Regulatory Decision Summary for Imbruvica

The purpose of this Supplemental New Drug Submission (SNDS) was to seek marketing authorization for a new indication of ibrutinib in combination with venetoclax for the treatment of adult patients with previously untreated chronic lymphocytic leukemia (CLL), including those with 17p deletion (del17p).

Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia (CLL/SLL; referred to as CLL hereafter) is a neoplastic disorder characterized by the clonal expansion of mature B cells in the blood, bone marrow, and lymphoid tissues, driven primarily by chronic B-cell receptor (BCR)-dependent signaling and impaired program cell death. Several kinases signal activation of downstream pathways permit CLL cells to survive. Ibrutinib inhibits the Bruton’s tyrosine kinase, reducing survival of CLL cells, and venetoclax inhibits B-cell lymphoma-2 (BCL-2), committing CLL cells to apoptosis.

The pivotal randomized, open-label, phase 3 study (Study 54179060CLL3001; GLOW) supports the market authorization of ibrutinib in combination with venetoclax for the first-line treatment of adult patients with previously untreated CLL. In the GLOW study, elderly (≥65 years) or unfit patients were randomized 1:1 to receive ibrutinib + venetoclax (Ibr+Ven) or the active comparator, chlorambucil + obinutuzumab (Clb+Ob). Clb+Ob is a recommended first-line treatment for this population. Patients with TP53 and del17p mutations were excluded, as these aberrations are associated with inferior outcomes with chemoimmunotherapy regimens (e.g., Clb+Ob).

The Ibr+Ven arm received ibrutinib (420 mg QD, orally) given as a lead-in treatment for three cycles (1 cycle = 28 days). Starting at Cycle 4, venetoclax dose ramp-up was initiated (from 20 mg to 400 mg over 5 weeks). Combined treatment with Ibr+Ven was administered for 12 cycles, in the absence of progressive disease (PD) or treatment-limiting toxicity. The Clb+Ob arm received treatment for six cycles. Chlorambucil tablets were administered orally at 0.5 mg/kg body weight on Days 1 and 15 of Cycles 1 through 6. Obinutuzumab was administered on Days 1, 8, and 15 of Cycle 1 and on Day 1 of Cycles 2 through 6. Each dose, administered intravenously, was equivalent to 1,000 mg except for the initial infusion in Cycle 1 where the same total dose was administered over Day 1 (100 mg) and Day 2 (900 mg). Assessments of disease response and progression were conducted in accordance with the 2008 International Workshop in CLL (iwCLL) criteria.

GLOW randomized 211 patients. Patients treated with Ibr+Ven demonstrated a statistically significant improvement in the primary efficacy endpoint of Progression-free Survival (PFS) based on assessment by an Independent Review Committee (IRC) at the primary analysis with a hazard ratio of 0.216 (95% CI: 0.131, 0.357; p<0.0001). This represented a 78% reduction in the risk of disease progression or death for participants treated with Ibr+Ven compared with Clb+Ob. The Ibr+Ven arm also demonstrated statistically significant improvement in the first two key secondary endpoints. The (1) Minimal Residual Disease (MRD) Negativity Rate in the bone marrow was 55.7% in the Ibr+Ven arm compared with 21.0% in the Clb+Ob arm (rate ratio 2.65; 95% CI: 1.75, 3.99; p<0.0001). The (2) Complete Response (CR) rate as assessed by IRC was 38.7% in the Ibr+Ven arm compared with the 11.4% in the Clb+Ob arm with a rate ratio of 3.43 (95% CI: 1.91, 6.15; p<0.0001). This was an important finding, as ibrutinib alone rarely produces CRs. The next key secondary endpoint was Overall Response Rate (ORR), which was not statistically significant between the treatment arms; this ended the formal statistical testing. With an overall median follow-up of 27.7 months, the median Duration of Response (DOR; a secondary endpoint) was supportive of Ibr+Ven treatment. For participants who achieved partial response or better, the DOR was 28.9 months (95% CI: 28.68, NE) in the Ibr+Ven arm compared with 21.1 months (95% CI: 15.9, 25.1) in the Clb+Ob arm.

The GLOW study was supported by the PCYC-1142-CA (CAPTIVATE) study, a single-arm, phase 2, two-cohort study in patients with previously untreated CLL. It enrolled 159 participants in the Fixed Duration Cohort (with very similar study design to GLOW), including 27 patients with TP53 and/or del17p mutations. The CR rate in participants without del17p (by Investigator), the primary efficacy endpoint, was 55.9% (95% CI: 47.5, 64.2), which was higher than the study-assumed minimum rate of 37% (1-sided p-value <0.0001). In the subgroup of participants with del17p/TP53 mutated the CR rate was 55.6%; the median duration of CR was not reached; the durable CR rate was 48.1%; the MRD Negativity Rate was 40.7% in the bone marrow and 81.5% in the peripheral blood. These data provided adequate support for inclusion of patients with del17p mutation in the indication.

The safety of GLOW was based on a median treatment duration of 13.8 and 5.1 months, respectively, for the Ibr+Ven and Clb+Ob arms. The safety profile of the Ibr+Ven combination was consistent with that of each of the products individually, and no new serious safety concerns were identified. The most common treatment-emergent adverse events (TEAEs; ≥20%) in the Ibr+Ven arm were diarrhea (50.9%), neutropenia (34.0%), and nausea (26.4%). Those reported more frequently (≥10% difference) in the Ibr+Ven vs. the Clb+Ob arm, respectively were diarrhea, rash, urinary tract infections, peripheral edema, atrial fibrillation, and hyperphosphatemia. The incidence of serious AEs was 57.5% in the Ibr+Ven arm and 64.8% in the Clb+Ob arm. At the primary analysis, there were 11 (10.4%) and 12 (11.4%) deaths in the Ibr+Ven and Clb+Ob arms, respectively. Deaths due to AEs occurred in seven (6.6%) and two (1.9%) participants, respectively. Among the seven deaths in the Ibr+Ven arm, four occurred during the ibrutinib lead-in period and, overall, six of seven were considered not related to study treatment. TEAEs led to treatment discontinuation in 19.8%, dose reduction in 26.4%, and dose interruption in 67% of participants in the Ibr+Ven arm.

The core Risk Management Plan (RMP) and the Canadian Addendum v9.0 were included as part of the submission. The Risk Minimization Measures section of the core RMP and Canadian Addendum was updated to include routine risk minimization measures for the risk of ‘cardiac failure’ and to align routine risk minimization measures for the risks of ‘atrial fibrillation’ and ‘cardiac arrhythmia’ with the current approved Canadian Product Monograph. No additional risk minimization measures were proposed. It was concluded that no new major safety issues were identified following its review and that the RMP was considered acceptable with no further follow-up required.

Overall, the data from the GLOW and CAPTIVATE studies provide evidence of clinical efficacy and, together with an adequate description of risks and benefits in the approved product monograph, the benefit-risk-uncertainty profile for the treatment of first-line CLL with the combination of Imbruvica with venetoclax was found to be favorable.