FDA Approves Venetoclax in Combination for AML in Adults

November 21, 2018

On November 21, 2018, the Food and Drug Administration granted accelerated approval to venetoclax (VENCLEXTA®, AbbVie Inc. and Genentech Inc.) in combination with azacitidine or decitabine or low-dose cytarabine 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 use of intensive induction chemotherapy.

Approval was based on two open-label non-randomized trials in patients with newly- diagnosed AML who were > 75 years of age or had comorbidities that precluded the use of intensive induction chemotherapy. Efficacy was established based on the rate of complete remission (CR) and CR duration.

Study M14-358 (NCT02203773) was a non-randomized, open-label clinical trial of venetoclax in combination with azacitidine (n=67) or decitabine (n=13) in newly- diagnosed patients with AML. In combination with azacitidine, 25 patients achieved a CR (37%, 95% CI: 26, 50) with a median observed time in remission of 5.5 months (range: 0.4-30 months). In combination with decitabine, 7 patients achieved a CR (54%, 95% CI: 25, 81) with a median observed time in remission of 4.7 months (range: 1.0-18 months). The observed time in remission is the time from start of CR to data cut-off date or relapse from CR.

Study M14-387 (NCT02287233) was a non-randomized, open-label trial of venetoclax in combination with low-dose cytarabine (n=61) in newly-diagnosed patients with AML, including patients with previous exposure to a hypomethylating agent for an antecedent hematologic disorder. In combination with low-dose cytarabine, 13 patients achieved a CR (21%, 95% CI: 12, 34) with a median observed time in remission of 6 months (range: 0.03-25 months).

The most common adverse reactions (≥30%) to venetoclax in combination with azacitidine or decitabine or low-dose cytarabine were nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, peripheral edema, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, back pain, myalgia, dizziness, cough, oropharyngeal pain, pyrexia, and hypotension.

The recommended venetoclax dose depends upon the combination regimen and is described in prescribing information for VENCLEXTA.

This indication is approved under accelerated approval and continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. FDA granted this application priority review, breakthrough therapy designation and orphan product designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

The ongoing phase 3 studies, VIALE-A (NCT02993523) and VIALE-C (NCT03069352), evaluate venetoclax in combination with azacitidine or low-dose cytarabine with overall survival as the primary endpoint and are intended as the confirmatory trials.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

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