News >

FDA Approval Sought for Frontline Venetoclax Combo in AML

Jason M. Broderick @jasoncology
Published: Thursday, Jul 12, 2018

Dr. Sandra Horning
Sandra Horning, MD
A supplemental New Drug Application (sNDA) has been submitted to the FDA for venetoclax (Venclexta) for use in combination with a hypomethylating agent or low-dose cytarabine (LDAC) for the first-line treatment of patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy, according to AbbVie and Genentech, the codevelopers of the BCL-2 inhibitor.

UPDATE 11/21/2018: FDA Approves Frontline Venetoclax in AML

The sNDA, is based on 2 phase Ib/II trials in this setting, the M14-358 study and the M14-387 study.1 In M14-358, combining venetoclax (400 mg) with azacitidine or decitabine led to a complete remission (CR) or CR with incomplete blood count recovery (CRi) rate of 73%. The median overall survival (OS) at >1 year of follow-up was 17.5 months (95% CI, 12.3–not reached).

M14-387 examined venetoclax (600 mg) in combination with LDAC. The CR/CRi rate with the combination in this study was 62%. The median OS at >1 year of follow-up was 11.4 months (95% CI, 5.7-15.7).

“Nearly 20,000 people will be diagnosed with AML in the United States this year, and many of them are not eligible to receive standard intensive chemotherapy,” Sandra Horning, MD, chief medical officer and head of Global Product Development, Genentech, said in a statement. “AML is an aggressive disease with the lowest survival rate of all leukemias, and we look forward to working closely with the FDA to bring this potential option to patients with this very difficult-to-treat blood cancer as soon as possible.”

The phase Ib open-label dose escalation and expansion M14-358 study (NCT02203773) included 212 treatment-naïve patients with AML aged ≥60 years who were not fit to receive intensive chemotherapy. Patients received venetoclax in combination with a hypomethylating agent (azacitidine or decitabine). Key outcome measures for the trial included CR/CRi, OS, and safety. Grade 3/4 adverse events (AEs) occurring in ≥10% of patients included anemia, low platelet count, decreased potassium levels, low white blood cell count with fever, and low white blood cell count.

The open-label phase Ib/II dose escalation and expansion M14-387 study (NCT02287233) included 94 previously untreated patients ≥60 years who were unfit to receive intensive chemotherapy. The main study endpoints were CR/CRi, objective response rate, OS, and safety. Grade 3/4 adverse events (AEs) experienced by at least 10% of patients included sepsis, decreased phosphate levels, high blood pressure, decreased potassium levels, pneumonia and low white blood cell count with fever.

In January 2016 venetoclax received an FDA breakthrough therapy designation for use in combination with hypomethylating agents in previously untreated patients with AML who are not eligible for standard high-dose induction treatment. In July 2017, the FDA granted venetoclax a breakthrough therapy designation for use in combination with LDAC in treatment-naïve elderly patients with AML who are ineligible for intensive chemotherapy.

The FDA breakthrough designation expedites the development and review of treatments that have demonstrated early potential to significantly improve outcomes over standard therapy for a serious condition.

In April 2016, the FDA granted an accelerated approval to venetoclax for patients with CLL harboring a 17p deletion, following at least 1 prior therapy. This was converted to a full approval in June 2018 when the FDA issued a standard approval to venetoclax for the treatment of patients with CLL/ SLL, with or without a 17p deletion, following at least 1 prior therapy. The FDA simultaneously approved venetoclax for use in combination with rituximab (Rituxan) in the same patient population.   

The FDA based this decision on the phase III MURANO trial, in which the median progression-free survival at 23 months' median follow-up was not reached with venetoclax plus rituximab compared with 18.1 months (95% CI, 15.8-22.3) with bendamustine plus rituximab (HR, 0.19; 95% CI, 0.13-0.28; P <.0001).2 The overall response rate was 92% versus 72%, respectively.


  1. Genentech Announces Submission of Supplemental New Drug Application for Venclexta for People With Previously Untreated Acute Myeloid Leukemia who are Ineligible for Intensive Chemotherapy. Published July 12, 2018. Accessed July 12, 2018.
  2. Seymour JF, Kippes TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia [published online March 22, 2018]. N Engl J Med. 2018; 378:1107-1120. doi: 10.1056/NEJMoa1713976.

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Publication Bottom Border
Border Publication