A follow-up study of the RESONATE phase III trial provides further support that ibrutinib, an inhibitor of Bruton tyrosine kinase, achieves greater progression-free survival (PFS) than ofatumumab, a high overall survival (OS) rate, and high tolerability among patients with chronic lymphoid leukemia (CLL) who have had at least one prior treatment. The most recent results of the RESONATE (PCYC-1112) trial, which were based on a median follow-up time of 44 months, were presented in a Poster Session (Abstract 7510) on June 5.
In the RESONATE trial, 391 patients with relapsed/refractory CLL were randomly assigned to receive 420 mg of oral ibrutinib once a day until disease progression or unacceptable toxicity occurred or intravenous ofatumumab for up to 24 weeks.1 At the interim analysis with a median follow-up time of 9 months, the disease had progressed in all but one of the patients taking ofatumumab, and those patients crossed over to the ibrutinib group.
At 3 years, when nearly all of the participants were receiving ibrutinib, the OS for the drug was 74%, and the PFS after a median of 44 months was 59%. The overall response rate was 91%; the rate of complete response or complete response with incomplete hematologic recovery was 9% and increased with time.
“These data definitively demonstrate that ibrutinib is a better therapy [than ofatumumab] for relapsed and refractory CLL,” presenter John C. Byrd, MD, of The Ohio State University Comprehensive Cancer Center, said.
The data also confirm that the response to ibrutinib improves over time, and its performance in the phase III trial confirmed the results of the phase II PCYC-1102-CA trial that led to the accelerated approval of the drug for relapsed/refractory CLL by the U.S. Food and Drug Administration in 2014, Dr. Byrd said. The results of another phase III trial, RESONATE-2 (PCYC-1115-CA),1 led to the approval of ibrutinib in 2016 for patients with CLL who had no prior treatment.
“With extended follow-up, we see that patients receiving ibrutinib have for virtually every side effect diminishing occurrence, including infections. That speaks to the drug improving the immune system of patients over time,” Dr. Byrd said. For example, skin rash and loose stool, which are often seen early in treatment, decreased in frequency after patients were on ibrutinib for several years, he said.
After 44 months of follow-up, 46% of patients in the trial remained on ibrutinib, 27% of them discontinued treatment because of disease progression, and 12% discontinued because of adverse events. The incidences of major hemorrhage and grade 3 or greater atrial fibrillation were each 6%.
Although the incidence of most grade 3 or greater adverse events decreased over time, the incidence of hypertension increased from 8% among patients the first year on ibrutinib to 23% after more than 2 years. “This is clearly an emerging toxicity over time to be aware of when you use ibrutinib,” Jennifer R. Brown, MD, PhD, of the Dana-Farber Cancer Institute, said during the Poster Discussion Session.
Dr. Brown noted that discontinuation rates for ibrutinib may increase with age and pointed to a retrospective analysis that suggested that discontinuation rates in clinical practice may be as high as 42% after a median of 7 months on the drug. She said that the higher rate could be related to differences between patients in clinical practice and in trials.
Among the unmet needs of ibrutinib were subgroups of patients with CLL who have mutations that are associated with early relapse, such as those with deletions in the 17p chromosomal arm, Dr. Brown said. The RESONATE trial follow-up found that patients who have deletions in the 11q chromosomal arm trended toward better PFS than those with deletions in 17p, but the difference was not statistically significant.
–Carina Storrs, PhD