Regulatory Decision Summary for IMBRUVICA

Mantle cell lymphoma (MCL) is a rare and incurable subtype of non-Hodgkin Lymphoma (NHL) representing approximately 6% of all new NHL cases per year. Mantle cell lymphoma occurs more often in men than in women, and the incidence of MCL increases with age. Patient demographics are similar in Canada compared with the rest of the world. In Canada, approved treatment options are limited and include chlorambucil and bortezomib.

Based on the results of a single-arm Phase 2 study (Study 1104), Imbruvica (ibrutinib) treatment in patients with relapsed or refractory MCL is considered to demonstrate promising evidence of efficacy. In this study, patients achieved an overall response rate (ORR) of 67.6% [number (n) = 75], with 20.7% (n = 23) complete responses (CRs) and 46.8% (n = 52) partial responses (PRs). The median duration of response (DOR) was estimated to be 17.5 months, and the median time to initial response was 1.9 months. Furthermore, response appeared to improve over time, and subgroup analysis suggested that the overall response to Imbruvica appears to be independent of prior treatment (bortezomib or lenalidomide), or known prognostic factors.

The most common treatment-emergent adverse events (TEAEs) in subjects with previously-treated MCL (reported in ≥20% of 120 subjects) were diarrhea, fatigue, nausea, peripheral edema, constipation dyspnea, upper respiratory tract infection, vomiting, decreased appetite, cough, and thrombocytopenia. A higher dose of Imbruvica was used for the treatment of MCL patients in clinical trials compared to chronic lymphocytic leukemia (CLL) patients (560 mg vs 420 mg daily, respectively). Overall, the safety profile of Imbruvica identified in the treatment of previously-treated MCL patients is consistent with that previously assessed in the CLL patient population, and the data support the conclusion that Imbruvica has a tolerable safety profile for the indicated patient population.

An exception to this consistency is in the rate of hemorrhagic events reported in MCL patients, where 8 patients (6.7%) in the integrated MCL population experienced a major hemorrhagic event, compared to 1.0% of patients in the pivotal CLL study (Study 1112). There were multiple potential contributing causes for bleeding in MCL patients, including concurrent use of anti-platelet agents or anticoagulants. Subsequent studies (including those in the CLL patient population) recommended against concomitant use of warfarin or other vitamin K antagonists and use of caution with concomitant use of other anticoagulants or medications that inhibit platelet function; this recommendation is included in the approved Product Monograph.

Similarly, atrial fibrillation was also reported more frequently in Study 1104 than in studies in CLL, with 10% of MCL patients treated with 560 mg daily Imbruvica reporting atrial fibrillation, compared to 5% previously reported for CLL patients treated with 420 mg daily. Based on the available data, it is not known if the increased incidence of reports in MCL patients is due to the higher dose used in this patient population.

The Product Monograph is the primary risk management strategy to manage the risks associated with Imbruvica. Warnings pertaining to the adverse events reported in clinical trials, and recommendations to the prescriber regarding dose modifications/interruptions that may be required to manage adverse events have been included. Risk factors, when present, are described, and recommendations for monitoring are provided. The Product Monograph is considered an appropriate measure for risk management of Imbruvica.

In conclusion, while the response rates achieved for MCL patients following treatment with Imbruvica are high with a considerably long duration of response, Study 1104 is limited by the absence of a comparator arm and uncertainties resulting from cross-study comparisons to other agents. Furthermore, duration of response should be confirmed in a larger patient population. As such, the data are considered to support promising evidence of efficacy with an acceptable safety profile and meet the requirements of approval under the NOC/c Guidance. Additional studies are required to confirm the benefit of Imbruvica in patients with relapsed or refractory MCL.