On April 21, 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).
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this application, a modified Project Orbis was undertaken because of the timing of submission to other regulatory agencies. Nevertheless, the FDA is collaborating with the Australian Therapeutic Goods Administration, Health Canada, and Swissmedic as they review the application.
Approval was based on the E1912 trial, a 2:1 randomized, multicenter, open-label, actively controlled trial of ibrutinib/rituximab compared to fludarabine/cyclophosphamide/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 daily until disease progression or unacceptable toxicity.
The main efficacy outcome measure was progression-free survival.
The trial demonstrated a statistically significant improvement in progression-free survival for patients receiving ibrutinib/rituximab compared with those receiving FCR (hazard ratio [HR] = 0.34, 95% confidence interval [CI] = 0.22–0.52, P < .0001). Median progression-free survival was not reached in either arm after a median follow-up duration of 37 months.
The most common adverse reactions (≥ 30%) reported in patients with CLL/SLL receiving ibrutinib were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea.
The recommended ibrutinib dose is 420 mg taken orally once daily with a glass of water. Rituximab was initiated in cycle 2 and administered at 50 mg/m2 on day 1, 325 mg/m2 on day 2, and 500 mg/m2 on day 1 of five subsequent cycles, for a total of six cycles.