On April 21, 2020, the U.S. Food and Drug Administration (FDA) expanded the indication of ibrutinib (Imbruvica®) to include its combination with rituximab for the initial treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). 

FDA Approves Ibrutinib Plus Rituximab for Chronic Lymphocytic Leukemia

The review was conducted under Project Orbis, an initiative of FDA’s Oncology Center of Excellence (OCE). Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. The application used a modified Project Orbis because of the timing of submission to other regulatory agencies. FDA is collaborating with the Australian Therapeutic Goods Administration, Health Canada, and Swissmedic to review the application. 

Approval was based on a 2:1 randomized, multicenter, open-label, actively controlled trial (E1912; NCT02048813) of ibrutinib with rituximab compared to fludarabine, cyclophosphamide, and rituximab (FCR) in 529 adult patients aged 70 years or younger with previously untreated CLL or SLL requiring systemic therapy. Patients with 17p deletion were excluded. Ibrutinib was administered at 420 mg once daily until disease progression or unacceptable toxicity.  

The main efficacy outcome measure was progression-free survival (PFS). The trial demonstrated a statistically significant improvement in PFS for patients receiving ibrutinib plus rituximab compared to those receiving FCR (HR = 0.34; 95% CI = 0.22, 0.52; p < 0.0001). Median PFS was not reached in either arm after a median follow-up of 37 months. 

The most common adverse reactions (≥ 30%) in patients with CLL or SLL receiving ibrutinib were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea. 

The recommended ibrutinib dose is 420 mg orally once daily with water. Rituximab was initiated in cycle 2 and administered at 50 mg/m2 on day 1 and 325 mg/m2 on day 2 for cycle 2 and at 500 mg/m2 on day 1 of five subsequent cycles for a total of six cycles. 

View full prescribing information for ibrutinib. 

FDA used the real-time oncology review and assessment aid pilot programs for the application and granted it priority review. Additionally, assessment aid is facilitating discussions among the regulatory agencies participating in Project Orbis. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.  

For assistance with single-patient oncology investigational new drug applications, contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.