2019 ASCO: CLL14 Trial Evaluates First-Line Venetoclax/Obinutuzumab in Previously Untreated CLL
The phase III CLL14 trial—reported by Fischer et al at the 2019 ASCO Annual Meeting (Abstract 7502) and in The New England Journal of Medicine—found that the BCL2 inhibitor venetoclax plus the monoclonal antibody obinutuzumab prolonged progression-free survival vs obinutuzumab and chlorambucil in patients with previously untreated chronic lymphocytic leukemia (CLL) and coexisting conditions. The trial supported the recent regulatory approval of venetoclax in previously untreated CLL.
Study Details
The open-label study included 432 patients with a score > 6 on the Cumulative Illness Rating Scale or calculated creatinine clearance < 70 mL/min from 196 sites in 21 countries. Patients were randomly assigned to receive venetoclax/obinutuzumab (n = 216) or obinutuzumab/chlorambucil (n = 216). As noted by the investigators, “With a median age of 72 years and a median Cumulative Illness Rating Scale score of 8, the trial population was representative of most patients with CLL.”
Treatment consisted of twelve 28-day cycles. Obinutuzumab was given at 100 mg on day 1, 900 mg on day 2, 1,000 mg on day 8, and 1,000 mg on day 15 of cycle 1, and then 1,000 mg on day 1 of cycles 2 through 6. Chlorambucil was given at 0.5 mg/kg on days 1 and 15 of each cycle until completion of 12 cycles. Venetoclax was initiated on day 22 of cycle 1, with a 5-week dose ramp-up to 400 mg daily for 1 week and continued at 400 mg daily until completion of cycle 12. The primary endpoint was investigator-assessed progression-free survival.
Progression-Free Survival
After a median follow-up of 28.1 months, progression-free survival events had occurred in 30 patients in the venetoclax/obinutuzumab group vs 77 in the obinutuzumab/chlorambucil group (hazard ratio [HR] = 0.35, P < .001). The estimated progression-free survival at 24 months was 88.2% vs 64.1%. The progression-free survival benefit was observed with venetoclax/obinutuzumab in subgroups with TP53 deletion, mutation, or both, and in patients with unmutated immunoglobulin heavy-chain genes.
At the time of analysis, all-cause mortality was 9.3% in the venetoclax/obinutuzumab group vs 7.9% in the obinutuzumab/chlorambucil group (P = .52). Response was achieved in 84.7% vs 71.3% of patients, with a complete response in 49.5% vs 23.1% (both P < .001).
Adverse Events
Grade 3 or 4 adverse events occurred in 78.8% of patients in the venetoclax/obinutuzumab group and in 76.6% of the obinutuzumab/chlorambucil group, with grade 3 or 4 neutropenia occurring in 52.8% vs 48.1% of patients and grade 3 or 4 infections occurring in 17.5% and 15.0%. Adverse events led to treatment discontinuation in 16.0% vs 15.4%.
The investigators concluded, “Among patients with untreated CLL and coexisting conditions, venetoclax/obinutuzumab was associated with longer progression-free survival than chlorambucil/obinutuzumab.”
Disclosure: The study was funded by F. Hoffmann–La Roche and AbbVie. For full disclosures of the study authors, visit coi.ascopubs.org or nejm.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
