CALQUENCE Hard capsule Ref.[51592] Active ingredients: Acalabrutinib

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors
ATC code: L01EL02

Mechanism of action

Acalabrutinib is a selective inhibitor of Bruton tyrosine kinase (BTK). BTK is a signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signalling results in B-cell survival and proliferation, and is required for cellular adhesion, trafficking, and chemotaxis.

Acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, leading to irreversible inactivation of BTK with minimal off-target interactions.

Pharmacodynamic effects

In patients with B-cell malignancies dosed with acalabrutinib 100 mg twice daily, median steady-state BTK occupancy of ≥95% in peripheral blood was maintained over 12 hours, resulting in inactivation of BTK throughout the recommended dosing interval.

Cardiac electrophysiology

The effect of acalabrutinib on the QTc interval was evaluated in 46 healthy male and female subjects in a randomised, double-blind thorough QT study with placebo and positive controls. At a supratherapeutic dose, 4-times the maximum recommended dose, Calquence did not prolong the QT/QTc interval to any clinically relevant extent (e.g., not greater than or equal to 10 ms) (see sections 4.4, 4.8 and 5.3).

Clinical efficacy and safety

Patients with previously untreated CLL

The safety and efficacy of Calquence in previously untreated CLL were evaluated in a randomised, multi-centre, open-label Phase 3 study (ELEVATE-TN) of 535 patients. Patients received Calquence plus obinutuzumab, Calquence monotherapy, or obinutuzumab plus chlorambucil. Patients 65 years of age or older, or between 18 and 65 years of age with coexisting medical conditions, were included in ELEVATE-TN, 27.9% patients had a CrCl of < 60 mL/min. Of the patients who were <65 years of age, 16.1% had a median CIRS-G score of 8. The study allowed patients to receive antithrombotic agents.

Patients who required anticoagulation with warfarin or equivalent vitamin K antagonists were excluded.

Patients were randomised in a 1:1:1 ratio into 3 arms to receive

• Calquence plus obinutuzumab (Calquence+G): Calquence 100 mg was administered twice daily starting on Cycle 1 Day 1 until disease progression or unacceptable toxicity. Obinutuzumab was administered starting on Cycle 2 Day 1 for a maximum of 6 treatment cycles. Obinutuzumab 1,000 mg was administered on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 2 followed by 1,000 mg on Day 1 of Cycles 3 up to 7. Each cycle was 28 days.
• Calquence monotherapy: Calquence 100 mg was administered twice daily until disease progression or unacceptable toxicity.
• Obinutuzumab plus chlorambucil (GClb): Obinutuzumab and chlorambucil were administered for a maximum of 6 treatment cycles. Obinutuzumab 1,000 mg was administered on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 1 followed by 1,000 mg on Day 1 of Cycles 2 up to 6. Chlorambucil 0.5 mg/kg was administered on Days 1 and 15 of Cycles 1 up to 6. Each cycle was 28 days.

Patients were stratified by 17p deletion mutation status (presence versus absence), ECOG performance status (0 or 1 versus 2) and geographic region (North America and Western Europe versus Other). After confirmed disease progression, 45 patients randomised on the GClb arm crossed over to Calquence monotherapy. Table 5 summarises the baseline demographics and disease characteristics of the study population.

Table 5. Baseline patient characteristics in (ELEVATE-TN) patients with previously untreated CLL:

The primary endpoint was progression-free survival (PFS) of Calquence+G arm versus GClb arm as assessed by an Independent Review Committee (IRC) per International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) 2008 criteria with incorporation of the clarification for treatmentrelated lymphocytosis (Cheson 2012). With a median follow-up of 28.3 months, PFS by IRC indicated a 90% statistically significant reduction in the risk of disease progression or death for previously untreated CLL patients in the Calquence+G arm compared to the GClb arm. Efficacy results are presented in Table 6.

Table 6. Efficacy results per IRC Assessments in (ELEVATE-TN) patients with CLL:

CI=confidence interval; HR=hazard ratio; NR=not reached; CR=complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial response.
^* Per IRC assessment
^† Based on stratified Cox-Proportional-Hazards model
^a Median OS not reached for both arms.

PFS results for Calquence with or without obinutuzumab were consistent across subgroups, including high risk features. In the high risk CLL population (17p deletion, 11q deletion, TP53 mutation or unmutated IGHV), the PFS HRs of Calquence with or without obinutuzumab versus obinutuzumab plus chlorambucil was 0.08 [95% CI (0.04, 0.15)] and 0.13 [95% CI (0.08, 0.21)], respectively.

Table 7. Subgroup analysis of PFS (Study ELEVATE-TN):

With long term data, the median follow-up was 58.2 months for Calquence+G arm, 58.1 months for Calquence arm and 58.2 months for the GClb arm. The median investigator assessed PFS for Calquence+G and Calquence monotherapy was not reached; and was 27.8 months in GClb arm. At the time of most recent data cut off, a total of 72 patients (40.7%) originally randomised to the GClb arm crossed over to Calquence monotherapy. The median overall survival had not been reached in any arm with a total of 76 deaths: 18 (10.1%) in the Calquence+G arm, 30 (16.8%) in the Calquence monotherapy arm, and 28 (15.8%) in the GClb arm.

Table 8. Efficacy Results per INV assessment in (ELEVATE-TN) Patients with CLL:

CI=confidence interval; HR=hazard ratio; NR=not reached
^* 95% confidence interval based on Kaplan-Meier estimation.
^† Estimate based on stratified Cox-Proportional-Hazards model for Hazard Ratio (95% CI) stratified by 17p deletion status (yes vs no)

Figure 1. Kaplan-Meier Curve of INV-Assessed PFS in (ELEVATE-TN) Patients with CLL (ITT Population):

Patients with CLL who received at least one prior therapy

The safety and efficacy of Calquence in relapsed or refractory CLL were evaluated in a randomised, multi-centre, open-label phase 3 study (ASCEND) of 310 patients who received at least one prior therapy not including BCL-2 inhibitors or B-cell receptor inhibitors. Patients received Calquence monotherapy or investigator’s choice of either idelalisib plus rituximab or bendamustine plus rituximab. The study allowed patients to receive antithrombotic agents. Patients who required anticoagulation with warfarin or equivalent vitamin K antagonists were excluded.

Patients were randomised 1:1 to receive either:

• Calquence 100 mg twice daily until disease progression or unacceptable toxicity, or
• Investigator’s choice:
  • Idelalisib 150 mg twice daily in combination with rituximab 375 mg/m² IV on Day 1 of the first cycle, followed by 500 mg/m² IV every 2 weeks for 4 doses, then every 4 weeks for 3 doses for a total of 8 infusions
  • Bendamustine 70 mg/m² (Day 1 and 2 of each 28-day cycle) in combination with rituximab (375 mg/m²/500 mg/m²) on Day 1 of each 28-day cycle for up to 6 cycles Patients were stratified by 17p deletion mutation status (presence versus absence), ECOG performance status (0 or 1 versus 2) and number of prior therapies (1 to 3 versus ≥4). After confirmed disease progression, 35 patients randomised on investigator’s choice of either idelalisib plus rituximab or bendamustine plus rituximab crossed over to Calquence. Table 9 summarizes the baseline demographics and disease characteristics of the study population.

Table 9. Baseline patient characteristics in (ASCEND) patients with CLL:

The primary endpoint was PFS as assessed by IRC IWCLL 2008 criteria with incorporation of the clarification for treatment-related lymphocytosis (Cheson 2012). With a median follow-up of 16.1months, PFS indicated a 69% statistically significant reduction in the risk of death or progression for patients in the Calquence arm. Efficacy results are presented in Table 10. The Kaplan-Meier curve for PFS is shown in Figure 2.

Table 10. Efficacy results per IRC Assessments in (ASCEND) patients with CLL:

CI=confidence interval; HR=hazard ratio; NR=not reached; CR=complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial response; PD=progressive disease
^* Per IRC assessment
^a Median OS not reached for both arms. P<0.6089 for OS.
^** CRi and nPR have values of 0.
^† Based on stratified Cox-Proportional-Hazards model

Figure 2. Kaplan-Meier curve of IRC-assessed PFS in (ASCEND) patients with CLL (ITT Population):

PFS results for Calquence were consistent across subgroups, including high risk features. In the high risk CLL population (17p deletion, 11q deletion, TP53 mutation and unmutated IGHV), the PFS HR was 0.27 [95% CI (0.17, 0.44)].

Table 11. Subgroup analysis of IRC-assessed PFS (Study ASCEND):

At final analysis, with a median follow-up of 46.5 months for Calquence and 45.3 months for the IR/BR, a 72% reduction in risk of investigator-assessed disease progression or death was observed for patients in the Calquence arm. The median investigator assessed PFS was not reached in Calquence and was 16.8 months in IR/BR. Efficacy results per Investigator Assessments (INV) are presented in Table 12. The Kaplan-Meier curve for INV assessed PFS is shown in Figure 3.

Table 12. Efficacy results at final analysis per INV assessments in (ASCEND) patients with CLL:

CI=confidence interval; HR=hazard ratio; NR=not reached; PD=progressive disease
^* Per INV assessment
^a Median OS not reached for both arms P=0.0783 for OS.
^† Based on stratified Cox-Proportional-Hazards model

Figure 3. Kaplan-Meier curve of INV-assessed PFS at final analysis in (ASCEND) patients with CLL:

Investigator assessed PFS results at final analysis for Calquence were consistent across subgroups, including high risk features and were consistent with the primary analysis.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Calquence in all subsets of the paediatric population in CLL (for information on paediatric use, see section 4.2).