Regulatory Decision Summary for Imbruvica

The efficacy and safety of Imbruvica for the treatment of MZL is supported by Study 1121 which is a multi-center, single arm phase 2 study of 63 adult patients with relapsed/refractory MZL who received at least one prior line of systemic therapy including at least one anti-CD20 regimen. The efficacy analysis included 60 patients with the 3 subtypes of MZL. The demographics of the patient population represent the targeted population with a median of 2 prior lines of systemic therapy. Imbruvica was administered orally at 560 mg once daily until disease progression or unacceptable toxicity.

The primary endpoint in this study was overall response rate (ORR; the proportion of patients who achieved either a partial response [PR] or a complete response [CR] as best response) per independent review committee (IRC) assessment. The ORR was 48.3% with 3.3% of the patients having achieved a CR and 45% with a PR for the efficacy population.

Per the IRC assessment, the median duration of response (DOR) was not reached, with 62% of all responders alive and progression-free at 18 months. The median follow up was 19.4 months. The median overall survival was not reached.

The efficacy results are of clinical relevance given the ORR observed is reasonable for a relapsed population, and even more so in this study where more than half of the patients have had 2 or more lines of prior treatment. Furthermore, the responses were durable as indicated by the median DOR of 19.4 months per the investigator assessment, and not reached per the IRC assessment.

In Study 1121, the median duration of ibrutinib exposure was 11.6 months. Treatment emergent adverse events (TEAEs) occurred in all 63 patients and the most common (≥ 20%) were fatigue, diarrhea, anemia, nausea, arthralgia, edema peripheral, thrombocytopenia, cough, dyspnea, and upper respiratory tract infection which were generally Grade 1-2 in severity. Grade 3 or higher TEAEs occurred in 66.7% of patients, and the most commonly reported ones (≥ 5%) were anemia, pneumonia, and fatigue. Serious TEAEs occurred in 44.4% of patients and the most common were pneumonia (7.9%), autoimmune hemolytic anemia, cellulitis, pneumothorax, and sepsis (3.2% each). The new adverse drug reactions identified in Study 1121 were anxiety (15.9%), hypoalbuminemia (14.3%), and hypokalemia (12.7%).

TEAEs leading to discontinuation occurred in 19.0% of patients, and TEAEs leading to dose reduction occurred in 9.5% of patients. The most common TEAEs leading to study treatment discontinuation were diarrhea, rash, and interstitial lung disease. Fatigue and stomatitis were the only TEAEs leading to dose reduction in more than 1 patient (2 patients each).

Treatment-emergent lymphocytosis, hemorrhagic events, cytopenias, infections, atrial fibrillation, other malignancies, hypersensitivity reactions, eye disorders, hepatobiliary disorders, interstitial lung disease, and hypertensive events were reported during Study 1121. These are part of the known safety profile of Imbruvica and the occurrences in Study 1121 are, in general, consistent with the incidence rates reported in the Imbruvica studies with other B-cell malignancies for the approved indications.

Considering the efficacy demonstrated in the pivotal study, and that the adverse events are tolerable, manageable, and consistent with the known safety profile of Imbruvica from other approved indications, the benefit-harm-uncertainty assessment is considered to be positive. Imbruvicas benefits are considered to outweigh the harms for the treatment of MZL in patients who require systemic therapy and have received at least one prior anti-CD20-based therapy.

The warnings, precautions and recommendations for dosage adjustments in the current approved Product Monograph are considered adequate and appropriate for the mitigation of harm for MZL patients. The proposed indication has been revised to include the specifications for the treatment of MZL in patients who have received prior anti-CD20 based therapy and require systemic therapy as this was considered to most appropriately reflect the patient population studied and enable prescribers to make informed decisions on the use of Imbruvica in MZL patients.