Detailed results from the interim analysis of the Phase III ASCEND trial presented at the 2019 European Hematology Association (EHA) Annual Congress in Amsterdam, The Netherlands, demonstrate that acalabrutinib (Calquence®; AstraZeneca) significantly prolonged the time patients live without disease progression in relapsed or refractory chronic lymphocytic leukemia (CLL).
The ASCEND (ACE-CL-309; NCT02970318) is a global, randomized, multicentre, open-label Phase III rial compared acalabrutinib with the physician’s choice of rituximab combined with idelalisib (IdR) or bendamustine (BR) in patients with relapsed or refractory 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). Patients in the second arm received physician’s choice of either rituximab in combination with idelalisib or rituximab in combination with bendamustine.
The primary endpoint of the trial is progression free survival (PFS) assessed by an independent review committee (IRC), and key secondary endpoints include physician-assessed PFS, IRC- and physician-assessed overall response rate (ORR) and duration of response (DoR), as well as overall survival (OS), patient reported outcomes (PROs) and time to next treatment (TTNT).
At a median follow-up of 16.1 months, results from the trial showed a statistically-significant and clinically-meaningful improvement in progression-free survival (PFS) for patients treated with acalabrutinib vs. IdR or BR, reducing the risk of disease progression or death by 69% (HR, 0.31; 95% CI, 0.20-0.49, p<0.0001). The median time without disease progression for patients treated with acalabrutinib has not yet been reached vs. 16.5 months in the control arm.
At 12 months, 88% of patients on acalabrutinib showed no disease progression compared to 68% for the control arm. The safety and tolerability of acalabrutinib was consistent with its established profile.
“These data add to the growing body of evidence to support the profile of acalabrutinib as a selective BTK inhibitor that offers a chemotherapy-free treatment option with a favorable safety profile in chronic lymphocytic leukemia, a life-threatening disease,” noted José Baselga, Executive Vice President, Oncology R&D at AstraZeneca.
“These data, along with our recent positive results from the Phase III ELEVATE-TN trial in previously-untreated chronic lymphocytic leukemia, will serve as the foundation for regulatory submissions later this year,” Baselga added.
“This is the first randomised trial to directly compare a BTK inhibitor as monotherapy with standard chemo-immunotherapy or idelalisib and rituximab combinations. With a significant improvement in progression-free survival and a favorable safety profile, acalabrutinib may become an important choice for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia,” Paolo Ghia, MD, Professor, Medical Oncology, Università Vita-Salute San Raffaele in Milan, and investigator of the ASCEND trial, explained.
Acalabrutinib, an inhibitor of Bruton Tyrosine Kinase (BTK) which binds covalently to BTK, thereby inhibiting its activity,  was granted accelerated approval by the US Food and Drug Administration (FDA) in October 2017 for the treatment of adult patients with MCL who have received at least one prior therapy.
In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.
Clinical trial program
As part of an extensive clinical development program, AstraZeneca and Acerta Pharma are currently evaluating acalabrutinib in 26 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, Waldenstrom macroglobulinaemia, follicular lymphoma, and multiple myeloma and other hematologic malignancies. Beyond the positive Phase III trials ASCEND and ELEVATE-TN, other Phase III trials in CLL are ongoing, including ELEVATE-RR (ACE-CL-006) evaluating acalabrutinib vs. ibrutinib in patients with previously-treated high-risk CLL, and ACE-CL-311 evaluating acalabrutinib in combination with venetoclax and with/without obinutuzumab in patients with previously-untreated CLL without 17p deletion or TP53 mutation.
Unmet medical need
Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in adults, with an estimated 191,000 new cases globally and 20,720 new cases in the US annually, and prevalence that is expected to grow with improved treatment. 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.
A Study of Acalabrutinib vs Investigator’s Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in R/R CLL – NCT02970318.
 Ghia P, Pluta A, Wach M, et al. ASCEND Phase 3 study of acalabrutinib vs. investigator’s choice of rituxumab plus idelalisib (idR) or bendamustine (BR) in patients with relapsed/refractory chronic lymphocytic leukaemia (CLL). Abstract LB2606 at: European Hematology Association 2019 Annual Meeting. Available online. Accessed June 2019.
 ClinicalTrials.gov. A Study of Acalabrutinib vs Investigator’s Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in R/R CLL. NCT02970318. Available online. Accessed June 2019.
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 National Institute of Health SEER Program. Cancer Stat Facts: Leukemia—Chronic Lymphocytic Leukemia (CLL). Available online. Accessed June 2019.
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