Venetoclax plus ibrutinib may induce treatment-free remission in patients with CLL
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Patients with chronic lymphocytic leukemia with undetectable minimal residual disease after first-line venetoclax plus ibrutinib achieved similar 1-year DFS whether they then received ibrutinib or placebo, according to study results.
These data from the phase 2 CAPTIVATE study, presented at the virtual ASH Annual Meeting and Exposition, suggest first-line venetoclax (Venclexta; AbbVie, Genentech) plus ibrutinib (Imbruvica; AbbVie/Pharmacyclics, Janssen) induced deep minimal residual disease (MRD) remission without the need for further treatment.
“The 1-year DFS rate of 95% in patients [randomly assigned] to placebo was similar to the rate for patients [randomly assigned] to ibrutinib, which supports a fixed-duration treatment after 12 cycles of the combination regimen and treatment discontinuation for patients who achieve confirmed undetectable minimal residual disease,” William G. Wierda, MD, PhD, researcher in the department of leukemia at The University of Texas MD Anderson Cancer Center, said during a presentation.
“Ibrutinib, a once-daily Bruton tyrosine kinase inhibitor, is the only targeted therapy to demonstrate significant OS benefit in randomized phase 3 studies in first-line CLL. Ibrutinib and venetoclax have synergistic and complementary antitumor activity via mobilization and clearance of CLL cells from protective niches and disease compartments beyond blood and bone marrow,” Wierda said.
The CAPTIVATE study aimed to evaluate first-line treatment with 12 cycles of ibrutinib plus venetoclax within two patient cohorts, including a MRD and fixed-duration cohort.
For the current analysis, researchers evaluated whether the combination regimen would lead to treatment-free remission at 1 year for those with confirmed undetectable MRD.
The study enrolled 164 patients (median age, 58 years; range, 28-69) with previously untreated CLL. Common baseline high-risk features among the cohort included deletion 17p (16%), deletion 11q (17%), deletion 17p or TP53 mutation (20%), complex karyotype (19%) and unmutated IGHV (60%).
Patients received three cycles of lead-in ibrutinib followed by 12 cycles of ibrutinib, dosed at 420 mg orally once daily, plus venetoclax, with a ramp-up to 400 mg orally once daily.
Previously reported data from this pre-randomization phase showed the combination induced high rates of undetectable MRD in the peripheral blood (75%) and bone marrow (72%).
Researchers randomly assigned patients with confirmed undetectable MRD after treatment completion 1:1 to placebo or ibrutinib. Patients without confirmed undetectable MRD were randomly assigned 1:1 to open-label treatment with ibrutinib or the combination regimen until disease progression.
DFS at 1 year in the confirmed undetectable MRD cohort served as the primary endpoint. Rates of undetectable MRD, response per International Workshop Group on CLL guidelines, PFS and safety served as secondary endpoints.
At a median 31.3 months (range, 15- 41), 90% of patients had completed the planned treatment protocol. Of these, 58% had confirmed undetectable MRD — defined as 100% undetectable MRD in the peripheral blood and bone marrow — and were randomly assigned to placebo (n = 43) or ibrutinib (n = 43). The 42% of patients who did not achieve undetectable MRD were randomly assigned to ibrutinib (n = 31) or continued on the combination regimen (n= 32).
Results showed DFS at 1 year in the confirmed undetectable MRD group was 95.3% (95% CI, 82.7-98.8) with placebo compared with 100% (95% CI, 100-100) with ibrutinib.
Among those with undetectable MRD, rates improved from 48% to 57% in peripheral blood and from 32% to 54% in bone marrow after random assignment to ibrutinib or the combination regimen.
PFS at 30 months was greater than 95% across all treatment arms.
The most common grade 3 or grade 4 adverse events among the overall study population included neutropenia (36%), hypertension (10%) thrombocytopenia (5%) and diarrhea (5%).
“Few patients required dose adjustment or treatment discontinuation,” Wierda said. “Adverse events generally decreased after the first 6 months of ibrutinib plus venetoclax combination and no new safety signals emerged over time.”
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Wierda WG, et al. Abstract 123. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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