Long-Term Follow-up of the Phase 3 Viale-a Clinical Trial of Venetoclax Plus Azacitidine for Patients with Untreated Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy

Background: Venetoclax (Ven), a highly selective oral BCL-2 inhibitor, in combination with azacitidine (Aza) is approved for the treatment of patients with intensive chemotherapy-ineligible newly diagnosed AML based on the positive results of the phase 3 VIALE-A study (NCT02993523) of placebo (Pbo) vs Ven in combination with Aza in this population (DiNardo et. al. NEJM, 2020). At a median follow-up of 20.5 (range, <0.1-30.7) months (mo), with 270 death events (75% OS) in January 2020, the median overall survival (OS) was 14.7 mo for the Ven+Aza group and 9.6 mo in the Pbo+Aza group (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.52 to 0.85; P<0.001). Complete remission (CR) was higher with Ven+Aza than with Pbo+Aza (36.7% vs 17.9%; P<0.001), as was complete remission + complete remission with incomplete hematologic recovery (CR+CRi) (66.4% vs 28.3%; P<0.001) (DiNardo et. al. NEJM, 2020). While the study met the statistical significance for its primary endpoint of overall survival at the 75% OS interim analysis in March 2020, with 270 OS events, a 100% final OS analysis was undertaken with 360 survival events (data cut-off of 01 December, 2021), with 2-years of additional follow-up to determine the long-term survival benefit of Ven+Aza. Here, we present the analysis of VIALE-A, after the occurrence of 100% of the pre-planned survival events. Methods: 431 patients with confirmed AML who were previously untreated and ineligible for intensive therapy were randomly assigned 2:1 to Aza plus either Ven (286 patients) or Pbo (145 patients). All patients received a standard dose of Aza (75 mg/m2 subcutaneously or intravenously on days 1 through 7 every 28-day cycle). Ven 400 mg after a 3 day ramp up to reach the target dose in Cycle 1 or a matching Pbo was administered orally, once daily, in 28-day cycles. Results: Median age was 76 years in both groups, approximately 60% were male and 76% were Caucasian. Molecular abnormalities of interest included FLT-3, observed in 14.1% of patients receiving VEN+AZA, IDH1/2, observed in 24.9% of pts, TP53, observed in 23.3% of pts and NPM1, observed in 16.6% of pts. With a median follow-up of 43.2 mo, the median overall survival was 14.7 mo (95% CI, 12.1 to 18.7) in the Ven+Aza group and 9.6 mo (95% CI, 7.4 to 12.7) in the Pbo+Aza group (HR, 0.58; 95% CI, 0.47 to 0.72; nominal P<0.001), maintaining the survival benefit since the interim analysis in the overall population (Figure 1). At this data-cut, 49 pts remained on the study (48 in the Ven+Aza group and 1 in the Pbo+Aza group). In patients with measurable residual disease (MRD) <10-3 who had achieved CR+CRi, median OS was reached at 34.2 mo (95% CI, 27.7-44.0) in the Ven+Aza group (N=69) and 25.0 mo (95% CI, 7.0-39.8) in the Pbo+Aza group (N=11). In CR + CRi patients with MRD >10-3, median OS was 18.7 mo (95% CI, 12.9-23.5) in the Ven+Aza group (N=96) and 15.1 mo (95% CI, 7.4, 26.1) in the Pbo+Aza group (N=24). For patients in the IDH1/2 mutant subgroup, median OS was reached at final analysis, at 19.9 mo (95% CI, 12.2-27.7) in the Ven+Aza group and 6.2 mo (95% CI, 2.3-12.7) in the Pbo+Aza group (HR, 0.314; 95% CI, 0.189 to 0.522; P<0.001) (Figure 2). Overall safety profiles were comparable between Ven+Aza and Pbo+Aza. Key treatment-emergent adverse events of any grade occurring in ≥20% of pts included nausea (44.5% in the Ven+Aza group vs 36.8% in the Pbo+Aza group), diarrhea (45.2% vs 34%), and constipation (43.8% vs 39.6%). Grade 3 or higher AEs (Ven+Aza vs Pbo+Aza) occurring in ≥10% of pts included thrombocytopenia (45.9% vs 39.6%), neutropenia (42.8% vs 28.5%), and febrile neutropenia (42.8% vs 18.8%). Serious adverse events occurred in 85.1% of pts in the Ven+Aza group and 77.1% of those in the Pbo+Aza group. Further characterization of pts with long term benefit is ongoing. Conclusions: The VIALE-A long-term follow up demonstrates sustained overall survival benefit with Ven+Aza in patients with AML ineligible for intensive chemotherapy compared to Pbo+Aza in all subgroups. Notably, the median OS for patients with MRD <10-3 who had achieved CR+CRi was 34.2 mo, and median OS for patients with IDH1/2 mutations treated with Ven+Aza was 19.9 mo. The VIALE-A 2-year follow-up analysis confirms the long-term survival benefit for patients treated with Ven+Aza, with no new safety findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal