Venetoclax FDA Submission Imminent Following Phase II CLL Success

Sandra Horning, MD

Sandra Horning, MD

Venetoclax (ABT-199) monotherapy showed promising phase II results, which will be submitted to regulatory agencies for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) harboring the 17p deletion, according to a statement from the codevelopers of the BCL-2 inhibitor, AbbVie and Genentech.

“Approximately 30% to 50% of people with relapsed or refractory chronic lymphocytic leukemia have the 17p deletion that makes their disease difficult to treat,” Sandra Horning, MD, chief medical officer and head of Global Product Development, said in a statement. “Venetoclax may help restore the natural process that allows these leukemic cells to self destruct, representing a potential new way of helping people with this form of CLL who typically have a poor prognosis and limited treatment options.”

Venetoclax received a breakthrough therapy designation from the FDA as a potential treatment for patients with 17p deletion CLL in May 2015. AbbVie and Genentech hope to complete regulatory filings by the end of 2015.

The primary endpoint of the open-label, single-arm phase II study was overall response rates (ORR) assessed using NCI-CWG criteria. Full data from the study were not yet made available and are being submitted for presentation at an upcoming medical meeting.

"The results from this study demonstrate the clinical activity of venetoclax in patients with relapsed/refractory CLL who have 17p deletion, a patient population that has historically been difficult to treat," Michael Severino, MD, executive vice president of research and development and chief scientific officer, AbbVie, said in a statement. "Based on these results, we intend to advance regulatory submissions for venetoclax and remain committed to the further development of this investigational medicine, and others in our pipeline, with the goal of delivering new treatment options for people affected by cancer."

In the study, labeled M13-982, 107 patients were enrolled into a main efficacy cohort, and 50 patients participated in a safety expansion arm. All patients were refractory or had relapsed on at least one prior therapy and had measurable disease. Secondary efficacy endpoints focused on complete response (CR), partial response (PR), and progression-free survival (PFS).

In a preceding phase I study, 105 patients at a median age of 66 years with CLL and small lymphocytic leukemia were treated with venetoclax at varying doses. Patients had received a median of 4 prior therapies and 28% harbored a 17p deletion. Eighty-three percent of patients had received prior therapy with fludarabine.

In results presented at the 2014 ASCO Annual Meeting, patients with deletion 17p CLL (n = 19) experienced an ORR of 79%, which consisted of 5 CRs (26%) and 10 PRs (53%). For patients who received the 400 mg or higher dose of venetoclax, the median PFS had not yet been reached at the April 2014 data cutoff. The estimated 24-month PFS rate at this dose level was 59%. The approximate median PFS across all doses was 18 months. For high-risk patients treated at the 400 mg dose or higher, the 24-month PFS rate was 54% (range, 31-71).

The most frequently reported all-grade adverse events (AEs) across all dose levels included diarrhea (40%), nausea (35%), neutropenia (36%), upper respiratory tract infection (33%), and fatigue (27%). The most frequently grade 3/4 AEs were neutropenia (33%), anemia (10%), and TLS, febrile neutropenia, thrombocytopenia, and hyperglycemia (7% each).

Seymour JF, Davids MS, Pagel JM, et al. ABT-199 (GDC-0199) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): High complete- response rate and durable disease control.J Clin Oncol.2014;32:5s, (suppl; abstr 7015)