By Mary Ellen Schneider
A final analysis of the phase 3 iNNOVATE trial found deepening responses and continued safety for the combination of ibrutinib and rituximab in patients with Waldenström’s macroglobulinemia, according to findings presented at the annual meeting of the American Society of Hematology.
“After this mature follow up of over 60 months, ibrutinib-rituximab shows ongoing superiority across different clinical outcomes,” said Christian Buske, MD, of the Comprehensive Cancer Center Ulm, University Hospital of Ulm, Germany, who presented the study results. “We did not observe new safety signals in patients with Waldenström’s macroglobulinemia, so that we can state that ibrutinib in combination with rituximab is a safe and efficient treatment.”
The final analysis of iNNOVATE examined 5 years of follow-up on the randomized study, which evaluated the use of ibrutinib and rituximab versus placebo and rituximab in 150 patients with confirmed, symptomatic Waldenström’s macroglobulinemia requiring treatment (Abstract 336).
In the trial, patients were randomized to once-daily ibrutinib 420 mg or placebo, plus rituximab at 375 mg/m2/week intravenously at weeks 1-4 and weeks 17-20. Patients in the placebo group could cross over to single-agent ibrutinib after disease progression. The trial included an elderly patient population with a median age of 70 years in the ibrutinib arm and 68 years in the placebo arm.
In the primary analysis at 30 months, researchers showed superior progression-free survival (PFS) for the combination of ibrutinib-rituximab, compared with placebo (N Engl J Med. 2018;378:2399-2410). In the current analysis, Dr. Buske reported a continued PFS advantage for the ibrutinib-rituximab combination. Median PFS was not reached in the ibrutinib arm, compared with 20.3 months in the placebo arm (Hazard Ratio [HR] 0.25, 95% CI 0.15-0.42; P less than 0.0001).
The PFS benefit was consistent across subgroups of patients, regardless of prior treatment status or genotype, Dr. Buske reported.
Major response rates in the ibrutinib arm increased and were sustained over time. At 60 months, the major response rate in the ibrutinib arm was 76%, up from 52% at 6 months. In comparison, the major response rate in the placebo arm was 31% at 60 months, up from 12% at 6 months. The median time to major response was also faster in the ibrutinib arm, at 3 months, compared with 6 months for placebo.
“It’s a fast-acting combination,” Dr. Buske said.
Dr. Buske also reported a sustained improvement in IgM and hemoglobin in the ibrutinib arm.
The median overall survival was not reached in either treatment arm. When adjusted for patient crossover to ibrutinib, the overall survival remained consistent with the original analysis, showing an improved hazard ratio of 0.64 (95% CI 0.26-1.62). At a follow-up of 63 months, 9 patients on ibrutinib-rituximab and 10 patients on placebo-rituximab had died.
The safety profile remained consistent with earlier reporting, showing no new safety signals. In fact, the prevalence of serious adverse events of clinical interest in the ibrutinib arm generally decreased over time. The most common grade 3-4 adverse events were atrial fibrillation, hypertension, neutropenia, and anemia.