Regulatory Decision Summary for IMBRUVICA

The clinical efficacy and safety of Imbruvica for the treatment of patients with previously untreated CLL was evaluated in a single pivotal study (Study PCYC 1115-CA). Study PCYC 1115-CA was a randomized, controlled, open-label study conducted in patients with previously untreated deletion 17-negative CLL aged65 years or older (N = 269). All patients met at least one of the International Workshop on CLL 2008 criteria for initiating treatment. Patients were randomized 1:1 to receive either Imbruvica 420 mg daily or chlorambucil. The primary efficacy endpoint was progression-free survival (PFS).

With a median follow-up of 18 months, there was a statistically significant improvement in the PFS of Imbruvica-treated patients over chlorambucil-treated patients (HR = 0.16; 95% CI: 0.091, 0.28; p<0.0001). Median PFS was not reached for the Imbruvica treatment arm and was 19 months for the chlorambucil treatment arm. The overall response rate was higher for the Imbruvica treatment arm (82%) than the chlorambucil treatment arm (35%). The analysis of overall survival (OS) showed that Imbruvica significantly reduced the risk of death by 84% (HR = 0.16; 95% CI; 0.048, 0.56; p<0.005); median OS was not reached in either of the treatment arms. In addition, a significantly greater proportion of patients in the Imbruvica treatment arm exhibited sustained improvement in the platelet count or hemoglobin level than in the chlorambucil treatment arm. In patients with baseline cytopenias, a significantly greater proportion of patients in the Imbruvica treatment arm exhibited sustained hematologic improvement than in the chlorambucil treatment arm (platelet count, 77% versus 43%; hemoglobin level, 84% versus 46%).

The most frequently reported treatment-emergent adverse events in the Imbruvica treatment arm were diarrhea, fatigue, cough, and nausea; in the chlorambucil treatment arm these were nausea, fatigue, neutropenia, anemia, and vomiting. Hypertension, a known adverse event with Imbruvica treatment, was identified as a new risk as it was reported at higher frequencies than in previous studies and there was a trend towards a higher prevalence rate with longer treatment. Other known adverse events with Imbruvica that occurred at higher frequencies in this study were major hemorrhage events (including intracranial hemorrhages), non-melanoma skin cancers (including basal and squamous cell carcinoma), and eye disorders. Overall, the safety profile of Imbruvica is generally consistent with what has been observed in the other indications, with the notable exceptions described above. The Product Monograph has been updated to provide information on the frequencies of these reported adverse events as well as recommendations for monitoring.

In conclusion, the benefit/risk profile of Imbruvica is considered to be positive for the use of Imbruvica in patients with previously untreated CLL, a condition for which new treatment options are needed. As noted at the initial approval for use of Imbruvica in patients with CLL, clinical effectiveness of Imbruvica in previously untreated patients with CLL with 17p deletion is based on the benefit observed in patients with CLL with 17p deletion who have received at least one prior therapy. Clinical trial data in previously untreated patients with CLL with 17p deletion are very limited.