Ibrutinib Superior to Ofatumumab for Previously Treated CLL or SLL

Chicago—At a median follow-up of 9.4 months, patients with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who received ibrutinib had a significant increase in overall survival and progression-free survival compared with a group who received ofatumumab, according to a randomized, multicenter, open-label, phase 3 study.

John Byrd, MD, professor of medicine, Comprehensive Cancer Center, Ohio State University, presented the results during the ASCO meeting, and the results were published in New England Journal of Medicine [2014; DOI:10.1056/NEJMoa1400376]. Pharmacyclics, which is jointly developing ibrutinib with Janssen Biotech, Inc., supported the study.

“This is a transformative drug,” said Olatoyosi Odenike, MD, associate professor, hematology and oncology, University of Chicago, Illinois.

Ibrutinib is an oral drug administered once daily and is the first Bruton’s tyrosine kinase inhibitor in clinical trials. Ofatumumab is administered via intravenous infusion and is FDA-approved in combination with chlorambucil for previously untreated patients with CLL and as a single agent for patients with CLL refractory to fludarabine and alemtuzumab.

Ibrutinib reduced the risk of disease progression by 78% (hazard ratio [HR], 0.215; P<.0001) and reduced the risk of death by 57% (HR, 0.434; P<.0049). At 6 months, the progression-free survival rate was 88% in the ibrutinib group and 65% in the ofatumumab group. At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was 42.6% in the ibrutinib group and 4.1% in the ofatumumab group (P<.001). The results were consistent regardless of baseline characteristics.

“This is a very important study because, for the very first time, it shows ibrutinib beats a standard comparator that is approved for the use of relapsed and refractory CLL,” Dr. Byrd said.

Dr. Byrd said that patients with CLL and SLL who are ≥65 years of age and have a short response duration to initial therapy have experienced poor outcomes and limited treatment options. “Identifying new therapies in this patient population, particularly in those that extend [patient] survival, is very important,” he said.

In this study, 391 patients with relapsed or refractory CLL were enrolled at 67 sites in the United States, Australia, and 7 European countries. They were randomized to receive 420 mg of ibrutinib once daily until disease progression or unacceptable toxicity or an initial 300 mg dose of ofatumumab followed by weekly 2000 mg doses for 7 weeks and then 2000 mg doses every 4 weeks for 16 weeks.

After the first 57 patients were enrolled, there was a crossover period where patients were allowed to receive ibrutinib if they had disease progression as confirmed by an independent review committee.

Dr. Byrd said there are concerns with ibrutinib possibly enhancing the progression to Richter’s transformation, a complication found in <10% of patients with CLL; 2 patients in each group of this study had Richter’s transformation. He added that the safety profile of ibrutinib was “acceptable” and the toxicities were “manageable.” Patients who received ibrutinib had higher rates of atrial fibrillation, while those who received ofatumumab had higher rates of neuropathy.—Tim Casey