Expanded FDA Label Sought for Ibrutinib/Rituximab With Long-Term Data in Waldenström Macroglobulinemia

A supplemental new drug application (sNDA) has been submitted to the FDA for review for the use of ibrutinib (Imbruvica) in combination with rituximab (Rituxan) as a treatment for patients with Waldenström macroglobulinemia, according to AbbVie, the developer of ibrutinib.¹

The application seeks to expand the label of the drug based on 5 years of follow-up data from the phase 3 iNNOVATE trial, which will be presented at an upcomingmedical meeting.

“Since [ibrutinib] became the first FDA-approved medicine to treat people living with Waldenström macroglobulinemia more than 5 years ago, it has significantly changed the treatment landscape for this rare and incurable form of non-Hodgkin lymphoma,” Danielle James, MD, MAS, Imbruvica Global Development Lead of Pharmacyclics LLC, an AbbVie company, said in a press release. “The latest submission reinforces how [ibrutinib] has provided an innovative treatment option for [these] patients and our commitment to supporting this patient community.”

The small molecule drug first received approval in January 2015 for use as a monotherapy in all lines of therapy in Waldenström macroglobulinemia, marking the first and only treatment for patients with the rare, indolent type of B-cell lymphoma.² Three years later, in August 2018, ibrutinib was approved for use in combination with rituximab as the first chemotherapy-free treatment option across all lines of therapy in this patient population.

The decision was based on earlier data from iNNOVATE, which had been presented at the 2018 ASCO Annual Meeting and simultaneously published in the New England Journal of Medicine. Results from the trial demonstrated that the combination reduced the risk of disease progression or death by 80% compared with rituximab alone in this patient population.^3,4

At a median follow-up of 26.5 months, the median progression-free survival (PFS) had not yet been reached with the combination, while the PFS was 20.3 months with rituximab alone (HR, 0.20; 95% CI, 0.11-0.38; P <.0001). The 30-month PFS rates observed with the combination and the monotherapy were 82% and 28%, respectively.

A total of 150 symptomatic patients were randomized to receive the combination (n = 75) or rituximab alone (n = 75). The median age of participants was 69 years, with 33% aged ≥75 years. Just under half (45%), of patients had not received prior treatment. Furthermore, 38% of patients were considered to be high risk in accordance with the International Prognostic Scoring System for Waldenström Macroglobulinemia. Seventy-nine percent of patients had extramedullary disease at baseline.

The 24-month PFS rate in treatment-naïve patients was 84% in the combination arm compared with 59% in the monotherapy arm. In patients with relapsed disease, the 30-month PFS rate was 80% and 22% with the combination and the monotherapy, respectively.

Moreover, in the overall patient population, the overall response rate (ORR) was 92% with the combination versus 42% with rituximab monotherapy (P <.0001). The major response rate in the combination arm was 72% versus 32% in the monotherapy arm (P <.0001).

At the time of data cutoff, three-fourths of patients who were receiving the ibrutinib combination remained on treatment. Seventy-three percent of those in the combination arm experienced sustained increases in hemoglobin level versus just 41% in the rituximab arm (P <.0001). The median time to next treatment had not been reached for the investigative arm versus 18 months for the control arm (HR, 0.96; P <.0001).

At 30 months, the overall survival (OS) rate was 94% in the investigative arm versus 92% in the control arm. Notably, 30 patients in the control arm were reported to have crossed over to receive single-agent ibrutinib.

With regard to safety, grade 3 or higher treatment-emergent adverse events (TEAEs) were reported in more than half of patients on both the combination and monotherapy arms, at 60% versus 61%, respectively. AEs that were grade 3 or higher in severity and more common in the ibrutinib-containing arm as compared with the rituximab arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%). More than half of the incidents of atrial fibrillation that were reported in the investigative arm presented in patients aged ≥75 years. Grade 3 or higher TEAEs more commonly reported in the rituximab arm as compared with the ibrutinib combination arm included igM flare (3% vs 0%) and infusion-related reactions (16% vs 1%).

“We’ve made significant progress in the treatment of Waldenström macroglobulinemia, which until a couple of years ago had limited treatment options including chemotherapy,” principal investigator Meletios A. Dimopoulos, MD, professor and chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine, said in the press release. “The iNNOVATE study continues to deliver strong clinical evidence supporting the long-term use of ibrutinib plus rituximab across first and second lines of therapy for [this patient population].”

References

1. Imbruvica (ibrutinib) seeks to expand US label with long-term data in Waldenström macroglobulinemia. News release. AbbVie. June 23, 2020. Accessed June 23, 2020. bit.ly/2BxS5GC.
2. US FDA approves Imbruvica (ibrutinib) for treatment of Waldenstrom’s macroglobulinemia (WM). News release. Pharmacyclics. January 29, 2015. Accessed June 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
4. Dimopoulos MA, Tedeschi A, Trotman J, et al. Phase 3 trial of ibrutinib plus rituximab in Waldenström’s macroglobulinemia N Engl J Med. 2018;378(25):2399-2410. doi: 10.1056/NEJMoa1802917