Calquence significantly prolonged time patients lived without disease progression or death in previously untreated CLL

AstraZeneca presented results from the interim analysis of the Phase III ELEVATE TN trial, showing that Calquence (acalabrutinib) combined with obinutuzumab or as monotherapy significantly improved progression-free survival (PFS) compared to chlorambucil plus obinutuzumab, a standard chemo-immunotherapy treatment, in patients with previously untreated chronic lymphocytic leukaemia (CLL).

The Independent Review Committee (IRC)-assessed results were presented at the 2019 American Society of Hematology Annual Meeting and Exhibition in Orlando, US. At a median follow-up of 28.3 months, Calquence in combination with obinutuzumab or as a monotherapy significantly reduced the risk of disease progression or death by 90% and 80%, respectively, vs. chlorambucil plus obinutuzumab.1

In an exploratory analysis, Calquence in combination or alone demonstrated consistent PFS improvements across most pre-specified subgroups of patients with high-risk disease characteristics, including the unmutated immunoglobulin heavy-chain variable gene (IGHV), del(11q) and complex karyotype. Overall, the safety and tolerability profile of Calquence observed in the ELEVATE TN trial was consistent with its known profile.

José Baselga, Executive Vice President, Oncology R&D said: "On the heels of approvals in the US, Australia and Canada, these full results provide further evidence that Calquence, as a new treatment option for patients with chronic lymphocytic leukaemia, demonstrates remarkable efficacy and a favourable tolerability profile. These results also provide, for the first time, post-hoc analysis data exploring the potential progression-free survival benefit of adding obinutuzumab to a BTK inhibitor such as Calquence versus BTK inhibitor monotherapy in a randomised trial."

Dr. Jeff Sharman, Director of Research at Willamette Valley Cancer Institute, Medical Director of Hematology Research for The US Oncology Network, and a lead author of the ELEVATE TN trial, said: "In the detailed results from the ELEVATE TN trial comparing Calquence to a commonly used chemo-immunotherapy treatment regimen, Calquence demonstrated a clinically meaningful improvement in progression-free survival, while maintaining its known tolerability and safety profile. These are encouraging results for a patient population that is known to face multiple comorbidities, and where tolerability is a critical factor in their treatment."

Adverse events (AEs) led to treatment discontinuation in 11.2% of patients treated with Calquence in combination with obinutuzumab and 8.9% of patients treated with Calquence monotherapy versus 14.1% of patients treated with chlorambucil plus obinutuzumab.1

With over two years of follow-up, 79% of patients in both the Calquence-containing arms remain on Calquence as a monotherapy. In the Calquence combination arm (n=178), the most common AEs of any grade (≥30%) included headache (39.9%), diarrhoea (38.8%) and neutropenia (31.5%). In the Calquence monotherapy arm (n=179), the most common AEs of any grade (≥30%) included headache (36.9%) and diarrhoea (34.6%). In the chlorambucil plus obinutuzumab arm (n=169), the most common AEs of any grade (≥30%) included neutropenia (45.0%), infusion-related reaction (39.6%) and nausea (31.4%).

These findings, along with previously reported data from the Phase III ASCEND trial in relapsed or refractory CLL, support the recent approvals of Calquence by the US FDA and the Australian Therapeutic Goods Administration for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL) and by Health Canada for CLL.2

In the US and Australia, Calquence (acalabrutinib) is approved for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) and in Canada for CLL. In the US, Canada, Australia, Brazil, Qatar, the United Arab Emirates, Mexico, Argentina, Singapore, Chile, and recently India, Calquence is also approved for adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Calquence was approved for MCL under accelerated review in the US; continued approval for previously treated MCL is contingent upon verification and confirmation of clinical benefit in confirmatory trials.

Calquence is a next-generation selective inhibitor of Bruton’s tyrosine kinase (BTK). It binds covalently to BTK, thereby inhibiting its activity.2,3,4,5 In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.2

As part of an extensive clinical development programme, 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 haematologic malignancies. Several Phase III clinical trials in CLL are ongoing, including ASCEND, ELEVATE TN, ELEVATE-RR (ACE-CL-006) evaluating Calquence versus ibrutinib in patients with previously treated high-risk CLL, and ACE-CL-311 evaluating Calquence in combination with venetoclax and with/without obinutuzumab versus chemoimmunotherapy in patients with previously untreated CLL without 17p deletion or TP53 mutation.

ELEVATE TN (ACE-CL-007) is a randomised, multicentre, 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 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 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).1,6

The primary endpoint is 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 is IRC-assessed PFS in the Calquence monotherapy arm compared to the chlorambucil and obinutuzumab arm. Other secondary endpoints include objective response rate, time to next treatment and overall survival.1,6

Chronic lymphocytic leukaemia (CLL) is one of the most common types of leukaemia in adults, with an estimated 105,000 new cases globally in 2016 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.7,8,9,10 In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes and these abnormal cells have difficulty fighting infections.7 As the number of abnormal cells grows there is less room for healthy white blood cells, red blood cells and platelets.7 This could result in anaemia, infection and bleeding.7 B-cell receptor signalling through BTK is one of the essential growth pathways for CLL.

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