Calquence Recommended for CHMP Approval for Chronic Lymphocytic Leukemia

AstraZeneca’s Calquence (acalabrutinib) has been recommended for marketing authorization in the European Union (EU) for the treatment of adult patients with chronic lymphocytic leukemia (CLL), the most common type of leukemia in adults.

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) based its positive opinion on results from two Phase III clinical trials, ELEVATE TN in patients with previously untreated CLL, and ASCEND in patients with relapsed or refractory CLL.

In the ELEVATE TN trial, Calquence combined with obinutuzumab and as monotherapy reduced the risk of disease progression or death by 90% and 80%, respectively, compared to standard chemo-immunotherapy treatment chlorambucil plus obinutuzumab, in patients with previously untreated CLL. In the ASCEND trial, 88% of patients with relapsed or refractory CLL taking Calquence remained alive and free from disease progression after 12 months compared to 68% of patients on rituximab combined with idelalisib or bendamustine.

“With its outstanding efficacy and tolerability profile, Calquence can offer important advantages to patients with chronic lymphocytic leukemia who are typically older, facing multiple comorbidities and often require treatment for many years. This positive recommendation brings us closer to providing a much-needed new treatment option to patients in Europe who are suffering from this chronic blood cancer,” José Baselga, Executive Vice President, Oncology R&D said.

The CHMP recommendation is for Calquence monotherapy or in combination with obinutuzumab for the treatment of adult patients with previously untreated CLL and for Calquence monotherapy for the treatment of adult patients with CLL who have received at least one prior therapy.

Calquence is approved in the US and in several other countries around the world for the treatment of adult patients with CLL and for adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Calquence is not approved for MCL in Europe.

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults, with an estimated 105,000 new cases globally in 2016, and the number of people living with CLL is expected to grow with improved treatment as patients live longer with the disease. In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes and these abnormal cells have difficulty fighting infections. As the number of abnormal cells grows there is less room for healthy white blood cells, red blood cells, and platelets. This could result in anemia, infection, and bleeding.4 B-cell receptor signaling through Bruton’s tyrosine kinase is one of the essential growth pathways for CLL.

ELEVATE TN (ACE-CL-007) was a randomized, multicenter, open-label Phase III trial evaluating the safety and efficacy of Calquence in combination with obinutuzumab, a CD20 monoclonal antibody, or Calquence alone versus chlorambucil, a chemotherapy, in combination with obinutuzumab in previously untreated patients with CLL. Patients 65 years of age or older, or between 18 and 65 years of age with a total Cumulative Illness Rating Scale (CIRS) >6 or creatinine clearance of 30 to 69mL/min, were enrolled. In the trial, 535 patients were randomized (1:1:1) into three arms. Patients in the first arm received chlorambucil in combination with obinutuzumab. Patients in the second arm received Calquence (100mg approximately every 12 hours until disease progression or unacceptable toxicity) in combination with obinutuzumab. Patients in the third arm received Calquence monotherapy (100mg approximately every 12 hours until disease progression or unacceptable toxicity).

The primary endpoint was progression-free survival (PFS) in the Calquence and obinutuzumab arm compared to the chlorambucil and obinutuzumab arm, assessed by an independent review committee (IRC), and a key secondary endpoint was IRC-assessed PFS in the Calquence monotherapy arm compared to the chlorambucil and obinutuzumab arm. Other secondary endpoints included objective response rate, time to next treatment and overall survival.

ASCEND (ACE-CL-309) was a global, randomized, multicenter, open-label Phase III trial evaluating the efficacy of Calquence in previously treated patients with CLL. In the trial, 310 patients were randomized (1:1) into two arms. Patients in the first arm received Calquence monotherapy (100mg twice daily until disease progression or unacceptable toxicity). Patients in the second arm received investigator’s choice of either rituximab, a CD20 monoclonal antibody, in combination with idelalisib, a PI3K inhibitor, or rituximab in combination with bendamustine, a chemotherapy.

The primary endpoint was PFS assessed by an IRC, and key secondary endpoints included physician-assessed PFS, IRC- and physician-assessed overall response rate and duration of response, as well as overall survival, patient-reported outcomes and time to next treatment.

Calquence (acalabrutinib) is a next-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK). Calquence binds covalently to BTK, thereby inhibiting its activity. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.

Calquence is approved in the US and in several countries around the world for the treatment of adult patients with chronic lymphocytic leukemia (CLL) and for adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. The US MCL indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. As part of an extensive clinical development program, AstraZeneca and Acerta Pharma are currently evaluating Calquence in 23 company-sponsored clinical trials. Calquence is being developed for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenström macroglobulinaemia, follicular lymphoma, and other hematologic malignancies.