sNDA Seeks Expanded Approval of Ibrutinib in Waldenström's Macroglobulinemia

"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 patients with Waldenström's macroglobulinemia."

A supplemental New Drug Application (sNDA) has been submitted to the FDA seeking expanded approval of ibrutinib (Imbruvica) in combination with rituximab (Rituxan) as treatment of patients with Waldenström's macroglobulinemia (WM), announced AbbieVie.1

The submission of this sNDA is based on the long-term data from the phase 3 iNNOVATE (PCYC-1127) study, which evaluated ibrutinib in combination with rituximab in patients with WM. These 5-year findings are the longest follow-up data currently available for BTK inhibition in WM.

"We've made significant progress in the treatment of Waldenström's macroglobulinemia, which until a couple years ago had limited treatment options including chemotherapy," said principal investigator Meletios A. Dimopoulos, MD, professor and chairman of the Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Athens, Greece, in a statement. "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 patients with Waldenström's macroglobulinemia."

The long-term analysis findings from the iNNOVATE clinical trial will be presented at an upcoming medical meeting. To date, ibrutinib is the only BTK inhibitor approved for the treatment of patients with WM.

The placebo-controlled, double-blind iNNOVATE study that enrolled 150 patients with relapsed/refractory and treatment-naïve WM to receive intravenous rituximab at 375 mg/m2 dose once weekly for 4 consecutive weeks followed by a second 4-week course of the drug following a 3-month interval. Patients were randomized to receive 420 mg ibrutinib once daily on a continuous schedule until treatment discontinuation criteria were met or placebo.

The primary end point of the study is progression-free survival (PFS), and secondary end points included overall response rate (ORR), hematological improvement, time-to-next treatment, overall survival (OS), and number of patients with adverse events (AEs) as a measure of safety and tolerability.

Ibrutinib received its approval as monotherapy in 2015 for the treatment of WM in all lines of therapy; this was the first and only FDA-approved treatment for WM that was administered orally. Ibrutinib received approval in 2018 as the first chemotherapy-free combination with rituximab.

The FDA’s approval of the combination was based on previously published findings from the iNNOVATE trial, which indicated that ibrutinib plus rituximab reduced the risk of disease progression or death by 80% compared with rituximab alone in this patient population. PFS data were not mature at the time of publication in the New England Journal of Medicine and presentation at the 2018 American Society of Clinical Oncology Annual Meeting.2

The 30-month PFS rate was 82% with the combination compared with 28% with rituximab alone. The ORR was 92% with ibrutinib versus 47% without, and the major response rate was 72% versus 32%, respectively (P <.0001). About 75% of patients remained on treatment at the data cutoff, and sustained increases in hemoglobin levels were observed in 73% of the patients in the combination arm versus 41% in the control arm (P <.0001). The median time to next treatment was not reached in the combination arm versus 18 months for the control (HR, 0.096; P <.0001).

The 30-month OS rate was 94% with the combination versus 92% with the control. Ibrutinib was administered for a median of 25.8 months (range, 1.0-37.2), and the primary reason for discontinuation was progressive disease (n = 7) and adverse events (n = 4).

Treatment-emergent AEs of grade ≥3 were observed in 60% of patients in the combination arm versus 61% in the control arm. Grade ≥3 treatment-emergent AEs occurring more frequently in the rituximab-alone arm than the combination arm included IgM flare (3% vs 0%) and infusion-related reactions (16% vs 1%), respectively. IgM flare of any grade was observed in 47% of the control arm compared with 8% of the combination arm. Grade ≥3 AEs that were more common with the addition of ibrutinib than rituximab aloneincluded atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%), respectively. Fifty-five percent of the incidents of atrial fibrillation in the ibrutinib arm occurred in patients aged ≥75 years.

"Since IMBRUVICA became the first FDA-approved medicine to treat people living with Waldenström's macroglobulinemia more than five years ago, it has significantly changed the treatment landscape for this rare and incurable form of non-Hodgkin's lymphoma," stated Danelle James, MD, MAS, IMBRUVICA global development lead, Pharmacyclics LLC, an AbbVie company.1 "This latest submission reinforces how IMBRUVICA has provided an innovative treatment option for WM patients and our commitment to supporting this patient community.”

WM, a rare and incurable form of non-Hodgkin lymphoma, affects older patients predominantly. WM is primarily found in the bone marrow, but it can also affect the lymph nodes and the spleen. According to the National Comprehensive Cancer Network, the current recommended treatment for WM is ibrutinib with or without rituximab.


IMBRUVICA (ibrutinib) seeks to expand US label with long-term data in Waldenström’s macroglobulinemia (WM). News Release. AbbVie. June 23, 2020. Accessed June 23, 2020.

Dimopoulos MA, Tedeschi A, Trotman J, et al. Phase 3 trial of ibrutinib plus rituximab in Waldenstroms macroglobulinemia [published online June 1, 2018). N Engl J Med. doi: 10.1056/NEJMoa1802917.