Results of the CLL14 trial, which were presented today at the 2019 Annual Meeting of the American Society of Clinical Oncology in Chicago, Illinois, resulted in the approval of the venetoclax combination for these patients in May.
Venetoclax has previously demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL). Now, a new study comparing the treatment in combination with obinutuzumab to the combination of chlorambucil and obinutuzumab has demonstrated that the venetoclax combination is associated with longer progression-free survival among previously untreated patients with CLL and coexisting conditions.
At 24 months, progression-free survival (PFS) was 88.2% among patients receiving venetoclax—obinutuzumab compared with 64.1% among patients receiving chlorambucil–obinutuzumab. This survival benefit was observed regardless of TP53 deletion, mutation, or both, in patients with unmutated IGHV, and in other subgroups.
Results of the CLL14 trial, which were presented today at the 2019 Annual Meeting of the American Society of Clinical Oncology in Chicago, Illinois, and published in the New England Journal of Medicine, led to the approval of the venetoclax combination for these patients in May.
The phase 3 trial spread across 21 countries at 196 sites and enrolled 432 patients with CD20+ CLL who were randomized 1:1 to receive either venetoclax—obinutuzumab or chlorambucil–obinutuzumab for 12 cycles of treatment that lasted 28 days each.
Obinutuzumab was administered intravenously for 6 cycles starting with 100 mg on day 1 and 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15 of cycle 1, and subsequently 1000 mg on day 1 during cycles 2 through 6. Chlorambucil was administered orally at 0.5 mg/kg on days 1 and 15 of each cycle until completion of the 12 cycles. Venetoclax was initiated on day 22 of cycle 1, starting with a 5-week dose ramp-up (1 week each of 20, 50, 100, and 200 mg, then 400 mg daily for one week), and then was administered at 400 mg daily until completion of cycle 12.
At data cutoff, patients had discontinued therapy for a median of 17.1 months in the venetoclax—obinutuzumab group and 17.9 months in the chlorambucil–obinutuzumab group.
In the 3 months following completion, there were higher rates of patients in the venetoclax group who were negative for minimal residual disease in peripheral blood (75.5% vs 35.2%) and in bone marrow (56.9% vs 17.1%).
“Minimal residual disease negativity was consistently more common across all subgroups and was more sustainable with venetoclax—obinutuzumab than with chlorambucil–obinutuzumab,” explained the researchers.
Patients treated with the venetoclax combination also had significantly higher rates of partial response (84.7% vs 71.3%) and complete response (49.5% vs 23.1%).
After median follow-up of 28.1 months, there were 14 events of disease progression and 16 deaths among those receiving venetoclax—obinutuzumab and 69 events of disease progression and 8 deaths among those receiving chlorambucil–obinutuzumab.
Median overall survival (OS) was not reached in either treatment group, and during the complete observation period, OS did not differ significantly between the 2 groups.
There was at least 1 adverse event of any grade among 94.3% of patients receiving venetoclax—obinutuzumab and in 99.5% of patients receiving chlorambucil–obinutuzumab. These adverse events resulted in treatment discontinuation among 16% of patients receiving the venetoclax combination and among 15.4% of patients receiving the chlorambucil combination.
The most common grade 3 or 4 adverse event was febrile neutropenia, and grade 3 or 4 infections were reported in 5.2% and 17.5% of patients receiving the venetoclax combination, respectively, and in 3.7% and 15% of patients receiving the chlorambucil combination, respectively. During treatment, 5 fatal adverse events occurred in the venetoclax—obinutuzumab group and 4 occurred in the chlorambucil–obinutuzumab group. Following treatment, 11 fatal adverse events occurred in the venetoclax–obinutuzumab group and 4 occurred in the chlorambucil–obinutuzumab group.
Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions [published online June 4, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1815281.