Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in adults, with an estimated 105,000 new cases globally in 2016. The number of people living with CLL is expected to grow as improved treatment allows patients to live longer with the disease.1,2,3,4
In an expert interview with touchONCOLOGY, Dr Carlos Doti, Global Medical Affairs Head for Haematology at AstraZeneca, discusses the clinical significance of acalabrutinib (Calquence®, AstraZeneca, Cambridge, UK) for the treatment of CLL and the phase III trial results that supported its recent Committee for Medicinal Products for Human Use (CHMP) recommendation.5
Q. What is the current standard of care in CLL, and what unmet needs and challenges do physicians face when treating patients with CLL?
Over the past several years, the treatment landscape for CLL has significantly changed with the introduction of oral targeted therapies. The recent developments in the management of CLL have shifted the standard of care from chemo-immunotherapy to these novel agents.
Even with the influx of new treatment options, there remains an unmet need for improved tolerability for patients who may require years of therapy. Patients with CLL are often older and face multiple comorbidities, making tolerability a critical factor in their treatment journey.1,6 Targeted therapies such as next-generation, selective Bruton’s tyrosine kinase (BTK) inhibitors, like acalabrutinib – which has showed long-term efficacy and tolerability – may potentially help address this need for those patients.
Q. What is the mechanism of action of acalabrutinib?
Acalabrutinib is a next-generation, selective inhibitor of BTK. Acalabrutinib binds covalently to BTK, thereby inhibiting its activity.7,8 In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion.7
Q. Please can you give an overview of the aims and design of the ELEVATE TN and ASCEND trials?
AstraZeneca’s phase III clinical trial program consisting of the ELEVATE-TN and ASCEND studies aimed to evaluate the safety and efficacy of acalabrutinib in patients with CLL.9,10
The ELEVATE-TN (ACE-CL-007) trial was a randomised, multicentre, open-label phase III trial evaluating the safety and efficacy of acalabrutinib in combination with obinutuzumab and acalabrutinib monotherapy versus obinutuzumab in combination with chlorambucil in 535 patients with previously untreated CLL. Comparison of Independent Review Committee (IRC)-assessed progression-free survival (PFS) between acalabrutinib with obinutuzumab versus obinutuzumab with chlorambucil was the primary endpoint, and comparison of IRC-assessed PFS between acalabrutinib monotherapy versus obinutuzumab with chlorambucil was a secondary endpoint. Other secondary endpoints included objective response rate, time to next treatment and overall survival.9
The ASCEND (ACE-CL-309) study was a randomised, multicentre, open-label phase III trial evaluating the safety and efficacy of acalabrutinib monotherapy versus rituximab in combination with the investigator’s choice of either bendamustine or idelalisib in 310 patients with relapsed or refractory CLL. The primary endpoint was IRC-assessed PFS, 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.10
Q. What were the safety and efficacy data that led to the recommendation for authorisation of acalabrutinib from the CHMP?
In July 2020, acalabrutinib was recommended for approval in the European Union (EU) by the CHMP for the treatment of adult patients with CLL. The positive opinion was based 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, acalabrutinib combined with obinutuzumab and acalabrutinib as monotherapy reduced the risk of disease progression or death by 90% and 80%, respectively, compared to standard chemo-immunotherapy treatment with chlorambucil plus obinutuzumab, in patients with previously untreated CLL.9 In the ASCEND trial, 88% of patients with relapsed or refractory CLL taking acalabrutinib remained alive and free from disease progression after 12 months compared to 68% of patients treated with rituximab combined with idelalisib or bendamustine.10
Across both trials, the safety and tolerability of acalabrutinib were consistent with its known profile.9,10
Q. How do you envisage acalabrutinib will fit into treatment strategies in clinical practice in Europe?
Acalabrutinib is approved in the US and in several 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. Now with the positive CHMP opinion of acalabrutinib for CLL, we are one step closer to bringing forward a new, chemotherapy-free treatment option to patients in Europe.
Given the availability of numerous therapies for CLL, it is important to develop a tailored treatment strategy for the individual patient. Targeted therapies, such as acalabrutinib, are an important option to consider for many patients with CLL. Compared to commonly-used chemotherapy regimens, acalabrutinib has demonstrated a significant improvement in PFS in patients across multiple settings, while maintaining a favourable tolerability and safety profile.9,10 Overall, this twice-daily oral pill offers an alternative to standard treatments like chemotherapy.
- American Cancer Society. What is Chronic Lymphocytic Leukemia? Available at: www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/what-is-cll.html (accessed 12 August 2020).
- National Cancer Institute. Chronic Lymphocytic Leukemia Treatment (PDQ®)–Patient Version. Available at: www.cancer.gov/types/leukemia/patient/cll-treatment-pdq (accessed 12 August 2020).
- Global Burden of Disease Cancer Collaboration. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: A systematic analysis for the global burden of disease study. JAMA Oncol. 2018;4:1553–68.
- Jain N, Chen Q, Ayer T, et al. Prevalence and economic burden of chronic lymphocytic leukemia (CLL) in the era of oral targeted therapies. Blood. 2015;126:871.
- European Medicines Agency. Calquence. Available at: www.ema.europa.eu/en/medicines/human/summaries-opinion/calquence (accessed 12 August 2020).
- Gordon MJ, Churnetski M, Alqahtani H, et al. Comorbidities predict inferior outcomes in chronic lymphocytic leukemia treated with ibrutinib. Cancer. 2018;124:3192–3200.
- Calquence® (acalabrutinib) Prescribing Information. Wilmington, DE, US: AstraZeneca Pharmaceuticals LP, 2019.
- Wu J, Zhang M, Liu D, et al. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016;9:21.
- Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naïve chronic lymphocytic leukaemia (ELEVATE-TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395:1278–91.
- Ghia P, Pluta A, Wach M, et al. ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;JCO1903355. doi:10.1200/JCO.19.03355.
Author profile: In his role at AstraZeneca, Carlos Doti is responsible for developing the medical strategy for the haematology franchise supporting the launches of acalabrutinib (Calquence®) worldwide and building up capabilities for AstraZeneca’s entry into acute myeloid leukaemia, myelodysplastic syndromes and aggressive non-Hodgkin lymphomas. Dr Doti is a haematologist by training and has extensive medical knowledge of cancer and haematologic malignancies. Dr Doti joined AstraZeneca in 2016, first as a Medical Director and then as the Oncology Business Unit Director in Argentina and Uruguay. Following this, he served as the lead of AstraZeneca’s haematology commercial team where he oversaw a cross-functional team supporting acalabrutinib in multiple geographies including Latin America, the Middle East and Asia-Pacific. He has more than a decade of experience within the pharmaceutical industry, and has previously served in medical affairs roles at Novo Nordisk A/S and Pfizer. During this time, he has gained extensive experience developing and executing portfolio/brand strategy, product launches and pricing and market access in the emerging markets. Dr Doti’s work is supported by more than 70 congress presentations and several peer-reviewed publications. He has also served as an investigator in more than 25 clinical trials in haemostasis, onco-haematology and infectious disease. Prior to joining the private sector, he was trained in haematology at both Mount Sinai Medical Center in New York, and the British Hospital in Buenos Aires, where he served as an attending physician.
Disclosure: Dr Carlos Doti is an employee of AstraZeneca, Gaithersburg, MD, US.
Support: Commissioned, edited and supported by Touch Medical Media, who commissioned the interview in liaison with Evoke KYNE. The ELEVATE-TN and ASCEND trials were supported by AstraZeneca.
Published: 27 August 2020
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