FDA Approves Venetoclax/Obinutuzumab Combo for Frontline CLL

The FDA has approved the combination of venetoclax (Venclexta) and obinutuzumab (Gazyva) for the frontline treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.

The approval is based on findings from the phase III CLL14 trial, in which the venetoclax combination reduced the risk of disease progression or death by 67% versus obinutuzumab plus chlorambucil in patients with treatment-naïve CLL and co-existing medical conditions (HR, 0.33; 95% CI, 0.22-0.51; P <.0001).

The overall response rate (ORR) was 85% (95% CI, 79%-89%) with venetoclax/obinutuzumab versus 71% (95% CI, 65%-77%) in the control arm (P = .0007). The complete response (CR) or CR with incomplete hematologic recovery (CRi) rates were 50% versus 23%, respectively (P <.0001).

The rate of minimal residual disease (MRD)-negativity in the bone marrow was 57% in the venetoclax arm compared with 17% in the obinutuzumab/chlorambucil arm. The MRD-negativity rates in the peripheral blood were 76% versus 35%, respectively.

"Patients never treated for their CLL have had to rely largely on chemotherapy as their initial treatment," lead CLL14 investigator Michael Hallek, MD, Department of Internal Medicine and Center of Integrated Oncology at the University Hospital Cologne in Germany, and Head of the German CLL Study Group, said in a press release.

"The approval of the Venclexta combination means that patients with previously untreated CLL now have a finite duration, chemotherapy-free treatment option that can allow them to live longer without disease progression, induce high rates of minimal residual disease negativity and, importantly, allow them to complete their course of therapy within 12 months. This is a major step forward in how previously untreated CLL is managed and further supports the growing benefits offered by Venclexta in CLL," added Hallek.

In the open-label, multicenter, phase III CLL14 trial (NCT02242942), the combination of fixed-duration venetoclax and obinutuzumab was compared with obinutuzumab and chlorambucil in 432 treatment-naïve patients with CLL and coexisting medical conditions. Patients were evenly randomized to receive 12 months of venetoclax alongside 6 months of obinutuzumab or 6 months of obinutuzumab followed by 6 months of chlorambucil.

Baseline characteristics were well balanced between the treatment arms. The median patient age was 72 years (range, 41-89), 67% were male, and 89% were white. The majority (88%) of patients had an ECOG performance status <2.

The primary endpoint of the trial was investigator-assessed progression-free survival (PFS); secondary endpoints included independent review committee—assessed PFS, MRD status, ORR, CR, CRi, overall survival, duration of response, event-free survival, time to next CLL treatment, and safety.

The median duration of follow-up was 28 months (range, 0.1-36). Median PFS was not reached in either arm.

The safety evaluation included 212 patients on the venetoclax arm and 214 patients on the control arm. Across all grade the most common adverse events (AEs) were neutropenia (60%), diarrhea (28%), fatigue (21%), nausea (19%), anemia (17%), and upper respiratory tract infection (17%).

The most common grade ≥3 AEs in the venetoclax arm were neutropenia (56% versus 52% in the control arm), anemia (8% vs 7%), diarrhea (4% vs 1%), vomiting (1% each), fatigue (2% vs 1%), and upper respiratory tract infection (1% each). In the venetoclax arm, AEs led to dose interruptions in 74% of patients, dose reductions in 21% of patients, and treatment discontinuation in 16% of patients.

Complete results of the study are scheduled to be presented early next month at the 2019 ASCO Annual Meeting. The FDA reviewed and approved the application for the venetoclax combination under the Real-Time Oncology Review pilot program, which is designed to have a more efficient review process to make therapies more quickly available to patients.

“Venclexta plus Gazyva is the only chemotherapy-free option of fixed duration that provides durable responses to help people live longer without progression of their disease, compared to a standard of care,” Sandra Horning, MD, chief medical officer and head of Global Product Development, at Roche (Genentech), which manufactures venetoclax (collaboration with AbbVie) and obinutuzumab, said in a press release.

FDA Prescribing Information for Venetoclax. https://www.rxabbvie.com/pdf/venclexta.pdf. Accessed May 15, 2019.