusion independence, composite CR and OS in molecular and cytogenetic subgroups, event-free survival, measurable disease via flow cytometry, and quality of life, as determined by patient-reported outcomes.

At the clinical data cutoff of January 4, 2020, the median time to first response was 1.3 months in the venetoclax/azacitidine arm versus 2.8 months in the control arm. The median duration of composite CR was 17.5 months (95% CI, 13.6-not reached [NR]) in the experimental arm versus 13.4 months (95% CI, 5.8-15.5) in the control arm. The duration of CR was 17.5 months (95% CI, 15.3-NR) in the venetoclax/azacitidine arm versus 13.3 months (95% CI, 8.5-17.6) in the azacitidine/placebo arm.

Additionally, CR plus a CR with partial hematologic recovery was achieved in 64.7% (95% CI, 58.8-70.2) of patients in the venetoclax/azacitidine arm and 22.8% (95% CI, 16.2-30.5) of those in the control arm (P < .001). The median time to first response was 1.0 month (range, 0.6-14.3) and 2.6 months (range, 0.8-13.2) in the experimental and control arms, respectively, while the duration of response was 17.8 months (95% CI, 15.3-NR) and 13.9 months (95% CI, 10.4-15.7), respectively.

Notably, the incidence of post-baseline transfusion independence was higher in patients on the experimental arm versus those in the control arm. Approximately 59.8% (95% CI, 53.9-65.5) of patients in the venetoclax/azacitidine arm achieved red-cell transfusion independence versus 35.2% (95% CI, 27.4-43.5) of those in the control arm (P < .001). Platelet transfusion independence was achieved in 68.5% of patients (95% CI, 62.8-73.9) who received venetoclax/azacitidine and 49.7% (95% CI, 41.3-58.1) of those who received azacitidine/placebo (P < .001).

Results from a molecular subgroup analysis demonstrated that 75.4% (95% CI, 62.7-85.5) of patients with IDH1/2 mutations in the venetoclax/azacitidine arm and 10.7% (95% CI, 2.3-28.2) of those in the control arm experienced a CR (P < .001). Patients with these mutations experienced 12-month OS rates of 66.8% versus 35.7% in the experimental and control arms, respectively (HR, 0.35; 95% CI, 0.20-0.60; P < .001).

Moreover, patients with FLT3 mutations experienced a CR rate of 72.4% (95% CI, 52.8-87.3) versus 36.4% (95% CI, 17.2-59.3), in the venetoclax/azacitidine and azacitidine/placebo arms, respectively (P = .02). In those with a NPM1 mutation the incidence of CR was 66.7% (95% CI, 46.0-83.5) and 23.5% (95% CI, 6.8-49.9), respectively (P = .012). In patients with TP53 mutations, the CR incidence rates were 55.3% (95% CI, 38.3-71.4) versus 0%, respectively (P < .001).

In patients with composite CR, measurable residual disease negativity was observed in 23.4% (95% CI, 18.6-28.8) of those who were given venetoclax/azacitidine versus 7.6% (95% CI, 3.8-13.2) of those who received azacitidine/placebo.

Additionally, the median OS among patients with de novo AML was 14.1 months (95% CI, 10.7-19.3) in the venetoclax/azacitidine arm and 9.6 months (95% CI, 6.8-13.0) in the azacitidine/placebo arm (HR, 0.67; 95% CI, 0.51-0.90). In those with secondary AML, the median OS was 16.4 months (95% CI, 9.7-24.4) and 10.6 months (95% CI, 4.9-13.2) in the experimental and control arms, respectively (HR, 0.56; 95% CI, 0.35-0.91).

In those with an intermediate cytogenetic risk, the median OS with the investigational regimen was 20.8 months (95% CI, 16.4-NR) and 12.4 months (95% CI, 9.1-15.8) with the control regimen (HR, 0.57; 95% CI, 0.41-0.79). For those who had a poor cytogenetic risk, the median OS was 7.6 months (95% CI, 5.3-9.9) and 6.0 months (95% CI, 3.6-10.7), respectively (HR, 0.78; 95% CI, 0.54-1.1).

The median event-free survival with the venetoclax/azacitidine combination was 9.8 months (95% CI, 8.4-11.8) versus 7.0 months (95% CI, 5.6- 9.5) with azacitidine/placebo (HR, 0.63; 95% CI, 0.50- 0.80; P < .001).

With regard to safety, adverse effects (AEs) experienced by both arms of the study included any grade of nausea (44% vs 35%), grade 3 or higher thrombocytopenia (45% vs 38%), grade 3 neutropenia (42% with venetoclax/azacitidine vs 28% with azacitidine/placebo, respectively), and grade 3 febrile neutropenia (42% vs 19%). Infections of any grade were reported in 85% of patients who were given the investigational regimen versus 67% of those who received the control regimen.

Serious AEs were observed in 83% and 73% of those in the investigational and control arms, respectively. All patients experienced at least 1 AE. The most common reason for trial discontinuation was death, which occurred in 56% of patients (n = 161) in the venetoclax/azacitidine arm and 75% of those in the control arm (n = 109). Death related to disease progression occurred in 27% of patients in the experimental arm and in 44% of those in the control arm.

“While this combination represents a key advance in AML therapy, improving both remission and survival rates in newly diagnosed patients with AML, many unfortunately will still relapse,” said DiNardo. “Our next steps include an evaluation of azacitidine and venetoclax as a backbone to which additional novel therapeutics are being evaluated in particularly high-risk populations."

In November of 2018, the FDA granted an accelerated approval to venetoclax for use in combination with azacitidine, decitabine, or low-dose cytarabine for adult patients with newly diagnosed AML who are 75 years of age or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.

References

1. DiNardo CD, Jonas BA, Pullarkat V et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Eng J Med. 2020;383:617-629. doi:10.1056/NEJMoa2012971
2. Combination therapy significantly improves survival outcomes for patients with acute myeloid leukemia. News release. University of Texas MD Anderson Cancer Center. August 12, 2020. Accessed August 13, 2020. https://bit.ly/3kSPtFJ