On April 11, 2016, the U. S. Food and Drug Administration approved venetoclax (VENCLEXTA tablets, marketed by AbbVie, Inc. and Genentech USA, Inc.) for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.
The approval was based on the results of a phase 2, single-arm trial of venetoclax for the treatment of patients with CLL harboring the 17p deletion who had received at least one prior therapy. The major efficacy outcome measure was overall response rate (ORR) according to the 2008 Modified IWCLL NCI-WG Guidelines for Tumor Response as evaluated by an independent review committee (IRC). Duration of response (DOR) was an additional outcome measure.
The trial enrolled 106 patients who had received at least one prior therapy with 17p deletion, as detected by an FDA-approved CLL fluorescence in situ hybridization (FISH) probe kit. Patients had a median of 2.5 prior treatments (range 1-10). The ORR by IRC was 80% (95% CI: 71%, 87%) with 8% complete remission (including 2% complete remission with incomplete marrow recovery). Minimal residual disease (MRD) was evaluated in peripheral blood and bone marrow for patients who achieved CR or CRi, following treatment with venetoclax. Three percent of the patients in the intent-to-treat population achieved a complete remission (CR or CRi) and were also negative for MRD in the bone marrow and peripheral blood. The median time to first response was 0.8 months (range: 0.1 to 8.1 months). Median duration of response (DOR) has not been reached with approximately 12 months median follow-up. The DOR ranged from 2.9 to more than 19.0 months.
Safety data were evaluated in 240 patients with previously-treated CLL who were treated with single-agent venetoclax at a target dose of 400 mg orally daily. The most common (greater than or equal to 20%) adverse reactions of any grade were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue. Serious adverse reactions were reported in 44% of patients, and the most common (greater than or equal to 2%) serious adverse reactions were pneumonia, febrile neutropenia, pyrexia, autoimmune hemolytic anemia, anemia, and tumor lysis syndrome (TLS).
Due to a rapid reduction in tumor volume, TLS is an important identified risk when initiating venetoclax. The risk of TLS is reduced with stratification by tumor burden, prophylaxis with hydration and anti-hyperuricemics, frequent blood chemistry monitoring and correction of electrolyte abnormalities. In patients with higher risk features, hospitalization for IV hydration, electrolyte monitoring, and aggressive correction of electrolyte abnormalities may be required. In 66 patients with CLL starting with a daily dose of 20 mg and increasing over 5 weeks to a daily dose of 400 mg, the rate of TLS was 6% with no clinical events. All events were laboratory TLS and occurred in patients who had a lymph node(s) greater than or equal to 5 cm or ALC greater than or equal to 25 x 109/L.
The recommended dose and schedule for venetoclax for the approved indication is a ramp-up schedule over 5 weeks. Dosing is initiated at 20 mg for 1 week, followed by 1 week at each dose level of 50 mg, 100 mg, and 200 mg, then the recommended daily dose of 400 mg until disease progression or unacceptable toxicity.
This application was approved before the Prescription Drug User Fee Act (PDUFA) goal date of June 29, 2016. Venetoclax received Orphan drug status for the treatment of CLL and was granted Breakthrough Therapy Designation for the 17p deletion CLL development program. The application was granted Priority Review, and the current indication was approved under FDA’s Accelerated Approval Program. A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).