Phase III VIALE-C trial | Venetoclax + LDAC fails to show improvement in OS for newly diagnosed patients with AML who are ineligible for intensive induction therapy

On February 28, 2020, it was announced that the VIALE-C trial, comparing venetoclax plus low dose cytarabine (LDAC) to placebo plus LDAC, failed to meet the primary endpoint of significant improvement in overall survival (OS) in patients with treatment-naïve acute myeloid leukemia (AML).¹ On the same date, results from the primary analysis were published on ClinicalTrials.gov.²

In November 2018, the U.S. Food & Drug Administration (FDA) granted accelerated approval to venetoclax in combination with azacitidine, decitabine, or LDAC for patients with newly diagnosed AML who were ineligible for intensive induction chemotherapy. The approval for venetoclax plus LDAC was based on promising results reported from a phase I/II trial (NCT02287233), previously reported by the AML Hub.³ The FDA approved the combination but required that the clinical benefit was be verified in a confirmatory trial — VIALE-C.⁴ No comment has been made from the FDA in light of the announcement and the indications for venetoclax currently remain unchanged.¹

Background: VIALE-C (M16-043; NCT03069352)

Given as venetoclax + LDAC vs placebo + LDAC throughout

• A randomized, double-blind, placebo-controlled phase III trial in patients with newly diagnosed AML who were ineligible for intensive chemotherapy¹
  • Median patient age: 76 (range, 36–93) vs 76 (range, 41–88)²
• Randomized (2:1) to either¹:
  • Venetoclax + LDAC (n = 143)
  • Venetoclax + placebo (n = 68)
  • Stratified by AML status (secondary or de novo), age (18–75 or ≥ 75) and region (US, European Union, China, Japan, or rest of world)²
• Dosing schedule²:
  • Venetoclax: 600 mg orally, once per day
  • Placebo: matched to venetoclax dosing
  • LDAC: 20 mg/m² subcutaneously on Days 1–10 of each 28-day cycle
  • Continued until disease progression, unacceptable toxicity, or withdrawal of consent
• In total, 142 patients in the venetoclax + LDAC and 68 in the placebo + LDAC arm received treatment with 103 and 56 completing treatment, respectively^1,2
• Median follow-up for primary analysis in both arms: 12 months¹

Results

Primary endpoint: OS¹

• Venetoclax + LDAC led to a 25% reduction in the risk of death vs placebo + LDAC. This was not statistically significant:
  • Hazard ratio (HR) 0.75 (95% CI, 0.52–1.07), p = 0.11
• Median OS:
  • At primary analysis: 7.2 vs 4.1 months
  • Post-hoc analysis with a further 6 months follow-up: 8.4 vs 4.1 months
    • HR 0.70 (95% CI, 0.50–0.99)

Secondary endpoints

• Complete remission (CR): 27.3% vs 7.4%¹
• CR or CR with incomplete blood count recovery (CRi): 47.6% vs 13.2%¹
• CR or CR with partial hematologic recovery: 46.9% vs 14.7%¹
• CR or CRi by initiation of Cycle 2: 34.3% vs 2.9%¹
• Event-free survival: 4.7 vs 2.0 months²
  • HR 0.58 (95% CI, 0.42–0.82), p = 0.002
• Patients with CR + CRi and minimal residual disease response: 5.6% vs 1.5%²

Safety

• The safety profile was consistent with previous trials reporting on this combination¹
• Serious adverse events (SAEs) were experienced by 66.9% of patients in the venetoclax + LDAC group and 61.8% in the placebo + LDAC group¹
• The most common SAEs were¹:
  • Febrile neutropenia: 16.9% vs  17.7%
  • Neutropenia: 2.8% vs 0%
  • Thrombocytopenia: 4.9% vs 2.9%
  • Anemia: 2.8% vs 0%
• Median time on study: 17.7 (0.2–20.8) vs 17.5 (0.1–23.5) months²

Future directions

In the founding phase I/II trial, venetoclax plus LDAC led to a median OS of 10.1 months (95% CI, 5.7–14.2) with a median duration of remission for patients in CR/CRi of 8.1 months (95% CI, 5.3–14.9). The authors of the phase I/II study concluded that the combination was tolerable and induced high remission rates.⁴ However, in this confirmatory phase III study, median OS with venetoclax plus LDAC was 7.2 months compared to 4.1 months with LDAC alone. This represented a 25% reduction in the risk of death compared to LDAC alone, which was not statistically significant.¹  

The results from this study are expected to be presented at an upcoming medical congress and published in full in due course.