In the randomized phase III iNNOVATE trial, adding ibrutinib to rituximab significantly improved PFS in patients with Waldenström macroglobulinemia.
Ibrutinib with rituximab (ibrutinib-RTX) is associated with prolonged progression-free survival (PFS) compared with placebo-RTX among patients with WaldenstrÃ¶m macroglobulinemia (WM), according to interim findings from the randomized phase III iNNOVATE study (NCT02165397; abstract 8003). The findings were presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 1–5 in Chicago.
“Significant improvements in PFS were observed for all WM patients, regardless of prognostic or genotypic factors,” said lead study author Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens School of Medicine in Athens, Greece. “There was a significantly higher major response rate [partial or complete responses] with ibrutinib-RTX versus placebo-RTX (72% vs 32%; P < .0001).”
The 30-month PFS rate was 82% with the ibrutinib combination vs 28% with just RTX, Dimopoulos reported. There was “no notable difference” in PFS between patients on ibrutinib-RTX who achieved partial or complete tumor responses (PR, CR), he noted.
The 30-month overall survival rate was 94% for patients in the ibrutinib-RTX group and 92% in the placebo-RTX group.
Ibrutinib is a once-daily, oral inhibitor of Bruton’s tyrosine kinase, and its use is associated with high response rates and durable responses in WM. RTX is a CD20-targeting antibody active in patients with treatment-naive or relapsed/refractory WM.
The authors enrolled patients with confirmed WM, measurable disease, and no RTX-refractory disease. Patients who received RTX within 12 months of the first trial dose were not eligible to participate. Patients were randomly assigned to the ibrutinib-RTX group (n = 75) or a placebo-RTX group (n = 75). Forty percent of patients in the ibrutinib-RTX group were 75 years of age or older, compared with 27% in the placebo group. Twelve percent and 24% had baseline splenomegaly, respectively.
The ibrutinib-RTX group patients received oral ibrutinib (420 mg once daily) and intravenous RTX (375 mg/m2 on day 1 of weeks 1 to 4 and 17 to 20), until disease progression.
Ninety-three percent of patients in the ibrutinib-RTX group completed RTX treatment, compared with only 71% in the placebo group. The median time on treatment was 25.8 months for the ibrutinib-RTX group and 15.5 months for the placebo-RTX group.
The researchers found rapid decline in median IgM among patients with baseline levels of at least 50 g/L. Ibrutinib-RTX was associated with superior rates of sustained hemoglobin improvement overall (73% vs 41%; P < .0001), and among patients with baseline hemoglobin ≤ 11 g/dL (95% vs 56%; P < .0001).
“There was a manageable safety profile, similar to the known safety profiles for each individual agent, with no unexpected toxicities,” Dimopoulos said. “There was a reduction in infusion-related reactions and IgM flare with ibrutinib-RTX.”
Grade ≥ 3 adverse events occurred in 60% of ibrutinib-RTX patients and 61% of placebo-RTX patients. For the ibrutinib-RTX group, the most common grade ≥ 3 toxicities were hypertension (13% with ibrutinib-RTX vs 4% with placebo-RTX), atrial fibrillation (12% vs 1%), and anemia (11% vs 17%).
Serious adverse events (SAEs) were reported for 43% of patients receiving ibrutinib-RTX group, compared with 33% of patients in the placebo-RTX group. SAEs included pneumonia (8% for ibrutinib-RTX vs 3% placebo-RTX), atrial fibrillation (7% vs 1%), and, for the ibrutinib-RTX group, respiratory tract infections (4%), anemia (3%, or 2 patients), arthralgia (3%), congestive cardiac failure (3%), gastroenteritis (3%), myocardial ischemia (3%), and fall (3%).
Major hemorrhage was reported for 4% of patients in each group and was associated with anticoagulant/antiplatelet therapy. (A total of 43% of patients in the ibrutinib-RTX group and 36% in the placebo-RTX group were using anticoagulant/antiplatelet medications.)
Five percent of patients in the ibrutinib-RTX group and 4% of those in the placebo-RTX group discontinued treatment because of adverse events. Three patients, all in the placebo-RTX group, died.