As reported in the Journal of Clinical Oncology by Buske et al, the final analysis of the pivotal phase III iNNOVATE trial has shown a continued progression-free survival benefit with the addition of ibrutinib to rituximab in patients with Waldenström’s macroglobulinemia after 50 months of follow-up.

At primary analysis with a median follow-up of 26.5 months, ibrutinib/rituximab showed superior progression-free survival and higher objective response rate vs rituximab alone, independent of patient genotype. The study supported the August 2018 approval of ibrutinib plus rituximab in this setting.

Study Details

In the international double-blind trial, 150 patients with previously treated or untreated symptomatic disease were randomly assigned to receive once-daily ibrutinib at 420 mg (n = 75) or placebo (n = 75) until disease progression or intolerable toxicity in combination with rituximab at 375 mg/m² on day 1 of weeks 1 to 4 and 17 to 20. Patients in the placebo/rituximab group could cross over to receive single-agent ibrutinib upon disease progression.

Patients who had been treated with prior rituximab had to have at least a minor response to their last rituximab-based regimen. The primary endpoint was progression-free survival.

Efficacy Endpoints

Median follow-up was 50 months (range = 0.5–63 months). Median progression-free survival was not reached (95% confidence interval [CI] = 57.7 months–not evaluable) in the ibrutinib/rituximab group vs 20.3 months (95% CI = 13.0–27.6 months) in the rituximab group (hazard ratio [HR] = 0.250, P < .0001).

Progression-free survival rates at 54 months were 68% vs 25% among all patients. According to genotype, 54-month rates were 70% vs 30% among patients with MYD88 wild-type/CXCR4 wild-type; 72% vs 25% among those with MYD88L265P/CXCR4 wild-type; and 63% vs 21% among those with MYD88L265P/CXCR4WHIM. According to prior treatment, 54-month rates could not be evaluated among previously untreated patients; 48-month rates were 70% vs 32%. In previously treated patients, 54-month rates were 68% vs 20%.

Partial response or better was achieved in 76% vs 31% of patients (P < .0001). At final analysis, sustained improvement in hemoglobin level was observed in 77% vs 43% (P < .0001).

Median time to next treatment was not reached vs 18 months (P < .0001), with 87% vs 29% not having received subsequent treatment at 54 months.

A total of 38 patients (51%) in the rituximab group received single-agent ibrutinib as next-line therapy, including 35 (47%) who crossed over during the study and 3 who received ibrutinib off-study. Median overall survival was not reached in either group (HR = 0.81, 95% CI = 0.33–1.99, P = .6430); estimated rates at 54 months were 86% vs 84%. In analysis adjusting for crossover, the hazard ratio was 0.64 (95% CI = 0.26–1.62).

Adverse Events

The median duration of ibrutinib treatment was 48 months. The most common grade ≥ 3 adverse events of interest in the ibrutinib/rituximab group were infections, anemia, atrial fibrillation, and hypertension, with the incidence of these events generally decreasing over time. During years 3 to 5 of treatment, two or fewer cases of atrial fibrillation were observed per year. No major hemorrhagic events occurred during the last 24 months of treatment.

One patient died during year 4 due to pneumonia, which was considered unrelated to treatment. Adverse events led to discontinuation of treatment in four patients during the last 24 months of treatment (due to pneumonia, atrial fibrillation, small cell lung cancer, and metastatic breast cancer).

The investigators concluded, “In the final analysis of iNNOVATE with a median follow-up of 50 months, ibrutinib/rituximab showed ongoing superiority across clinical outcomes in patients with Waldenström’s macroglobulinemia regardless of MYD88 or CXCR4 mutation status, prior treatment, and key patient characteristics.”

Christian Buske, MD, of the Institute of Experimental Cancer Research, Comprehensive Cancer Center Ulm, University Hospital Ulm, Germany, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Pharmacyclics LLC, an AbbVie Company. For full disclosures of the study authors, visit ascopubs.org.