Regulatory Decision Summary for Imbruvica

Imbruvica is currently indicated for the treatment of patients with previously treated chronic lymphocytic leukemia (CLL) based on a phase 3 trial (Study 1112) supporting its use as monotherapy. The safety and efficacy of Imbruvica in combination with bendamustine and rituximab (BR) for the treatment of these patients was evaluated in a pivotal study (Study CLL3001), the objective of which was to demonstrate a benefit of using Imbruvica plus BR over BR alone. Study CLL3001 was a randomized, double-blind, placebo-controlled phase 3 trial in patients with relapsed or refractory CLL without 17p deletion, including 64 patients with clinical presentation of small lymphocytic lymphoma. Patients (n = 578) were randomized 1:1 to receive either Imbruvica 420 mg daily or placebo in combination with BR. The primary efficacy endpoint was progression-free survival (PFS) as evaluated by an independent review committee (IRC).

At a median duration of treatment of 14.7 months in the Imbruvica + BR arm, and 12.8 months in the placebo + BR arm, there was a statistically significant improvement in PFS with the combination of Imbruvica with BR (HR = 0.20; 95% CI: 0.15, 0.28; p < 0.0001). The median PFS was not reached with the Imbruvica + BR arm and was 13.3 months for the placebo + BR arm. The IRC-assessed overall response rate (ORR) was higher for the Imbruvica + BR arm (82.7%) than the placebo + BR arm (67.8%). The IRC-assessed complete response rate/complete response with incomplete marrow recovery (CR/CRi) rate was also higher for the Imbruvica + BR arm (10.4%) than the placebo + BR arm (2.8%), indicating a deeper response to the combination therapy.

As the objective of Study CLL3001 was not to demonstrate a benefit of using Imbruvica plus BR over Imbruvica monotherapy, a cross-study comparison with Study 1112 was made. With similar time on study (17 months for Study CLL3001; 19 months for Study 1112), the investigator-assessed overall response, 12- and 18-month PFS and 12-month overall survival rates were similar for Imbruvica in combination with BR and Imbruvica monotherapy (86% vs. 83%; 88% vs. 84%; 79% vs. 76%; and 93% vs. 90%). However, deeper responses may be achieved with the combination therapy. With further follow up of Study CLL3001 (median 25 months), investigator-assessed CR/CRi rate was reported to have increased to 34%; while in Study 1112, the investigator-assessed CR/CRi rate with a median follow-up of 30 months was 9%. Further, Imbruvica in combination with BR provides an alternative treatment option based on patient characteristics.

Study CLL3001 excluded patients with del17p as this patient population responds poorly to standard chemotherapy options for CLL, including BR. In a supportive phase 1b, open label study, 7 patients with previously treated CLL with del17p received Imbruvica in combination with BR. Of the 7 patients, 5 responded to treatment. While limited, these data support the efficacy of Imbruvica in combination with BR in this high-risk patient group.

The overall safety profile of Imbruvica in combination with BR was consistent with the known individual safety profiles of Imbruvica and BR, with no unexpected safety signals identified for the combination.

In conclusion, Health Canada considers the benefit/risk to be positive for the use of Imbruvica in combination with BR in patients with previously treated CLL. However, clinical data for this use in CLL with del17p are limited.