Michael Severino, MD
The Committee for Medicinal Products for Human Use (CHMP) has recommended approval of venetoclax (Venclexta) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have a 17p deletion (del[17p]) or TP53
mutation and are not good candidates for or have failed on a B-cell receptor (BCR) pathway inhibitor. The potential indication would also be for patients who do not harbor the deletion or mutation but have progressed on both a BCR inhibitor and chemoimmunotherapy.
The positive opinion for the BCL-2 inhibitor has been sent to the European Commission, which usually issues its final approval decision within 2 to 3 months of the CHMP recommendation.
"People living with CLL who have failed other treatments or who harbor the 17p deletion or TP53
mutation have limited options and typically a poor prognosis. Today's CHMP positive opinion marks a major step forward for these patients," Michael Severino, MD, executive vice president of Research and Development and chief scientific officer at AbbVie, which is codeveloping venetoclax with Genentech, said in a statement.
"This innovation delivers on AbbVie's promise to develop cancer medicines where an unmet need exists. We will continue to work with European regulators to make venetoclax available to appropriate CLL patients," added Severino.
In the phase II M13-982 study, venetoclax elicited responses in nearly 80% of patients with relapsed/refractory del(17p) CLL.1
The open-label, single-arm, multicenter trial included 106 patients with relapsed/refractory del(17p) CLL. The median age was 67 years (range, 37-85 years) and patients had received a median of 2.5 prior regimens (range, 1-10). Many of the patients were refractory to fludarabine and bendamustine therapy.
Patients received venetoclax once daily with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over a period of 5 weeks with tumor lysis syndrome prophylaxis. Patients were treated with 400 mg of venetoclax daily dosed continuously until disease progression or discontinuation. As of the interim data cutoff (April 30, 2015), the median time on study was 12.1 months (range, 0.3-21.5 months).
Overall, 79.4% (95% CI, 71%-87%) of the 106 patients evaluated in the clinical trial responded to venetoclax monotherapy according to the independent review committee evaluation, including 8 patients (7.5%) with a complete remission (CR) or a CR with incomplete marrow recovery (CRi). Of 45 patients evaluated for minimal residual disease (MRD), 18 attained MRD-negative status in their peripheral blood.
When presenting the data at the 2015 ASH Annual Meeting, lead study author Stephan Stilgenbauer, MD, of the University of Ulm, Germany, said one of the most noteworthy outcomes of the study was the impact of venetoclax on the change in absolute lymphocyte count among participants. Only 4 of the 87 patients with baseline lymphocytosis did not normalize to <4x109
. In addition, the median time to normalization was 22 days (range, 2-122 days).
The median time to first response was 0.8 months (range, 0.1-8.1 months) and the median time to CR/CRi was 8.2 months (range, 3.0-16.3 months). At 12 months' median follow-up, the median duration of response had not been reached (range, 2.9-19 months).
In the realm of adverse events (AEs), Stilgenbauer said patients treated with venetoclax during the trial experienced AEs that were comparable to or less prevalent than those experienced by individuals receiving frontline chemotherapy.
Ninety-six percent of 103 evaluable patients experienced a treatment-emergent AE of any grade, including 76% with grade 3/4 events. The most common all-grade AEs included neutropenia (43%), diarrhea (29%), and nausea (29%).
Infections occurred in a total of 77 patients (72%), but there were only 16 patients (15%) who had upper respiratory tract infections of any grade including only 2 patients (2%) with grade 3/4 infections. Stilgenbauer said it was “reassuring” that respiratory infections were uncommon and that the overall infection rate was “lower than expected in this high-risk population.”
Simultaneous with the presentation of the phase II data at ASH, results of a phase I dose-escalation study of venetoclax among patients with CLL were published in The New England Journal of Medicine
In this study, the ORR was 79% with venetoclax among 116 patients treated during the study, including a CR in 20% of participants. The 15-month progression-free survival estimate for patients who received the highest dose of 400 mg per day was 69%.
All participants in that study had relapsed CLL and more than one-third were refractory to their last treatment, but the study was not restricted to patients with a 17p deletion.
- Stilgenbauer S, Eichhorst BF, Schetelig JS, et al. Venetoclax (ABT-199/GDC-0199) monotherapy induces deep remissions, including complete remission and undetectable MRD, in ultra-high risk relapsed/refractory chronic lymphocytic leukemia with 17p deletion: results of the pivotal international phase II study. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract LBA6.
- Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Eng J Med. 2016;374(4):311-322.