FDA Approval Sought for Ibrutinib in Marginal Zone Lymphoma

Peter F. Lebowitz, MD, PhD

A supplemental new drug application (sNDA) has been submitted to the FDA for the use of ibrutinib (Imbruvica) as a treatment for patients with marginal zone lymphoma (MZL), according to Janssen, which codevelops the BTK inhibitor with AbbVie.

The sNDA is based on the phase II PCYC-1121 trial (NCT01980628), which examined single-agent ibrutinib in patients with MZL following at least 1 prior therapy. Results from the trial will be presented at an upcoming medical meeting, Janssen noted in its statement.

“We are encouraged by the results of this study of ibrutinib in yet another type of B-cell malignancy," Peter F. Lebowitz, MD, PhD, global oncology head, Janssen, said in a statement. "This FDA submission represents an exciting and important step toward a potential new treatment option for MZL patients who currently have a great unmet need. Currently there are no therapies approved for this rare form of cancer."

The single-arm, open-label, international PCYC-1121 trial included 63 patients with splenic MZL, nodal MZL, or extranodal MZL. Patients were required to have received 1 or more prior therapies, including at least 1 anti-CD20 regimen.

Ibrutinib was administered orally at 560 mg once daily until progression or unacceptable toxicity. Overall response rate (ORR) was the primary endpoint, with duration of response and safety as secondary outcome measures. The full study data have been submitted to a peer-reviewed journal for publication.

A phase I study that assessed ibrutinib in patients with relapsed/refractory B-cell malignancies, including MZL, was previously published in the Journal of Clinical Oncology. The study included 56 patients with follicular lymphoma (16), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; 16), mantle cell lymphoma (MCL; 9), diffuse large B-cell lymphoma (7), MZL (4), and Waldenström’s macroglobulinemia (4).

The median age across the trial was 65 years (range, 41-82) and sixty-eight percent of patients were male. The median number of prior regimens was 3 (range, 1-10), including prior rituximab (Rituxan) in 93% of patients.

Patients received either 1.25-12.5 mg/kg of once daily ibrutinib for 28 days followed by 7 days off, or a continuous daily dose of 8.3 mg/kg or 560 mg of ibrutinib until disease progression or unacceptable toxicity. The primary endpoints were safety and determining the dose-limiting toxicity for each patient. Tumor response was the secondary outcome measure.

Among 50 evaluable patients, the ORR was 60% (n = 30), including a complete response rate of 16% (n = 8) and a partial response (PR) rate of 44% (n = 22). The median progression-free survival was 13.6 months.

Among the 4 patients with MZL, 1 patient had a PR, 1 patient had stable disease, 1 patient had progressive disease, and 1 patient was not evaluable.

Ibrutinib was well tolerated overall and the majority of adverse events (AEs) were grade 1 or 2. Grade 3/4 AEs included non-cough respiratory (7.1%), diarrhea (3.6%), decreased appetite/dyspepsia (3.6%), fatigue (3.6%), pyrexia (1.8%), and nausea/vomiting (1.8%)

“We continue to explore the use of ibrutinib in non-Hodgkin lymphoma, including marginal zone lymphoma and its three sub-types, given its unique mechanism of action and ability to target the B-cell receptor pathway," Darrin Beaupre, MD, PhD, head of Early Development and Immunotherapy at Pharmacyclics, an AbbVie company. "MZL in its advanced stages is currently an incurable form of hematologic cancer and new treatment options are needed. We look forward to working with the FDA and our partners at Janssen to bring this promising treatment to patients with MZL."

Ibrutinib has approved FDA indications for the treatment of patients with MCL, CLL/SLL, and Waldenström’s macroglobulinemia.

Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31(1):88-94.