ASCO 2014: Ibrutinib Significantly Delays Disease Progression and Extends Survival in Relapsed CLL
Early findings from the phase III RESONATE study indicate that ibrutinib (Imbruvica) produces durable tumor responses and marked improvement in survival over standard ofatumumab (Arzerra) for patients with relapsed chronic lymphocytic leukemia (CLL). “With ibrutinib, about 80% of patients were still in remission at 1 year, twice as many as we would expect with standard therapy,” said the study’s lead author John C. Byrd, MD, Professor of Medicine at The Ohio State University Comprehensive Cancer Center in Columbus, reporting the results at a press briefing during the 2014 ASCO Annual Meeting in Chicago (Abstract LBA7008). “Although the follow-up was short in this study, the data definitely support the use of ibrutinib before anything else in this setting.”
Good Target, Good Drug
Ibrutinib is a first-in-class, oral covalent inhibitor of Bruton’s tyrosine kinase. In February 2014, the agent was approved for the treatment of CLL by the U.S. Food and Drug Administration through its accelerated review process
Responding to a question from a reporter at the ASCO press briefing on targeted therapies, Dr. Byrd explained that the expression of Bruton’s tyrosine kinase throughout different tissues is not widespread and it can be targeted very effectively by ibrutinib. “So you have a good target and a good drug. Together that makes a good therapy for diseases where Bruton’s tyrosine kinase is important,” Dr. Byrd noted.
Elderly patients, who account for the majority of patients with CLL, often cannot tolerate intensive chemotherapy, which together with an antibody such as rituximab (Rituxan), is the standard treatment for CLL. Ofatumumab is an alternative option for such patients, but studies have shown it is much less effective than intensive chemotherapy.
Significantly Higher Response Rates
The study enrolled 391 patients who had relapsed/refractory CLL or small lymphocytic lymphoma that had progressed after two or more prior therapies. Patients had a median age of 67 years, and 40% were older than 70 years.
Patients were randomly assigned to receive oral ibrutinib at 420 mg once daily until disease progression or unacceptable toxicity (n = 195) or to receive ofatumumab at an initial dose of 300 mg followed by 11 doses at 2,000 mg (n =196).
At a median follow-up of 9.4 months, the response rates were significantly higher in the ibrutinib group compared to the ofatumumab group: 42.6% vs 4.1% (P < .001). An additional 20% of patients treated with ibrutinib had a partial response with persistent lymphocytosis.
“At 6 months, the progression-free survival in the ibrutinib group was 88%, whereas with ofatumumab, it was 65%,” Dr. Byrd reported. “This was highly significant, with a hazard ratio of 0.215, which equated to a reduction in risk of progression or death of more than 78%.” Ibrutinib had similarly high activity in two very high-risk groups of patients, those with 17p deletions and those with disease refractory to purine analog chemoimmunotherapy.
Opportunity to Cross Over
Based on promising data from the phase II study, patients in the ofatumumab group were offered the opportunity to cross over to the ibrutinib group. Dr. Byrd reported that the positive impact of ibrutinib on overall survival was significant despite the crossover of 57 patients with confirmed progressive disease. There was a 57% reduction in risk of death among patients receiving ibrutinib vs olfatumumab.
Overall, both ibrutinib and ofatumumab were well tolerated and did not frequently result in dose reduction or treatment discontinuation. Diarrhea, minor bleeding, and atrial fibrillation were more common in the ibrutinib group, whereas peripheral neuropathy was more common in the ofatumumab group. There had been concern about whether ibrutinib would enhance progression to Richter’s transformation, but in the phase III study, the frequency of Richter’s was confirmed in two patients in both treatment groups. Renal toxicity was similar between the two groups.
New Treatment Option for CLL
“These results provide a compelling new treatment option for patients with chronic lymphocytic leukemia, including older adults with this disease, and will significantly change practice," commented Olatoyosi Odenike, MD, ASCO Expert on leukemia and Associate Professor of Hematology/Oncology in the Department of Medicine at the University of Chicago. “The issue now is how to best use the drug and how to most effectively move this into the frontline setting,” she added. “This is a transformative drug. There is just no other way to put it.”
This research was supported by Pharmacyclics. Dr. Byrd reported research funding from Pharmacyclics. For full disclosures of the study authors, view the study abstract at abstract.asco.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
