The FDA ( U.S. Food and Drug Administration ) has provided full approval to Venclexta ( Venetoclax ) in combination with Azacitidine, or Decitabine, or low-dose Cytarabine ( LDAC ) for the treatment of newly-diagnosed acute myeloid leukemia ( AML ) in adults who are age 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.
The approval is supported by data from the phase 3 VIALE-A ( M15-656 ) and VIALE-C ( M16-043 ) studies and updated data from the phase 1b M14-358 and the phase 1/2 M14-387 studies.
The FDA previously granted accelerated approval to VENCLEXTA for this indication in 2018.
The approval is significant because data from VIALE-A trial has shown that newly-diagnosed patients, who cannot undergo intensive chemotherapy, lived longer when treated with Venetoclax plus Azacitidine than those treated with Azacitidine alone.
Positive overall survival ( OS ) data seen at an interim analysis of the VIALE-A trial led to an early submission supporting the FDA approval of Venclexta in acute myeloid leukemia.
The trial showed patients on the active regimen of Venetoclax plus Azacitidine achieved a 34% reduction in the risk of death compared to Azacitidine in combination with placebo ( hazard ratio [ HR ]=0.66 [ 95% CI: 0.52-0.85 ], p less than 0.001 ).
The median overall survival for patients in the Venetoclax arm was 14.7 months ( 95% CI: 11.9, 18.7 ) versus 9.6 months in the placebo arm ( 95% CI: 7.4, 12.7 ).
Additionally, patients in the Venetoclax plus Azacitidine arm achieved a complete remission ( CR ) rate of 37% ( 95% CI: 31%, 43% ) with a median duration of CR of 18.0 months ( 95% CI: 15.3, - ) compared with patients in the placebo plus Azacitidine arm with a CR rate of 18% ( 95% CI: 12%, 25% ) with a median duration of CR of 13.4 months ( 95% CI: 8.7, 17.6 ).
The observed safety profile was generally consistent with the known safety profile of Venetoclax in combination with Azacitidine.
For patients taking Venetoclax in combination with Azacitidine, the most frequent serious adverse reactions ( ARs; greater than or equal to 5% ) at first use were febrile neutropenia ( 30% ), pneumonia ( 22% ), sepsis ( excluding fungal; 19% ) and hemorrhage ( 6% ).
In the VIALE-C trial the median overall survival for Venetoclax in combination with LDAC was 7.2 months ( 95% CI: 5.6, 10.1 ) and 4.1 months for LDAC in combination with placebo ( 95% CI: 3.1, 8.8 ).
The hazard ratio for the primary endpoint of overall survival was 0.75 ( 95% CI: 0.52-1.07; p=0.114 ).
The trial did not meet its primary endpoint of statistically significant improvement of overall survival for patients with AML who are ineligible for intensive chemotherapy at the time of the planned analysis.
Efficacy was based on the rate of CR and duration of CR with supportive evidence of rate of CR + complete remission with partial hematologic recovery ( CR+CRh ), duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence.
In the Venetoclax arm, the most frequent serious adverse reactions were ( 10% or more ) pneumonia ( 17% ), febrile neutropenia ( 16% ) and sepsis ( excluding fungal; 12% ).
Acute myeloid leukemia is an aggressive and difficult-to-treat blood cancer with a low survival rate. Despite recent advances in available therapies, the five-year survival rate for patients diagnosed with acute myeloid leukemia remains approximately 29%.
Acute myeloid leukemia typically worsens quickly, and due to age or comorbidities, not all patients are eligible to receive intensive chemotherapy. ( Xagena )
Source: Abbvie, 2020