SUMMARY: The FDA on November 21, 2018 granted accelerated approval to VENCLEXTA® (Venetoclax) 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. The American Cancer Society estimates that in 2018, 19,520 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,670 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy. Even with the best available therapies, the 5 year Overall Survival in patients 65 years of age or older is less than 5%.
The pro-survival (anti-apoptotic) protein BCL2 is over expressed by AML cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). VENCLEXTA® is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells.
The present FDA approval was based on two open-label non-randomized clinical trials in patients with newly diagnosed AML who were 75 years of age or older 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.
The M14-358 study is an open-label, phase Ib dose escalation and expansion study which evaluated the safety and efficacy of VENCLEXTA® in combination with HypoMethylating Agents, Azacitidine or Decitabine. This study included a subpopulation of 80 patients who received VENCLEXTA® (daily ramp-up to a final dose of 400 mg once daily) in combination with a hypomethylating agent, either Azacitidine (N=67) or Decitabine (N=13). Patients were hospitalized for monitoring during the ramp-up and received prophylaxis for Tumor Lysis Syndrome. Azacitidine was administered at 75 mg/m2 SC or IV on days 1-7 of each 28-day cycle and Decitabine was administered at 20 mg/m2 IV on days 1-5 of each 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity. Majority of patients in each treatment group had an ECOG performance status of 0 or 1. In the Azacitidine group, 64% of patients had intermediate cytogenetic risk and 34% had poor cytogenetic risk whereas this was 38% and 62%, respectively in the Decitabine group.
The median follow up was 7.9 months for the Azacitidine group and 11 months for the Decitabine group. The Complete Response rate was 37% in the Azacitidine group with a median observed time in remission of 5.5 months. The rates of CR with partial hematologic recovery were 24%. In combination with Decitabine, the CR rate was 54%, with a median observed time in remission of 4.7 months. The CR with partial hematologic recovery was 7.7%.
The M14-387 study is an open-label, phase Ib/II dose escalation and expansion study which evaluated the safety and efficacy of VENCLEXTA® in combination with Low Dose Ara-C (Cytarabine). This study included a subpopulation of 61 AML patients who received VENCLEXTA® plus low-dose Cytarabine. Included patients had newly diagnosed AML, and some patients had previous exposure to a HypoMethylating Agent for an antecedent hematologic disorder. Patients received VENCLEXTA® (daily ramp-up to a final dose of 600 mg orally once daily). Patients were hospitalized for monitoring during the ramp-up and received prophylaxis for Tumor Lysis Syndrome. Cytarabine was given at 20 mg/m2 SC on days 1-10 of each 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity.
At a median follow-up of 6.5 months, the CR rate was 21%, with a median observed time in remission of 6 months. The rate of CR with partial hematologic recovery was 21%. The most common adverse reactions to VENCLEXTA® in combination with Azacitidine, Decitabine or low-dose Cytarabine were fever, nausea, vomiting, diarrhea, fatigue, cytopenias, myalgias, dyspnea, peripheral edema and hypotension.
This FDA approval marks a significant advance for patients with Acute Myeloid Leukemia, who are unable to tolerate standard intensive induction chemotherapy. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm626499.htm