Update from the RESONATE Trial: Ibrutinib versus Ofatumumab in Relapsed/Refractory CLL
Ibrutinib, a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor, has been shown to be effective in treating relapsed/refractory chronic lymphocytic leukemia (CLL), and for patients with CLL and a deletion in chromosome 17p (del17p; Byrd JC, et al. N Engl J Med. 2013;369:32-42), and has been found to be superior to the anti-CD20 monoclonal antibody ofatumumab in improving progression-free survival (PFS), overall survival (OS), and overall response rate (ORR; Byrd JC, et al. N Engl J Med. 2014;371:213-223). However, the role of prognostic factors in CLL is not yet fully understood, including the implications of new genetic markers associated with high-risk CLL. At ASH 2014, Brown and colleagues reported the updated results from the phase 3 RESONATE study comparing the safety and efficacy of ibrutinib versus ofatumumab relative to the patients’ genetic features and previous treatment exposure (Blood. 2014;124. Abstract 3331).
The 391 patients in RESONATE were randomized to receive ibrutinib (N = 195) daily until disease progression or until unacceptable toxicity, or ofatumumab (N = 196) for up to 24 weeks. At an interim analysis with a median follow-up of 9.4 months, the Independent Data Monitoring Committee recommended that patients in the ofatumumab arm be provided access to ibrutinib. Of the patients in RESONATE, 32% had del17p and 32% had deletion in chromosome 11q (del11q), with 24% having complex cytogenetics (?3 abnormalities) and 68% of patients with unmutated IGVH. Additional gene mutations at baseline included 19% of patients with NOTCH1, 23% with SF3B1, 36% with TP53, and 1% with MYD88.
With a median follow-up of 16 months, the median PFS and 18-month OS rates were significantly longer in patients receiving ibrutinib than in those receiving ofatumumab (not reached vs 8.1 months; P <.001; and 85% vs 78%, respectively). Patients with a higher number (?3) of previous therapies and del11q were associated with significantly lower 12-month PFS rates in ofatumumab-treated patients but not in patients receiving ibrutinib. The investigator-assessed ORRs were 90% with ibrutinib and 25% with ofatumumab (P <.001).
Compared with patients receiving ofatumumab, patients receiving ibrutinib had improved 12-month PFS, regardless of their baseline genetics, complex cytogenetics, or number of previous therapies (P <.001 for ibrutinib vs ofatumumab for all comparisons).
The median treatment duration was longer for ibrutinib than for ofatumumab (16 months vs 5 months, respectively), and the most common grade 1/2 adverse events (AEs) for ibrutinib included diarrhea, fatigue, and nausea. The most frequent grade 3/4 AEs for ibrutinib included neutropenia, pneumonia, thrombocytopenia, anemia, and hypertension.
This study showed that ibrutinib significantly improved investigator-assessed PFS, OS, and ORR relative to ofatumumab in patients with CLL who had received ?1 prior therapy, regardless of high-risk baseline genetics or the number of previous therapies.