On 19 January, 2017, the US Food and Drug Administration (FDA) has approved ibrutinib (IMBRUVICA®) for the treatment of patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy. Accelerated approval was granted for this indication based on overall response rate (ORR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Ibrutinib is jointly developed and commercialised by Janssen Biotech, Inc., and Pharmacyclics LLC, an AbbVie company.
MZL is a slow-growing B-cell lymphoma occurring in lymphocytes at the edges of lymph nodes and various tissues, including the stomach, salivary glands, thyroid gland, eyes, lungs and spleen. MZL accounts for approximately 12% of all cases of non-Hodgkin’s lymphoma in adults. The median age of diagnosis is 65 years old. Prior to the approval of ibrutinib, there were no FDA-approved therapies specifically for this disease.
The approval is based on results from the multicentre, open-label single arm, phase II PCYC-1121 trial assessing the safety and efficacy of ibrutinib in 63 patients with MZL who received at least one prior therapy, including all 3 subtypes: mucosa-associated lymphoid tissue (MALT; n=32), nodal MZL (NMZL; n=17), and splenic MZL (SMZL; n=14).
The responses were assessed by an Independent Review Committee using criteria adopted from the International Working Group criteria for malignant lymphoma and demonstrated a 46% ORR (95% CI: 33.4-59.1), with 3.2% of patients achieving complete responses (CR) and 42.9% achieving partial responses (PR). Efficacy was observed across all three MZL subtypes (ORR of 46.9%, 41.2%, and 50.0% for MALT, nodal, and splenic subtypes, respectively). The median duration of response (DOR) was not reached (range, 16.7-NR), with median follow-up of 19.4 months. The median time to initial response was 4.5 months (range, 2.3-16.4). These data were presented at the 58th Annual American Society of Hematology (ASH) Meeting in December 2016.
Warnings and precautions for ibrutinib include hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, second primary malignancies, tumour lysis syndrome and embryo-foetal toxicity. The most common (>20%) adverse events (AEs) of all grades included thrombocytopenia (49%), fatigue (44%), anaemia (43%), diarrhoea (43%), bruising (41%), musculoskeletal pain (40%), hemorrhage (30%), rash (29%), nausea (25%), peripheral oedema and arthralgia (24% each), neutropenia (22%), cough (22%), and dyspnoea and upper respiratory tract infection (21% each). The most common (>10%) grade 3 or 4 AEs were decreases in haemoglobin and neutrophils (13% each) and pneumonia (10%).
This approval broadens the indication for ibrutinib to include relapsed/refractory marginal zone lymphoma. It represents fifth indication for ibrutinib in the US.
Janssen and Pharmacyclics are continuing an extensive clinical development programme for ibrutinib, including phase III study commitments in multiple disease areas.
Ibrutinib was one of the first therapies to receive US approval after having received the FDA’s Breakthrough Therapy Designation. Ibrutinib targets and blocks Bruton's tyrosine kinase.