Approval Sought for Ibrutinib Combination in Patients With Mantle Cell Lymphoma

A Type II variation application seeking the approval of a new indication for the combination of ibrutinib (Imbruvica), bendamustine, and rituximab (Rituxan) in adult patients with previously untreated mantle cell lymphoma (MCL) who are not candidates for autologous stem cell transplant (ASCT) has been submitted to the European Medicines Agency (EMA).¹

Findings from the phase 3 SHINE trial (NCT01776840), which examined the combination in patients with newly diagnosed MCL aged 65 years or older, is the basis of the application. Results showed that the combination demonstrated a significant improvement in progression-free survival (PFS) compared to rituximab alone.

“MCL can be a difficult blood cancer to treat, and despite progress in this area of the last few years, an unmet need remains for new treatment approaches,” Edmond Chan, MBChB, MD (Res), EMEA therapeutic area lead hematology, at Janssen-Cilag Limited, stated in a press release. “This submission to the EMA is a testament to our commitment to deepening the impact ibrutinib can have for patients and represents an important step toward providing patients and health care professionals with the addition of targeted therapy to standard therapy.”

The trial included 523 participants with MCL who had clinical stage II, III, or IV disease by Ann Arbor classification.²Eligibility for participation was open to patients with at least 1 measurable site of disease, and an ECOG performance status of 0 or 1. Additionally, patients could not have received prior therapies for their disease.

Patients were randomized 1:1 to receive either ibrutinib or placebo, both in combination with an open-label bendamustine plus rituximab background treatment for a maximum of 6 cycles. Of the participants who achieved a complete (CR) or partial response (PR), open-label background therapy with rituximab maintenance was continued every second cycle for up to 12 additional doses. Patients then received ibrutinib or placebo in addition to this background treatment.

In the experimental treatment arm, bendamustine was given intravenously (IV) at a dose of 90 mg/m2 on days 1 and 2 of cycles 1 through 6, and IV rituximab was delivered at a dose of 375 mg/m2on day 1 of cycles 1 through 6. If either CR or PR was achieved at this time, patients were administered rituximab at the same dose on day 1 of every second cycle for up to 12 additional doses. Additionally, ibrutinib was given orally, once a day at a dose of 560 mg, continually starting on day 1 of cycle 1. Either combination was given until progressive disease, intolerable toxicity, or study completion.

If stable disease following initial chemoimmunotherapy was achieved, patients continued to receive ibrutinib or placebo until progressive disease, intolerable disease, or study end. Patients who experienced disease progression needed to discontinue study treatment.

The primary end point of the trial was PFS, with secondary end points including overall survival, overall response rate, minimal residual disease negativity rate, duration of response, time to next treatment, number of participants affected by adverse events, toxicity, and other various pharmacokinetic measures.

The trial, which met its primary end point, will have its data shared at an upcoming medical conference, according to a press release issued by the Janssen Pharmaceutical Companies of Johnson & Johnson.

“As the first approved BTK inhibitor, ibrutinib has now been used to treat more than 250,000 patients globally. It is also the first BTK inhibitor to be studied as a frontline treatment option for patients with MCL. We are committed to the continued development of ibrutinib in B-cell malignancies where unmet needs remain in our efforts to make meaningful differences and change outcomes for patients,” Craig Tendler, MD, global head of late development, Diagnostic & Medical Affairs, Hematology & Oncology, at Janssen Research & Development, LLC, added in the press release.

References

1. Janssen seeks approval of a new indication for IMBRUVICA (ibrutinib) for use in patients with untreated mantle cell lymphoma. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson; March 8, 2022. Accessed April 5, 2022. https://bit.ly/3r2wHQM

2. A study of the Bruton’s Tyrosine Kinase inhibitor ibrutinib given in combination with bendamustine and rituximab in patients with newly diagnosed mantle cell lymphoma. ClinicalTrials.gov. Updated March 25, 2022. Accessed April 5, 2022. https://clinicaltrials.gov/ct2/show/NCT01776840