Phase 3 Viale-a Study: Ven Plus Aza for AML Treatment

The positive results of the phase 3 VIALE-A study (NCT02993523) of placebo (Pbo) vs. Ven in combination with Aza in this population led to the approval of venetoclax (Ven), a highly selective oral BCL-2 inhibitor, for the treatment of patients with intensive chemotherapy-ineligible newly diagnosed AML (DiNardo et al. NEJM, 2020). Median overall survival (OS) was 14.7 months for the Ven+Aza group and 9.6 months for the Pbo+Aza group (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.52 to 0.85; P<0.001), with 270 death occurrences (75% OS) in January 2020. Complete remission (36.7% vs. 17.9%; P<0.001) and CR+CRi (66.4% vs. 28.3%; P<0.001) were both greater with Ven+Aza than with Pbo+Aza (DiNardo et al. NEJM, 2020).

At the 75% OS interim analysis in March 2020, with 270 OS events, the study met its primary endpoint statistically; however, a 100% final OS analysis was performed with 360 survival events (data cut-off of 01 December 2021) and 2 years of additional follow-up to determine the long-term survival benefit of Ven+Aza. After all expected survival events, they offer the VIALE-A analysis here. Untreated, ineligible for intensive therapy, AML patients (n=431) were randomized to receive either Aza plus Ven (286 patients) or Pbo (145 patients). Every 28 days, patients were given a regimen of Aza (75 mg/m2 subcutaneously or intravenously on days 1-7). Oral 400 mg Ven or a matched Pbo was given once daily for 28 days, with dosing beginning with a 3-day ramp-up to the target dose in Cycle 1.

Each group had a median age of 76. Around 60% were male, and about 76% were White. Patients treated with VEN+AZA had an increased incidence of FLT-3 abnormalities (14.1%), IDH1/2 abnormalities (24.9%), TP53 abnormalities (23.3%), and NPM1 abnormalities (16.6%). Median overall survival was 14.7 months (95% CI, 12.1 to 18.7) in the Ven+Aza group and 9.6 months (95% CI, 7.4 to 12.2) in the Pbo+Aza group (HR, 0.58; 95% CI, 0.47 to 0.72; nominal P<0.001), with a median follow-up of 43.2 months. This survival benefit has been sustained since the interim analysis of the entire population. A total of 49 points were still enrolled in the study at the time of the cut-off analysis (1 in the Pbo+Aza group and 48 in the Ven+Aza group). Median overall survival (OS) was 34.2 months (95% confidence interval [CI], 27.7-44.0) in the Ven+Aza group (N=69) and 25.0 months (95% CI [CI], 7.0-39.8) in the Pbo+Aza group (N=11) among patients with MRD 10-3 who achieved CR+CRi. Median overall survival (OS) in patients with CR+CRi and MRD>10-3 was 18.7 months (95% CI, 12.9-23.5 months) in the Ven+Aza group (N=96) and 15.1 months (95% CI, 7.4, 26) in the Pbo+Aza group (N=24).

Median overall survival (OS) was 19.9 months (95% confidence interval [CI], 12.2-27.7) for patients in the IDH1/2 mutant subgroup who received Ven+Aza versus 6.2 months (95% CI], 2.3-12.7) for those who received Pbo+Aza (HR, 0.314; 95% CI, 0.189 to 0.522; P<0.001) (Figure 2). The risk profiles for Ven+Aza and Pbo+Aza were similar overall. 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. 39.0%) were the most common treatment-emergent adverse events of any grade. Thrombocytopenia (45.9% vs. 39.6%), neutropenia (42.8% vs. 28.5%), and febrile neutropenia (42.8% vs. 18.5%) were all AEs that occurred in 10% of patients who received Ven+Aza or Pbo+Aza.

Patients in the Ven+Aza group were more likely to experience serious adverse events than those in the Pbo+Aza group (85.1 vs. 77.1%). Patient groups likely to reap long-term benefits are still being studied. Long-term follow-up from the VIALE-A trial shows that Ven+Aza is superior to Pbo+Aza across all subgroups of patients with AML who are not candidates for aggressive treatment. Notably, the median overall survival (OS) for patients with an MRD of 10-3 who achieved CR+CRi was 34.2 months, while the median OS for patients with IDH1/2 mutations treated with Ven+Aza was just 19.9 months. Long-term survival benefit for Ven+Aza-treated patients is confirmed by a 2-year follow-up study of the VIALE-A trial, with no new safety findings.

Source: https://ash.confex.com/ash/2022/webprogram/Paper158518.html

Clinical trial: https://clinicaltrials.gov/ct2/show/NCT02993523/

Pratz, K. (2022). 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. [online] ash.confex.com. Available at: https://ash.confex.com/ash/2022/webprogram/Paper158518.html.