Calquence ( Acalabrutinib ), a next-generation selective Bruton’s tyrosine kinase ( BTK ) inhibitor, has been approved in the European Union ( EU ) for the treatment of adult patients with chronic lymphocytic leukaemia ( CLL ).
Acalabrutinib binds covalently to BTK, thereby inhibiting its activity. In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.
The approval by the European Commission ( EC ) was based on positive results from two phase III clinical trials, ELEVATE-TN in patients with previously untreated chronic lymphocytic leukaemia and ASCEND in patients with relapsed or refractory chronic lymphocytic leukaemia.
In the ELEVATE-TN phase III trial, Acalabrutinib combined with Obinutuzumab and as monotherapy reduced the risk of disease progression or death by 90% and 80%, respectively, compared with standard chemo-immunotherapy treatment Chlorambucil plus Obinutuzumab, in patients with previously untreated chronic lymphocytic leukaemia.
In the ASCEND phase III trial, 88% of patients with relapsed or refractory chronic lymphocytic leukaemia taking Acalabrutinib remained alive and free from disease progression after 12 months compared with 68% of patients on Rituximab combined with Idelalisib or Bendamustine.
Data from the interim results of the trials were published in The Lancet and Journal of Clinical Oncology, respectively.
ELEVATE-TN was a randomised, multicentre, open-label trial evaluating the safety and efficacy of Acalabrutinib in combination with Obinutuzumab, a CD20 monoclonal antibody, or Acalabrutinib alone versus Chlorambucil, a chemotherapy, in combination with Obinutuzumab in previously untreated patients with chronic lymphocytic leukaemia.
Patients 65 years of age or older, or between 18 and 65 years of age with a total Cumulative Illness Rating Scale more than 6 or creatinine clearance of 30 to 69 mL/min, were enrolled.
In the trial, 535 patients were randomised ( 1:1:1 ) into three arms. Patients in the first arm received Chlorambucil in combination with Obinutuzumab. Patients in the second arm received Acalabrutinib ( 100 mg approximately every 12 hours until disease progression or unacceptable toxicity ) in combination with Obinutuzumab. Patients in the third arm received Acalabrutinib monotherapy ( 100 mg approximately every 12 hours until disease progression or unacceptable toxicity ).
The primary endpoint was progression-free survival ( PFS ) in the Acalabrutinib 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 progression-free survival in the Acalabrutinib monotherapy arm compared to the Chlorambucil and Obinutuzumab arm. Other secondary endpoints included objective response rate, time to next treatment and overall survival ( OS ).
ASCEND was a global, randomised, multicentre, open-label trial evaluating the efficacy of Acalabrutinib in patients with relapsed or refractory chronic lymphocytic leukaemia.
310 patients were randomised ( 1:1 ) into two arms.
Patients in the first arm received Acalabrutinib monotherapy ( 100 mg 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 progression-free survival assessed by an IRC, and key secondary endpoints included physician-assessed progression-free survival, IRC- and physician-assessed overall response rate and duration of response, as well as overall survival, patient-reported outcomes and time to next treatment.
Chronic lymphocytic leukaemia is the most common type of leukaemia in adults, with an estimated 105,000 new cases globally in 2016, and the number of people living with chronic lymphocytic leukaemia is expected to grow with improved treatment as patients live longer with the disease.
In chronic lymphocytic leukaemia, 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 anaemia, infection, and bleeding. B-cell receptor signalling through BTK is one of the essential growth pathways for chronic lymphocytic leukaemia. ( Xagena )
Source: AstraZeneca, 2020