Ibrutinib Outperforms Ofatumumab, Extends Survival in Patients with CLL

August 2014, Vol 5, No 6

In a head-to-head study comparing ibrutinib (Imbruvica) and ofatumu­mab (Arzerra) for the second-line treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), ibrutinib significantly improved progression-free survival (PFS) time, overall survival (OS), as well as response rate (Byrd JC, et al. N Engl J Med. 2014;371:213-223). These results came from the phase 3 randomized RESONATE trial. The results of this trial were also presented at the 2014 American Society of Clinical Oncology (ASCO) annual meeting.

Ibrutinib is a first-in-class, oral covalent inhibitor of Bruton’s tyrosine kinase, whereas ofatumumab is a monoclonal antibody that binds to the CD20 antigen on the CLL or SLL cells. In the multicenter, open-label RESONATE trial, 391 patients with relapsed or refractory CLL or SLL in whom 1 or more therapies had failed were randomized in a 1:1 ratio to receive ibrutinib (N = 195) 420 mg once daily or ofatumumab (N = 196) 300 mg intravenously, at week 1, followed by 2000 mg weekly for 7 weeks and then every 4 weeks for 16 weeks.

The primary end point was PFS, with secondary end points evaluating OS and response rate. The median follow-up time was 9.4 months.

Ibrutinib significantly extended PFS, with the median not reached (88% at 6 months) at the follow-up compared with a median PFS of 8.1 months in the ofatumumab group (hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.15-0.32; P <.001).

Furthermore, ibrutinib significantly improved OS duration (HR for death, 0.43; 95 CI, 0.24-0.79; P = .005), with the risk of death reduced by 57%. The OS rate was 90% at 12 months in the ibrutinib group versus 81% in the ofatumumab group.

Overall, 57 patients in the ofatumumab group whose disease had progressed had crossed over and began receiving ibrutinib at the time this analysis. The partial response rate was much higher for patients in the ibrutinib group than for patients in the ofatumumab group—43% vs 4%, respectively.

In the ibrutinib group, 20% of the patients showed partial response with lymphocytosis: if these patients are included, the resulting response rate is 63%. Similar effects were observed in patients with chromosome 17p13.1 deletion or those with resistance to purine analogs.

More patients in the ibrutinib group than in the ofatumumab group had at least 1 adverse event of grade ?3 (57% vs 47%, respectively). Adverse events (grade ?3) that occurred more often in the ibrutinib group than in the ofatumumab group included diarrhea (4% vs 2%, respectively) and atrial fibrillation (3% vs 0%, respectively). Bleeding-related adverse events of any grade were also more common in the ibrutinib group (44%) than in the ofatumumab group (12%).

These results support ibrutinib as an effective single-agent therapy for difficult-to-treat patients with CLL or SLL, given its positive effect on PFS, OS, and response rate. The improvement in survival was observed across all subgroups that were examined. Phase 3 trials examining the effect of ibrutinib in previously untreated patients with CLL or SLL are ongoing.

Commenting on the study at ASCO 2014, lead investigator John C. Byrd, MD, said, “Ibrutinib beat a standard comparator in CLL for the first time. If I were a patient with CLL, I would want this drug. In the relapsed and refractory setting after 1 prior therapy, there is no good reason not to give this drug outside of a few circumstances.”

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