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.


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


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.


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.