Accelerated Approvals Withdrawn for Ibrutinib in Mantle Cell Lymphoma, Marginal Zone Lymphoma


Accelerated approvals for ibrutinib (Imbruvica) for patients with mantle cell lymphoma and with marginal zone lymphoma voluntarily withdrawn based on data that were insufficient to support conversion to full approval.

Janssen Pharmaceutical Companies of Johnson & Johnson and its partner, Pharmacyclics, an AbbVie Company, have announced the voluntarily withdrawal of the accelerated approvals for ibrutinib (Imbruvica) for patients with mantle cell lymphoma (MCL) who were administered at least 1 prior therapy, and with marginal zone lymphoma (MZL) who require systemic therapy and were administered at least 1 prior anti-CD20-based therapy. The withdrawals do not affect the other approved indications for ibrutinib in the United States.1

The companies announced that the voluntarily withdrawal was based on requirements related to the FDA’s issuing of the accelerated approval for MCL and MZL, which were granted based on overall response rates in phase 2 clinical studies. To confirm clinical benefit following accelerated approvals, additional studies are required by the FDA.

The confirmatory trials included the phase 3 SHINE study (NCT01776840) in previously untreated patients with MCL, and the phase 3 SELENE study (NCT01974440) in patients with relapsed or refractory follicular lymphoma (FL) or MZL. Based on the findings from these studies, the FDA advised that the primary outcomes were deemed insufficient to support conversion to full approval.1

“We pursued accelerated approvals for MCL and MZL indications for Imbruvica in the US to offer a treatment to patients who at the time had limited therapeutic options. While we are disappointed in the outcome of the confirmatory trials for these indications, we remain confident in the benefit/risk profile of Imbruvica for patients living with multiple forms of blood cancer around the world,” said Roopal Thakkar, senior vice president, chief medical officer, AbbVie, in a press release.1

Ibrutinib is a once-daily oral medication that blocks the Bruton’s tyrosine kinase (BTK) protein, which is necessary for normal and abnormal B cells to multiply and spread. By blocking BTK, ibrutinib can help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs. Ibrutinib was first approved by the FDA in 2013 and is currently indicated for adult patients in 6 disease areas, including 5 hematologic cancers.

SHINE, a multi-centered, phase 3, randomized trial, evaluated the addition of ibrutinib to bendamustine-rituximab (BR) in the upfront treatment of MCL. Patients aged 65 years or older with a median age of 71 years were randomized in a 1:1 ratio to 6 cycles of BR, with or without ibrutinib 560 mg daily, those achieving a partial response or better continued placebo/ibrutinib plus rituximab maintenance.

The primary endpoint was progression-free survival (PFS) as assessed by the study investigators. PFS was 80.6 months in the ibrutinib group vs 52.9 months in the placebo group (HR 0.75; 95%CI 0.59-.96, p=0.01).2 The SHINE trial achieved the primary endpoint with a significant PFS advantage in patients with previously untreated MCL, but did not demonstrate an overall survival advantage.

Further, adding ibrutinib to chemoimmunotherapy was found to increase adverse events compared to the placebo-controlled arm, according to the results, which were published in The New England Journal of Medicine. The SELENE study did not meet the primary endpoint of PFS.

“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 Imbruvica 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.3 “Imbruvica has transformed how patients with B-cell malignancies are treated and is the most comprehensively studied and prescribed therapy in its class.”


1. Update on IMBRUVICA® (ibrutinib) U.S. Accelerated Approvals for Mantle Cell Lymphoma and Marginal Zone Lymphoma Indications. AbbVie. News release. April 7, 2023.

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(26):2482-2494. doi:10.1056/NEJMoa2201817

3. Update on IMBRUVICA® (ibrutinib) U.S. Accelerated Approvals for Mantle Cell Lymphoma and Marginal Zone Lymphoma Indications. Janssen. News release. April 7, 2023.

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