FDA Updates Ibrutinib Label to Include Long-Term Waldenström Macroglobulinemia Data

December 23, 2020 - The FDA has updated the prescribing information for ibrutinib to include safety and efficacy data for the agent in combination with rituximab in the treatment of patients with Waldenström macroglobulinemia.

The FDA has updated the prescribing information for ibrutinib (Imbruvica) to include safety and efficacy data for the agent in combination with rituximab (Rituxan) in the treatment of patients with Waldenström macroglobulinemia.1

The update decision was based on findings from a final analysis of the phase 3 iNNOVATE trial, where the use of the combination led to significantly higher rates of progression-free survival (PFS) than the use of placebo plus rituximab, in those who were treatment naïve and in those with disease recurrence.

"We're encouraged by this latest recognition from the FDA as it underscores our commitment to supporting those impacted by Waldenström's macroglobulinemia, a rare and incurable form of non-Hodgkin's lymphoma," Danelle James, MD, MAS, IMBRUVICA Global Development Lead, Pharmacyclics LLC, an AbbVie company, stated in a press release. "[Ibrutinib] is the only FDA-approved treatment for these patients and now includes more than five years of safety and efficacy data to help provide better understanding of how to treat this rare blood cancer."

Earlier findings from iNNOVATE showed that the combination resulted in an 80% reduction in the risk of disease progression or death versus rituximab alone in this patient population.2,3 At a median follow-up of 26.5 months, the median progression-free survival (PFS) had not yet been reached with the regimen, while the PFS was 20.3 months with single-agent rituximab (HR, 0.20; 95% CI, 0.11-0.38; P <.0001). The 30-month PFS rate reported with the combination was 82% vs 28% with the monotherapy.

The trial enrolled a total of 150 symptomatic patients who were then randomized to receive either the combination regimen (n = 75) or rituximab alone (n = 75). The median age of participants was 69 years, with 33% aged 75 years or older. Forty-five percent of participants were treatment naïve. Additionally, 38% of patients were determined to be high risk, according to the International Prognostic Scoring System for Waldenström Macroglobulinemia. At baseline, 79% of patients had extramedullary disease.

In treatment-naïve patients, the PFS rate at 24 months was 84% in the combination arm vs 59% in the single-agent arm. In patients with relapsed disease, the PFS rate at 30 months was 80% with the combination vs 22% with the monotherapy.

Additionally, in the overall patient population, the combination elicited an overall response rate (ORR) of 92%, while the monotherapy induced an ORR of 42% (P <.0001). The major response rates in the combination and monotherapy arms were 72% vs 32%, respectively (P <.0001).

At the time of data cutoff, three-fourths of patients who were receiving the combination continued to receive treatment. Seventy-three percent of those in the combination arm had sustained increases in hemoglobin level vs 41% in the monotherapy arm (P <.0001). The median time to next treatment had not been reached for with the combination vs 18 months with the monotherapy (HR, 0.96; P <.0001).

The overall survival (OS) rate was 94% at 30 months in the investigative arm vs 92% in the control arm. Notably, 30 patients in the control arm crossed over to receive single-agent ibrutinib.

Regarding safety, grade 3 or higher treatment-emergent toxicites were observed in more than half of patients on both the combination and monotherapy arms, at 60% vs 61%, respectively. Adverse effects that were grade 3 or higher and more common in the ibrutinib-containing arm as compared with the rituximab arm comprised atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).

More than half of the incidents of atrial fibrillation that were reported in the combination arm presented in patients who were aged 75 years or older. Grade 3 or higher treatment-emergent adverse effects more commonly experienced by those in the rituximab arm vs those in the ibrutinib combination arm included igM flare (3% vs 0%) and infusion-related reactions (16% vs 1%).

Ibrutinib was first approved by the FDA in 2013 and is now indicated for patients with various types of blood cancer, as well as those with chronic graft-versus-host disease. In 2015, the single agent was approved for use in patients with Waldenström macroglobulinemia. Most recently, in 2018, ibrutinib received regulatory approval for use in combination with rituximab based on data from the primary analysis of iNNOVATE.


  1. Imbruvica (ibrutinib) US prescribing information updated to include long-term data for Waldenström macroglobulinemia (WM). News release. AbbVie. December 23, 2020. Accessed December 23, 2020. http://prn.to/38taBg5.
  2. US FDA approves Imbruvica (ibrutinib) for treatment of Waldenstrom’s macroglobulinemia (WM). News release. Pharmacyclics. January 29, 2015. Accessed December 23, 2020. prn.to/3fR0FPy.
  3. Dimopoulos MA, Tedeschi A, Trotman J, et al. Randomized phase 3 trial of ibrutinib/rituximab vs placebo/rituximab in Waldenström's macroglobulinemia. J Clin Oncol. 2018;36(suppl 15):8003. doi:10.1200/JCO.2018.36.15_suppl.8003