FDA Approves First Nonchemotherapy Combination Regimen for Patients With Waldenström’s Macroglobulinemia

Get Permission

ON AUGUST 27, 2018, the U.S. Food and Drug Administration (FDA) approved the combination of ibrutinib (Imbruvica) and rituximab (Rituxan) for patients with Waldenström’s macroglobulinemia. The recent approval expands the label for ibrutinib in Waldenström’s macroglobulinemia beyond its current approved use as monotherapy to include combination use with rituximab.

This approval represents the first approved nonchemotherapy combination option for the treatment of Waldenström’s macroglobulinemia. Ibrutinib is a first-in-class, once-daily oral agent that works by targeting and blocking Bruton’s tyrosine kinase, inhibiting the survival and spread of cancer cells.

Phase III iNNOVATE Study

THIS RECENT approval is based on results from the randomized, double-blind, placebo-controlled iNNOVATE study (PCYC-1127), the largest phase III study of a nonchemotherapy combination in patients with Waldenström’s macroglobulinemia. The iNNOVATE study evaluated ibrutinib in combination with rituximab vs placebo plus rituximab in 150 patients with either relapsed/refractory disease or previously untreated Waldenström’s macroglobulinemia.

At a median follow-up of 26.5 months, a significant improvement in the independent review committee–assessed primary endpoint of progression-free survival was seen with ibrutinib plus rituximab as compared with placebo plus rituximab (30-month progression-free survival rates were 82% vs 28%, respectively). Patients in the ibrutinib-plus-rituximab treatment arm experienced an 80% reduction in the relative risk of disease progression or death compared with patients treated with placebo-plus-rituximab (hazard ratio = 0.20, 95% confidence interval = 0.11–0.38; P < .0001). The data were presented at the 2018 ASCO Annual Meeting and published simultaneously in The New England Journal of Medicine.1,2

Meletios A. Dimopoulos, MD

Meletios A. Dimopoulos, MD

“Results from iNNOVATE showed significant improvement in progression-free survival at 30 months and demonstrated the superiority of [ibrutinib] plus rituximab over rituximab monotherapy in Waldenström’s macroglobulinemia,” said Meletios A. Dimopoulos, MD, Professor and Chairman of the Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, in Greece, and iNNOVATE lead study investigator. “Based on these results, [ibrutinib] in combination with rituximab may be considered as a first- and second-line option for appropriate people diagnosed and living with [Waldenström’s macroglobulinemia].”

“The clinical data generated for [ibrutinib] plus rituximab in the treatment of Waldenström’s macroglobulinemia offers physicians evidence to consider this combination regimen for newly diagnosed patients,” he added.

The recommended dose of ibrutinib for Waldenström’s macroglobulinemia is 420 mg orally once daily until disease progression or unacceptable toxicity as a single agent or in combination with rituximab. When administering ibrutinib in combination with rituximab, clinicians should consider administering ibrutinib prior to rituximab when given on the same day.

About Ibrutinib

IBRUTINIB WAS first approved by the FDA in 2013, and today it is indicated in six disease areas, including five hematologic cancers—chronic lymphocytic leukemia with or without 17p deletion (del17p), small lymphocytic lymphoma with or without del17p, Waldenström’s macroglobulinemia, previously treated mantle cell lymphoma, previously treated marginal zone lymphoma, and previously treated chronic graft-vs-host disease. Ibrutinib is the first and only FDA-approved drug in Waldenström’s macroglobulinemia, marginal zone lymphoma, and chronic graft-vs-host disease.

Ibrutinib first received FDA approval in Waldenström’s macroglobulinemia as monotherapy in January 2015 via the Breakthrough Therapy designation pathway, making it the first FDA-approved therapy for the disease. The expanded label marks the ninth FDA approval for ibrutinib since 2013. ■


1. Dimopoulos MA, Tedeschi A, Trotman J, et al: Randomized phase 3 trial of ibrutinib/rituximab vs placebo/rituximab in Waldenstrom’s macroglobulinemia. 2018 ASCO Annual Meeting. Abstract 8003. Presented June 1, 2018.

2. Dimopoulos MA, Tedeschi A, Trotman J, et al: Phase 3 trial of ibrutinib plus rituximab in Waldenstrom’s macroglobulinemia. N Engl J Med 378:2399-2410, 2018.