Ibrutinib Withdrawn From Market by Developer for MCL and MZL Indications


Mixed study results for ibrutinib have led the developer to voluntarily withdraw the agent from the United States market for the treatment of mantle cell and marginal zone lymphoma subgroups.

The Bruton’s tyrosine kinase inhibitor, ibrutinib (Imbruvica) has been voluntarily withdrawn from the United States market as a treatment option for patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy, and for the treatment of patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least 1 prior anti-CD20-based therapy.1

The withdrawal decision was made by The Janssen Pharmaceutical Companies of Johnson & Johnson in collaboration with Pharmacyclics, an AbbVie Company, following a consultation with the FDA regarding procedural guidance on accelerated approvals. The decision has no impact on other indications for ibrutinib.

“We fully support the FDA accelerated approval pathway, which patients rely on for timely access to promising treatments that may improve or extend their lives. While withdrawing these indications was a difficult decision, we remain confident in the benefit/risk profile of [ibrutinib] in its approved indications and are committed to its continued development,” said Craig Tendler, MD, vice president, late development and global medical affairs, Janssen Research & Development, LLC, in a press release. “Imbruvica has transformed how patients with B-cell malignancies are treated and is the most comprehensively studied and prescribed therapy in its class.”

Ibrutinib was previously granted accelerated approval by the FDA by the for the 2 indications based on results from the phase 2 PCYC-1104 study (NCT01236391) and the randomized phase 3 RAY study (NCT01646021), but continued approval was contingent upon clinical benefit being shown in phase 3 confirmatory studies. The developer aimed to demonstrated further benefit of ibrutinib in the phase 3 SHINE study (NCT01776840) in previously untreated patients with MCL, and the confirmatory phase 3 SELENE study (NCT01974440) in patients with relapsed or refractory follicular lymphoma (FL) or MZL.


In the SHINE study, ibrutinib was administered with the standard combination of bendamustine and rituximab (Rituxan) or placebo with bendamustine/rituximab in 523 patients with previously-untreated MCL.2

The ibrutinib combination achieved a median progression-free survival (PFS) of 80.6 months (95% CI, 61.0 months-not evaluable [NE]) compared with 52.9 months (95% CI, 43.7-71.0 months) in the placebo arm (HR, 0.75; 95% CI, 0.59-0.96; = .01), meeting the primary end point of the study. The PFS was markedly longer than previously shown with rituximab (Rituxan) plus cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) combined with rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP), and bendamustine in a phase 3 study of patients with newly-diagnosed MCL.3

blood cancer, hematologic malignancies, MCL, MZL, blood cells | Image Credit: © abhijith3747 - [stock.adobe.com]

Image Credit: © abhijith3747 [stock.adobe.com]

Results from the SHINE study showed that the 7-year overall survival (OS) rate in the ibrutinib-treated patients was 55.0% compared with 56.8% in the placebo arm (HR 1.01; 95% CI, 0.81-1.40), showing no significant difference between the 2 arms. The complete response rate was 65.5% with the ibrutinib combination vs 57.6% with placebo (= 0.06). The percentage of patients with an objective response was 89.7% in the ibrutinib arm vs 88.5% in the placebo arm. Following treatment, minimal residual disease was undetectable in 62.1% of the ibrutinib group compared with 56.5% in the placebo group.

Adverse events (AEs) of any-grade occurred in all patients in the ibrutinib group compared with 98.8% of the placebo group. Grade 3 or 4 AEs occurred in 81.5% of the ibrutinib arm vs 77.3% of the placebo arm. The most common grade 3/4 AEs observed with ibrutinib vs placebo, respectively, were neutropenia (47.1% vs 48.1%), pneumonia (20.1% vs 14.2%,), lymphopenia 16.2% vs 11.9%), anemia (15.4% vs 8.8%), thrombocytopenia (12.7% vs 13.1%), rash (12.0% vs 1.9%), and leukopenia (10.0% vs 11.2%).

The AEs of clinical interest included atrial fibrillation, hypertension, diarrhea, major hemorrhage, and arthralgia. There was 1 patient in each arm who experienced pneumocystis pneumonia, and aspergillus infection was seen in 4 patients treated with the ibrutinib combination vs 1 in the placebo group. AEs were the main cause of death for 28 patients in the ibrutinib group vs 16 patients in the placebo arm. The other deaths in the study were caused by either cardiac disorder or coronavirus.

The positive efficacy and tolerable safety shown with ibrutinib in the SHINE resulted in the making of the confirmatory SELENE study.

Treatment with ibrutinib plus R-CHOP in the SELENE study was explored in 838 patients with previously-treated indolent non-Hodgkin lymphoma. The study failed to meet its primary end point of OS, according to The Janssen Pharmaceutical Companies.1

Further results from the study will be presented at an upcoming medical meeting.


1. Update on IMBRUVICA® (ibrutinib) U.S. accelerated approvals for mantle cell lymphoma and marginal zone lymphoma indications. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. April 7, 2023. Accessed April 10, 2023. https://bit.ly/43xjnFR

2. Wang ML, Jurczak W, Jerkeman M, et al. Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma. N Engl J Med. 2022; 386:2482-2494. doi.10.1056/NEJMoa2201817

3. Robak T, Jin J, Pylypenko H, et al. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol. 2022;19(11):1449-1458. doi:10.1016/S1470-2045(18)30685-5

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