, results of a randomized phase 3 trial show.
The results make ibrutinib plus rituximab “a new standard of care” for the disease, said investigator Meletios A. Dimopoulos, MD, with the Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Greece.
“This is a combination with remarkable activity as far as progression-free survival is concerned, and well tolerated,” Dr. Dimopoulos said in a presentation of the data here at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO).
Ibrutinib, a BTK inhibitor, was approved as a single agent in 2015 for the treatment of Waldenström’s macroglobulinemia.* Clinical practice guidelines from the National Comprehensive Cancer Network (NCCN) list ibrutinib as an “other” recommended regimen, noting that study data show a “lower overall and absence of major responses” reported for MYD88 wild-type patients.Rituximab alone and in combination with other agents has clinical activity in Waldenström’s. Moreover, preclinical studies have shown that rituximab and ibrutinib have synergistic activity, Dr. Dimopoulos said, presenting data from the iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia that was published concurrently in the New England Journal of Medicine.
They initiated a study of 150 symptomatic patients randomized to either ibrutinib plus rituximab or placebo plus rituximab, with a primary end point of progression-free survival.
They also assessed mutational status of MYD88 and CXCR4 in bone marrow samples, given that previous data suggest outcomes of ibrutinib treatment for this disease depend on MYD88 and CXCR4 mutational status, they said in the report.
Progression-free survival at 30 months was 82% for ibrutinib plus rituximab, compared to 28% for placebo plus rituximab (hazard ratio for progression or death, 0.20; P less than 0.001). Further, ibrutinib and rituximab had a benefit that was independent of the MYD88 or CXCR4 genotype, the investigators reported.
“Response rates with ibrutinib–rituximab were similar across different CXCR4 genotypes, but were slightly lower among patients who did not have the activating MYD88 L265P mutation, which triggers the growth of malignant cells through BTK and hematopoietic-cell kinase, both of which are targeted by ibrutinib,” they wrote.
Atrial fibrillation of grade 3 or higher occurred in 12% of the ibrutinib-rituximab and in 1% of placebo-rituximab groups. In the ibrutinib-rituximab group, the majority of these cases occurred in patients older than 75 years of age, Dr. Dimopoulos reported at ASCO.
Grade 3 or greater hypertension occurred in 13% and 4% of the ibrutinib-rituximab and placebo-rituximab groups respectively, while respiratory tract infections occurred in 4% and 0%. Conversely, the ibrutinib-rituximab arm had a lower rate of grade 3 or greater infusion reactions (1% vs. 16%), he said.
Based on this report, ibrutinib plus rituximab is “appealing, primarily in MYD88-mutated patients, which is the vast majority of Waldenström’s patients,” said Craig Hofmeister, MD, MPH, who commented on the study in a ASCO presentation discussing the results of this trial.
Dr. Hofmeister, of Winship Cancer Institute, Emory University, Atlanta, noted the numerically lower response rate in patients without the MYD88 mutation “makes me wonder whether I would want to have ibrutinib if I was MYD88 wild type.”
Atrial fibrillation and infections on the ibrutinib-rituximab regimen may require close monitoring and should be managed appropriately, he added. “Atrial fibrillation seems to be a consistent theme with ibrutinib, certainly in patients who are older and have probably more heart disease.”
The study (NCT02165397) was funded by Pharmacyclics and Janssen Research and Development. Dr. Dimopoulos reported personal fees from Amgen, Celgene, Janssen, and Takeda, outside of the submitted work. Co-authors reported disclosures related to Pharmacyclics, Bristol-Myers Squibb, Gilead, Roche, and AbbVie, among others. Dr. Hofmeister had no relevant financial disclosures.
SOURCE: Dimopoulos MA, et al. N Engl J Med. 2018 Jun 1. ASCO Abstract 8003.
*Correction, 8/27/2018: An earlier version of this story misstated the date of ibrutinib's approval as a single agent in the treatment of Waldenström’s .