Washington, DC - An interim analysis of a large phase 3 clinical trial found that the combination of ibrutinib plus rituximab was superior to standard treatment for patients age 70 and younger with previously untreated chronic lymphocytic leukemia (CLL). The trial met its primary endpoint of an improvement in progression-free survival (the length of time patients live before their disease worsens). The combination also improved overall survival, the trial’s secondary endpoint. In general, patients in the ibrutinib–rituximab arm were less likely to experience serious side effects than those in the standard treatment arm.

Until now, the standard treatment for previously untreated CLL has been a six-month course of FCR, which combines the chemotherapy drugs fludarabine and cyclophosphamide with rituximab.

The data and safety monitoring board overseeing the trial, known as E1912, recommended that these results be released immediately given their significance to public health. The findings were presented as a late-breaking abstract at the American Society of Hematology (ASH) annual meeting on December 4, 2018. The trial was sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, and designed by researchers with the ECOG-ACRIN Cancer Research Group.

"These results are practice-changing and immediately establish ibrutinib and rituximab as the new standard of care for the initial treatment of CLL in patients age 70 and younger," said lead investigator Tait Shanafelt, M.D., a professor of hematology at the Stanford University School of Medicine in Palo Alto, California. "The E1912 trial showed that the combination of ibrutinib and rituximab not only provided better leukemia control, it also prolonged life and had fewer side effects."

"These definitive results show why large trials like this, that test new therapies in an effort to achieve clinically meaningful benefit for patients, are so important," said Richard F. Little, M.D., of the Cancer Therapy Evaluation Program at NCI.

The study was conducted through NCI’s National Clinical Trials Network. Pharmacyclics LLC provided ibrutinib and clinical trial support funding under a cooperative research and development agreement with NCI and a separate agreement with ECOG-ACRIN.

CLL is one of the most common types of leukemia in adults. It typically occurs during or after middle age and rarely occurs in individuals under the age of 40. Ibrutinib and rituximab are targeted treatments. Ibrutinib interferes with the survival of lymphocytic leukemia cells, and rituximab enhances the ability of the body’s immune system to destroy the cells. Ibrutinib is approved by the U.S. Food and Drug Administration for the treatment of some blood cancers, including CLL.

The trial enrolled 529 patients between January 2014 and June 2016. Those enrolled in the trial were adults age 70 and younger who had never received treatment for CLL and required treatment. Patients were randomly assigned to receive either the ibrutinib–rituximab combination or FCR.

The first planned interim analysis for progression-free survival was performed in September 2018. With a median follow-up of 33.4 months, the hazard ratio for progression-free survival favored the ibrutinib group over the FCR group (HR=0.352). This means that, at any given time, the risk of disease progression was reduced by about two-thirds (65 percent) for patients in the ibrutinib group compared with the FCR group. This observed improvement in progression-free survival exceeded the trial design target. Overall survival was also superior for patients in the ibrutinib arm.

According to the data and safety monitoring board’s recommendation, the outcome has been disclosed to all patients participating in the study and their physicians. Patients who are receiving ibrutinib in the trial can continue therapy, as long as it remains effective. All patients assigned to FCR have completed treatment and are continuing to be monitored per standard of care. Quality of life was rigorously measured in both arms, and the data are awaiting analysis.

Findings from another NCI-supported trial on ibrutinib in patients with CLL were also presented at the ASH meeting and published in The New England Journal of Medicine. The A041202 trial — an international phase 3 clinical trial coordinated by the Alliance for Clinical Trials in Oncology — demonstrated that ibrutinib produces superior progression-free survival compared with standard chemoimmunotherapy (bendamustine plus rituximab) in previously untreated patients with CLL who are age 65 and older. The study found that adding rituximab to ibrutinib did not improve progression-free survival beyond ibrutinib alone.

"These two NCI-funded trials have collectively established ibrutinib-based therapy as the first line treatment for CLL patients of any age," Dr. Little said.