Ibrutinib Versus Ofatumumab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Results From the Randomized Phase III RESONATE™ (PCYC-1112) Trial

Abstract

304 Ibrutinib Versus Ofatumumab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Results From the Randomized Phase III RESONATETM (PCYC-1112) Trial J Jennifer R. Brown, MD, PhD1, John C. Byrd, MD2, Susan O’Brien, MD3, Jacqueline C. Barrientos, MD4, Neil E. Kay, MD5, Nishitha M. Reddy, MBBS, MD6, Steven Coutre, MD7, Constantine S. Tam, MBBS, MD8, Stephen Mulligan, MBBS, PhD, FRACP, FRCPA9, Ulrich Jaeger, MD10, Stephen Devereux, PhD, FRCP, FRCPath11, Paul M. Barr, MD12, Richard Furman, MD13, Thomas Kipps, MD, PhD14, Florence Cymbalista, MD, PhD15, Maria Fardis, PhD, MBA16, Jesse McGreivy, MD16, Fong Clow, DSc16, Danelle F. James, MD, MAS16, Peter Hillmen, MD, PhD, FRCP, FRCPath17 1Dana-Farber Cancer Institute, Boston, MA, USA; 2The Ohio State University Medical Center, Columbus, OH, USA; 3University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4North Shore Long Island Jewish Health System, Manhasset, NY, USA; 5Mayo Clinic, Rochester, MN, USA; 6Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 7Stanford University School of Medicine, Stanford, CA, USA; 8Peter MacCallum Cancer Centre and St. Vincent’s Hospital, Melbourne, Australia; 9Royal North Shore Hospital, Sydney, Australia; 10Medical University of Vienna, Vienna, Austria; 11Kings College Hospital, NHS Foundation Trust Denmark Hill, London, UK; 12University of Rochester Cancer Center, Rochester, NY, USA; 13Weill Cornell Medical College/New York Presbyterian Hospital, New York, NY, USA; 14Moores UCSD Cancer Center, San Diego, CA, USA; 15Hopital Avicenne, Paris, France; 16Pharmacyclics, Inc., Sunnyvale, CA, USA; 17The Leeds Teaching Hospitals, St. James Institute of Oncology, Leeds, UK Context: Ibrutinib, a first-in-class, once-daily oral, covalent inhibitor of Bruton’s tyrosine kinase, demonstrated single-agent activity and an acceptable safety profile in a phase II relapsed/refractory (R/R) CLL/SLL study (Byrd et al. NEJM 2013). Ibrutinib is FDA approved for CLL patients who have received ≥1 prior therapy, and for patients with del(17p) CLL. Objective: Interim safety and efficacy results from an international, multicenter, open-label, randomized phase III study of single-agent ibrutinib vs ofatumumab in R/R CLL/SLL Patients: Patients with R/R CLL/SLL who received ≥1 previous therapy considered inappropriate for purine analogs Main Outcome Measures: Independent Review Committee-assessed PFS (primary); overall survival (OS), ORR, safety (secondary) Intervention: 420 mg oral ibrutinib daily or IV ofatumumab 300/2000 mg (12 doses) Results: 391 patients (median age 67 years, 40% ≥70 years, 30% del17p); 195 randomized to ibrutinib, 196 to ofatumumab. Ibrutinib patients had median 3 prior therapies vs 2 for ofatumumab. Ibrutinib significantly improved PFS (median not reached vs 8.1 months; HR 0.215, 95% CI 0.146-0.317, P<0.0001; 78.5% risk reduction), and OS (median not reached; HR 0.434, 95% CI 0.238-0.789, P=0.0049; 57% risk reduction) vs ofatumumab. Ofatumumab patients (n=57) with confirmed progressive disease crossed over to the ibrutinib arm. ORR by IRC, including partial response with lymphocytosis: 62.6% for ibrutinib vs 4.1% for ofatumumab. Similar effects were seen in del(17p) and purine analog-refractory subsets. Most frequent adverse events (AEs) for ibrutinib vs ofatumumab: diarrhea (47.7% vs 17.8%), fatigue (27.7% vs 29.8%), and nausea (26.2% vs 18.3%). Any-grade atrial fibrillation was observed more frequently with ibrutinib (5.1% vs 0.5%). Major hemorrhage rates: 1% for ibrutinib vs 1.6% for ofatumumab. Drug discontinuation due to AEs: 4.1% for ibrutinib vs 3.6% for ofatumumab. At median time on study of 9.6 months, 86% of ibrutinib patients were continuing treatment. Conclusions: Single-agent ibrutinib significantly improved PFS, OS, and ORR in patients with previously treated CLL/SLL compared with ofatumumab. The effect of ibrutinib on PFS was observed irrespective of baseline features, including del(17p) or purine analog-refractory disease. The safety profile was comparable with that reported previously. These results support ibrutinib as an effective therapy for patients with previously treated CLL.