Ibrutinib in combination with obinutuzumab has been approved by the FDA for treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). This is the first approval for a non-chemotherapy combination regimen for treatment-naïve patients with CLL/SLL, and marks the tenth FDA approval for ibrutinib since its U.S. launch in November 2013. The approval expands the label for ibrutinib in frontline CLL/SLL beyond its use as a monotherapy to include combination use with obinutuzumab.
“In just a few years, ibrutinib has become an important treatment for chronic lymphocytic leukemia. Ibrutinib as a single agent—and now as a combination with obinutuzumab—provides patients with CLL with an alternative to frontline treatment with chemoimmunotherapy,” said Carol Moreno, MD, PhD, Consultant Hematologist, Hospital de la Santa Creu Sant Pau, Autonomous University of Barcelona, and lead investigator of the iLLUMINATE study.
This approval is based on results from the phase III iLLUMINATE study (PCYC-1130). At a median follow-up of 31 months, ibrutinib plus obinutuzumab showed a significant improvement in Independent Review Committee (IRC)-evaluated progression-free survival compared with chlorambucil plus obinutuzumab (median not evaluable vs. 19 months; HR=0.23; 95% CI: 0.15-0.37; P<0.0001), with a 77 percent reduction in risk of progression or death. Patients with high-risk disease (17p deletion/TP53 mutation, 11q deletion, or unmutated IGHV) treated with ibrutinib plus obinutuzumab experienced an 85 percent reduction in risk of progression or death (HR=0.15; 95% CI: 0.09-0.27). The IRC-evaluated overall response rate was 89 percent in the ibrutinib plus obinutuzumab arm versus 73 percent in the chlorambucil plus obinutuzumab arm. The data were recently presented in an oral session at the 2018 ASH Annual Meeting (Abstract 691) and simultaneously published in The Lancet Oncology (2018; doi:10.1016/S1470-2045(18)30788-5).
The FDA also updated the ibrutinib label to include additional long-term efficacy data supporting its use as a monotherapy in CLL/SLL, with approximately 5 years of follow-up from the phase III RESONATE (PCYC-1112) and RESONATE-2 (PCYC-1115, PCYC-1116) international studies.
Warnings and precautions include hemorrhage, infections, cytopenias, cardiac arrhythmias, hypertension, second primary malignancies, tumor lysis syndrome, and embryo-fetal 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. When administering ibrutinib in combination with rituximab or obinutuzumab, doctors should consider administering ibrutinib prior to rituximab or obinutuzumab when given on the same day.
Ibrutinib is a once-daily oral medicine that works differently than chemotherapy as it blocks the Bruton's tyrosine kinase (BTK) protein. The BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiply and spread. By blocking BTK, ibrutinib may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.
Ibrutinib is approved in more than 90 countries and, to date, has been used to treat more than 135,000 patients worldwide across approved indications. It was first approved by the FDA in November 2013, and today is indicated in six disease areas, including five hematologic cancers—CLL with or without 17p deletion (del17p), SLL with or without del17p, Waldenström's macroglobulinemia (WM), previously treated patients with mantle cell lymphoma, previously treated patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy—and previously treated patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.
Ibrutinib is the first and only FDA-approved medicine in WM, MZL, and cGVHD. It has been granted four Breakthrough Therapy Designations by the FDA, and it was one of the first medicines to receive U.S. approval through the Breakthrough Therapy Designation.