First-Line Ibrutinib Confirmed for CLL Free

The targeted therapy ibrutinib (Imbruvica; Janssen) should be a standard of care for many patients with chronic lymphocytic leukemia (CLL), according to results from two phase III trials. The Bruton tyrosine kinase inhibitor, given alone or in combination with the CD20-specific antibody rituximab (Rituxan; Genentech), improved outcomes—including progression-free survival (PFS)—when compared with chemoimmunotherapy regimens. The data were presented at the 2018 American Society of Hematology (ASH) Annual Meeting in San Diego, CA, December 1–4.

Ibrutinib has been FDA-approved since 2016 as a first-line treatment for CLL. However, presenter Jennifer Woyach, MD, of The Ohio State University Comprehensive Cancer Center in Columbus, noted that patients 65 years and older—the population most likely to develop this disease—are still commonly given bendamustine–rituximab (BR) to start, and until now no trial has compared this chemoimmunotherapy combination with first-line ibrutinib. Additionally, first-line ibrutinib has not been tested against fludarabine and cyclophosphamide plus rituximab (FCR), a more effective chemoimmunotherapy regimen typically limited to younger patients due to side effects in older patients.

Two NCI-sponsored trials were designed to address these data gaps. The first, recently published, was conducted by Woyach and the Alliance North American Intergroup, enrolling 547 patients age 65 and older who were randomly assigned to receive ibrutinib, ibrutinib plus rituximab (IR), or BR. Woyach reported an improvement in PFS at 2 years for patients given ibrutinib alone or IR—87% and 88%, respectively, compared with 74% in the BR cohort. There were no significant differences in overall survival (OS), however; the results also suggest that adding rituximab to ibrutinib does not improve the drug's efficacy. Woyach noted that severe nonhematologic side effects were more common in the ibrutinib arms, so “close monitoring remains important, as well as strategies to limit toxicity.”

In the second trial, carried out by the ECOG-ACRIN Cancer Research Group, 529 patients age 70 and younger were randomly assigned 2:1 to receive IR or FCR. Compared with FCR, IR reduced the risk of disease progression and death by 65% and 83%, respectively, and was associated with less severe side effects. Clinical trials generally aim to either improve efficacy or reduce treatment side effects, said Tait Shanafelt, MD, of Stanford School of Medicine in California, who presented the results, “and this trial is one of the rare circumstances where we've done both.”

“Both trials are positive for ibrutinib, so I think certainly there will be less use of chemoimmunotherapy for patients with CLL in the frontline setting,” said Nitin Jain, MD, of The University of Texas MD Anderson Cancer Center in Houston, who was not involved in either study.

Jain noted that some clinicians already treat older patients with first-line ibrutinib, but the Alliance results are likely to change clinical practice among those who still give BR—although the lack of an OS benefit may mean that not all will make the switch. As for the ECOG-ACRIN trial, it clearly indicates that IR should be used over FCR in most younger patients, he said—an exception being those with IGHV-mutated disease, for whom IR did not significantly improve outcomes, according to a subanalysis reported by Shanafelt. In that group, “I think it will come down to a discussion between the patient and the clinician of what they want to do,” Jain said.

Jain also observed that the Alliance finding that rituximab may not add to ibrutinib's efficacy supports data in relapsed/refractory CLL that his team presented at the 2017 ASH meeting. He thinks these results may prompt some clinicians to begin treating patients of all ages with ibrutinib monotherapy.

Phase III trials are now investigating whether ibrutinib, which is currently administered indefinitely, can be given for a fixed duration if combined with another targeted therapy like the BCL2 inhibitor venetoclax (Venclexta; AbbVie/Genentech)—an approach that could ultimately lower costs and reduce long-term side effects. “I think that's where the field is moving,” Jain said. –Catherine Caruso