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FDA Approves Ibrutinib in Combination With Obinutuzumab in Treatment-Naive CLL/SLL


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ON JANUARY 28, 2019, the U.S. Food and Drug Administration (FDA) approved ibrutinib (Imbruvica), a Bruton’s tyrosine kinase inhibitor, in combination with obinutuzumab in treatment-naive patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). This is the first approval of a nonchemotherapy combination regimen for treatment-naive patients with CLL/SLL.

iLLUMINATE Trial

THIS APPROVAL is based on results from the phase III iLLUMINATE trial. At a median follow-up of 31 months, ibrutinib plus obinutuzumab showed a significant improvement in independent review committee–evaluated progression-free survival compared with chlorambucil plus obinutuzumab (median not evaluable vs 19 months; hazard ratio [HR] = 0.23; 95% confidence interval [CI] = 0.15–0.37; P < .0001), with a 77% reduction in the risk of disease progression or death.

Patients with high-risk disease (17p deletion/TP53 mutation, 11q deletion, or unmutated immunoglobulin heavy chain variable region gene) treated with ibrutinib plus obinutuzumab experienced an 85% reduction in the risk of disease progression or death (HR = 0.15; 95% CI = 0.09–0.27). The independent review committee–evaluated overall response rate was 89% with ibrutinib plus obinutuzumab vs 73% with chlorambucil plus obinutuzumab.

The data were presented in an oral session at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 691)1 and simultaneously published by Moreno et al in The Lancet Oncology.2

Safety

WARNINGS AND precautions with ibrutinib include hemorrhage, infections, cytopenias, cardiac arrhythmia, hypertension, second primary malignancies, tumor-lysis syndrome, and embryofetal toxicity. The most common adverse reactions (occurring in 20% or more of patients) of all grades in patients treated with ibrutinib plus obinutuzumab in the iLLUMINATE study were neutropenia (48%), thrombocytopenia (36%), rash (36%), diarrhea (34%), musculoskeletal pain (33%), bruising (32%), cough (27%), infusion-related reaction (25%), hemorrhage (25%), and arthralgia (22%).

The recommended dose of ibrutinib for CLL/SLL is 420 mg orally once daily until disease progression or unacceptable toxicity as a single agent or in combination with obinutuzumab or bendamustine and rituximab.

The FDA also updated the ibrutinib label to include additional long-term efficacy data supporting its use as monotherapy for CLL/SLL, with approximately 5 years of follow-up from the phase III RESONATE and RESONATE-2 international studies.

REFERENCES

1. Moreno C, Greil R, Demirkan F, et al: Ibrutinib + obinutuzumab versus chlorambucil + obinutuzumab as first-line treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: Results from phase 3 iLLUMINATE. 2018 ASH Annual Meeting & Exposition. Abstract 691. Presented December 3, 2018.

2. Moreno C, Greil R, Demirkan F, et al: Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 20:43-56, 2019.


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