Tthe US Food and Drug Administration ( FDA ) has approved Calquence ( Acalabrutinib ) for adult patients with chronic lymphocytic leukaemia ( CLL ) or small lymphocytic lymphoma ( SLL ).
The US approval was granted under the FDA’s Real-Time Oncology Review and newly established Project Orbis programmes.
The approval is based on positive results from the interim analyses of two phase III clinical trials, ELEVATE-TN in patients with previously untreated CLL and ASCEND in patients with relapsed or refractory CLL.
Together, the trials have shown that Calquence in combination with Obinutuzumab ( Gazyva ) or as a monotherapy significantly reduced the relative risk of disease progression or death versus the comparator arms in both 1st-line and relapsed or refractory CLL.
Across both trials, the safety and tolerability of Calquence were consistent with its established profile.
The trial showed a statistically significant and clinically meaningful improvement in progression-free survival ( PFS ) for patients treated with either Calquence in combination with Obinutuzumab or Calquence monotherapy versus Chlorambucil chemotherapy plus Obinutuzumab, a current standard-of-care combination used in the control arm.
In the Calquence combination arm, risk of disease progression or death was reduced by 90% ( hazard ratio, HR 0.10; 95% CI, 0.06-0.17, p less than 0.0001 ) and in the monotherapy arm it was reduced by 80% ( HR 0.20; 95% CI, 0.13-0.30, p less than 0.0001 ).
The median time to disease progression for patients treated with Calquence in combination with Obinutuzumab or as a monotherapy has not yet been reached versus 22.6 months ( 95% CI, 20-28 ) for Chlorambucil plus Obinutuzumab.
In patients treated with the combination of Calquence plus Obinutuzumab, adverse reactions led to treatment discontinuation in 11% of patients and a dose reduction of Calquence in 7% of patients.
In the monotherapy arm, adverse reactions led to discontinuation in 10% and dose reduction in 4% of patients.
In the control arm, adverse reactions led to regimen discontinuation in 14% of patients with a dose reduction of Chlorambucil in 28% of patients.
There were no dose reductions for Obinutuzumab.
In 1,029 patients with haematologic malignancies who were treated with Calquence 100mg approximately every 12 hours across multiple clinical trials, where 88% received treatment for at least six months and 79% received treatment for at least one year, serious or grade greater than or equal to 3 infections occurred in 19%, and grade 3 atrial fibrillation and flutter occurred in 1.1% of patients.
In the same patient population, major haemorrhage occurred in 3.0% (s erious or grade greater than or equal to 3 bleeding or any central nervous system bleeding ), with fatal haemorrhage occurring in 0.1% of patients.
Second primary malignancies ( all grades ) including skin cancers occurred in 12% of patients.
The US approval is among the first to be granted under Project Orbis, an initiative of the US FDA Oncology Center of Excellence, which provides a framework for concurrent submission and review of oncology medicines among international partners.
The FDA, the Australian Therapeutic Goods Administration, and Health Canada collaborated on this review.
Acalabrutinib is a next-generation selective inhibitor of Bruton’s tyrosine kinase ( BTK ). It 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.
ELEVATE-TN is a randomised, multicentre, open-label phase III 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 CLL.
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 ( 100mg twice daily until disease progression or unacceptable toxicity ) in combination with Obinutuzumab. Patients in the third arm received Acalabrutinib monotherapy ( 100mg twice daily until disease progression or unacceptable toxicity ).
The primary endpoint is 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 is IRC-assessed PFS in the Acalabrutinib monotherapy arm compared to the Chlorambucil and Obinutuzumab arm. Other secondary endpoints include objective response rate, time to next treatment and overall survival.
ASCEND is a global, randomised, multicentre, open-label phase III trial evaluating the efficacy of Acalabrutinib in previously treated patients with CLL.
In the trial, 310 patients were randomised ( 1:1 ) into two arms. Patients in the first arm received Acalabrutinib 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 is PFS assessed by an IRC, and key secondary endpoints include 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.
Chronic lymphocytic leukaemia is one of the most common types of leukaemia in adults, with an estimated 105,000 new cases globally each year and 20,720 new cases in the US in 2019, 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 anaemia, infection and bleeding.
B-cell receptor signalling through BTK is one of the essential growth pathways for CLL. ( Xagena )
Source: AstraZeneca, 2019