Efficacy
In the phase Ib/II study, the complete remission (CR) plus complete remission with incomplete blood count recovery (CRi) rate was 54% with median time to first CR/CRi 1.4 months (range, 0.8 to 14.9 months). Patients with de-novo AML (CR/CRi 71%), intermediate-risk cytogenetics (CR/CRi 63%) and without prior HMA exposure (CR/CRi 62%) had the highest rates of CR/CRi. For patients achieving CR/CRi after venetoclax plus LDAC (Ven/LDAC), the median duration of remission was 8.1 months (95% CI, 5.3 to 14.9 months). The median OS for all patients was 10.1 months (95% CI, 5.7 to 14.2 months). Survival was better for patients achieving CR/CRi, and patients with no response had poor outcomes (Figure 1). Patients without prior HMA exposure had a longer median OS than patients previously treated with HMA (13.5 months vs 4.1 months). Patients with mutations in NPM1 or IDH1/2 had above average CR/CRi rates (89% and 72%, respectively), whereas those with p53 or FLT3 mutations had lower CR/CRi rates (30% and 44%), respectively.r
Figure 1: Overall survival based on response in the phase Ib/II studyr
© Journal of Clinical Oncology 2019
In the phase III trial, pre-planned analysis at 12 months (Figure 2A) showed 40% (57 of 143) and 31% (21 of 68) of patients remained alive in the venetoclax and placebo arms, respectively. Median OS for patients treated with venetoclax plus LDAC was 7.2 months vs. 4.1 months for the placebo plus LDAC, with a hazard ratio (HR) (venetoclax vs. placebo) of 0.75 (95% CI, 0.52-1.07). There was no significant benefit with Ven/LDAC over LDAC monotherapy; however, this initial analysis was associated with early censoring of patients with less than 6 months follow-up. Additional follow-up at 18 months (Figure 2B) showed majority of patients passed the median OS in both arms (8.4 months for Ven/LDAC vs 4.1 months for LDAC/placebo). HR between venetoclax vs placebo treatment arms after this additional follow-up was 0.70 (95% CI, 0.50-0.99, p=0.04).r
Figure 2: Overall survival in the phase 3 trialr
© Blood 2020
Post-hoc analysis of variables revealed significant factors associated with response to venetoclax. CR/CRi and CR was achieved in 48% and 27% of patients receiving venetoclax, compared to 13% and 7% in the placebo arm. Responses in the venetoclax arm were faster, with higher remission rates accompanied by a longer median EFS (4.7 months vs. 2 months). Rates of transfusion independence were higher for venetoclax-treated patients compared to those receiving LDAC alone (37% vs. 16%). Patient subgroups with NPM1- (median OS not reached) and IDH1/2-mutant AML (median OS 19.4 months) demonstrated promising survival outcomes.r
Longer term follow-up with 2 years of follow-up in the final analysis showed, with a median follow-up of 34.7 months, that median OS with Ven/LDAC vs. LDAC/placebo was unchanged (8.4 vs. 4.1 months). Two-year OS was 21.5% vs. 12.4%. No new adverse event signal was noted.r
A key difference between VIALE-A (azacitidine plus venetoclax vs. azacitidine plus placebo) and VIALE-C is that VIALE-C included patients who had received prior HMA therapy (20% of patients included). Patients who did not receive prior HMA treatment had a longer OS (8.9 months (95% CI, 6.6-10.9)) than those who received prior HMA therapy (5.6 months (95% CI, 3.4-9.6)). OS was greater for those with de novo AML vs. secondary AML (9.2 vs.5.6 months). Patients with NPM1 mutations had the best OS; median OS was 25.3 (95% CI, 9.9-not reached), 11.2 (95% CI, 3.4-23.6), 5.9 (95% CI, 1.6-20.8), and 2.8 (95% CI, 2.1-3.6) months in patients with NPM1, IDH1/2, FLT3, and TP53 mutations, respectively. CR/CRi responses in patients who received Ven/LDAC were durable, with 31.6% remaining in remission for more than 2 years.r
In addition to the inclusion of those patients with prior HMA therapy (who had poorer survival outcomes), VIALE-C recruited fewer patients, and targeted a more aggressive HR for OS compared with VIALE-A; factors that would impact survival outcomes in VIALE-C compared to VIALE-A.rr