FDA Grants Venetoclax Breakthrough Designation for CLL

May 7, 2015

The FDA has granted a breakthrough therapy designation to the Bcl-2 inhibitor venetoclax (GDC-0199/ABT-199) for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia who harbor a 17p deletion (del[17p]).

Sandra Horning, MD

The designation will help expedite the companies’ development of venetoclax. AbbVie and Genentech plan to file for regulatory approval of the agent before the end of the year.

“The breakthrough therapy designation of venetoclax supports the continued development of this investigational medicine in CLL patients with 17p deletion,” Michael Severino, MD, executive vice president of Research and Development and chief scientific officer at AbbVie, said in a statement.

Previously released data have demonstrated the efficacy of venetoclax for use as a single agent and in combination regimens to treat patients with CLL.

In a phase Ib trial presented at the 2014 ASCO Annual Meeting, single-agent venetoclax had an objective response rate (ORR) of 79%. ORR was 78% and 79% for patients with del(17p) and fludarabine (F)-refractory CLL, respectively. The median duration of response was 20.5 months.

The ORR included a 22% combined rate of complete remission (CR) and CR with incomplete blood count recovery (CRi). At 1-year, 91% of patients achieving a CR and 65% of those who had a partial response remained progression-free. Nine of the 14 patients who achieved a CR/CRi were evaluable for minimal residual disease (MRD), with five testing MRD-negative, four of who were F-refractory.

The most frequently reported all-grade adverse events (AEs) included diarrhea (37%), nausea (36%), neutropenia (35%), upper respiratory tract infection (29%), and fatigue (27%). Grade 3/4 toxicities affecting at least three patients included neutropenia (32%), anemia (8%), tumor lysis syndrome (TLS; 8%, including 1 G5), and febrile neutropenia, thrombocytopenia, hyperglycemia, and hypokalemia (6% each). At the time of the data cutoff, 28 patients had discontinued treatment, including 18 for progressive disease, eight for toxicity, and two for other circumstances.

Data from a phase Ib, open-label, dose-escalation, multicenter study presented at the 2014 ASH Annual Meeting showed an ORR of 88% with venetoclax plus rituximab (Rituxan) in 34 evaluable patients with relapsed/refractory CLL. Eleven patients (32%) had a CR/CRi. Fourteen patients tested MRD-negative, 13 in bone marrow and one in peripheral blood.

The most common all-grade AEs were neutropenia (47%), nausea (41%), diarrhea (37%), pyrexia (31%), headache (31%), fatigue, upper respiratory tract infection, and cough (each 29%). Neutropenia (47%), thrombocytopenia (16%), and anemia (14%) were the most frequently reported grade 3/4 AEs. Forty-one percent of patients had serious AEs, including pyrexia in 6% and 4% each with febrile neutropenia, infusion-related reaction, TLS, and Richter’s transformation.

There was one patient fatality due to hyperkalemia in the setting of TLS. The event led to a modified dosing scheme, with no TLS reported in 32 patients subsequently dosed under the new design. Based on the toxicity profile, the recommended dosage for a higher-stage trial was 400 mg daily.

Combination therapy with venetoclax and the BTK-inhibitor ibrutinib (Imbruvica) demonstrated promising early activity in CLL cell lines, according to data presented at a special AACR conference focused on hematologic malignancies that was held in September 2014.

In the analysis, synergistic apoptosis was observed with the combination of venetoclax and ibrutinib in circulating tumor cells (CTCs) from patients with CLL and mantle cell lymphoma. Molecular analysis in the study suggested that interactions between p53 and BIM were responsible for the synergy between the two agents. Moreover, off-target apoptosis was not seen in normal T cells.

Venetoclax has also shown promise in acute myeloid leukemia and is being examined in other hematologic malignancies.

Tremendous progress has been made in CLL in recent years, with ASCO even naming the vastly improved outlook for patients with CLL as its inaugural “Cancer Advance of the Year” in January. ASCO was specifically recognizing the approval of four new therapeutic options for CLL over 2013/2014: ibrutinib, idelalisib (Zydelig), obinutuzumab (Gazyva), and ofatumumab (Arzerra). If eventually approved, venetoclax would add yet another CLL treatment option, particularly for those high-risk patient subsets with del(17p).

“People who have relapsed or refractory CLL with a 17p deletion typically have a poor prognosis, and do not respond to many currently available treatment options,” Sandra Horning, MD, Chief Medical Officer and Head of Global Clinical Development at Genentech, said in a statement. “We are pleased that the FDA has granted venetoclax breakthrough therapy designation and hope this regulatory pathway will help us bring venetoclax to people with this difficult-to-treat disease soon.”