Acalabrutinib + Chemoimmunotherapy Approved in the EU as First and Only BTK Inhibitor for 1st-line Mantle Cell Lymphoma

Acalabrutinib (Calquence®; AstraZeneca) in combination with bendamustine (Treanda®; Cephalon, a subsidiary company of Teva Pharmaceutical) and rituximab (Rituxan® / MabThera®; Genentech/Roche) has been approved in the European Union (EU) for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are not eligible for autologous stem cell transplant.

MCL is a rare and typically aggressive form of non-Hodgkin lymphoma, often diagnosed at an advanced stage. [1][2]

MCL comprises about 3-6% of non-Hodgkin lymphomas, with an annual incidence of 0.5 per 100,000 population in Western countries; It is estimated that there are more than 21,000 patients diagnosed with MCL in the US, UK, France, Germany, Spain, Italy, Japan and China.[3][4][5]

While MCL patients initially respond to treatment, patients do tend to relapse.[4]

European approval
Acalabrutinib is a second-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK). The drug binds covalently to BTK, thereby inhibiting its activity.[6] 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 follows the positive opinion in March 2025 of the Committee for Medicinal Products for Human Use and was based on positive results from ECHO Phase 3 trial, presented at the European Hematology Association (EHA) 2024 Hybrid Congress in Madrid, Spain (#LBA3439) and published in The Journal of Clinical Oncology.

The study results showed that acalabrutinib combination regimen reduced the risk of disease progression or death by 27% compared to standard-of-care chemoimmunotherapy (hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.57-0.94; p=0.016). Median PFS was 66.4 months for patients treated with the Calquence combination (n=299) versus 49.6 months with standard-of-care chemoimmunotherapy alone (n=299).

The secondary endpoint of Overall Survival (OS) showed a favorable trend for the acalabrutinib combination compared to standard-of-care chemoimmunotherapy, further supporting the clinical benefit of this combination (HR 0.86; 95% CI 0.65-1.13; p=0.2743). The OS data were not mature at the time of this analysis and the trial will continue to assess OS as a key secondary endpoint.

The ECHO study randomized, double-blind, placebo-controlled, multi-centre Phase III trial evaluating the efficacy and safety of acalabrutinib plus bendamustine and rituximab compared to SoC chemoimmunotherapy (bendamustine and rituximab) in adult patients at or over 65 years of age (n=635) with previously untreated MCL.

The ECHO trial enrolled patients from May 2017 to March 2023, continuing through the COVID-19 pandemic. Prespecified PFS and OS analyses censoring for COVID-19 deaths were conducted to assess the impact of COVID-19 on the study outcome in alignment with the US Food and Drug Administration (FDA). Participating patients were randomized 1:1 to receive either acalabrutinibor placebo administered orally twice per day, continuously, until disease progression or unacceptable toxicity. Additionally, all patients received six 28-day cycles of bendamustine on days 1 and 2 and rituximab on day 1 of each cycle, followed by rituximab maintenance for two years if patients achieved a response after induction therapy.

The study outcomes further confirmed that Progression Free Survival (PFS) was further improved in both arms, with the acalabrutinib combination reducing the risk of disease progression or death by 36% (HR 0.64; 95% CI; 0.48-0.84; p=0.0017). Median PFS was not reached among patients treated with the acalabrutinib combination versus 61.6 months for standard-of-care chemoimmunotherapy (HR 0.64, 95% CI, 0.48-0.84; p=0.0017). A favorable trend was seen for OS in this analysis for the acalabrutinib combination (HR 0.75; 95% CI 0.53-1.04; p=0.0797).

The primary endpoint is PFS assessed by an Independent Review Committee; other efficacy endpoints include overall survival (OS), overall response rate, duration of response and time to response.

First-line treatment option
“This approval provides a new first-line treatment option for patients in the EU with mantle cell lymphoma, an aggressive lymphoma with a dismal long-term outcome still today. With a progression-free survival improvement of more than 16 months for these patients, the acalabrutinib combination is a much-needed advance in this challenging disease,” noted Martin Dreyling, MD, Department of Medicine, University Hospital LMU Munich, and investigator in the trial.

“Treatment with the acalabrutinib combination in first-line mantle cell lymphoma demonstrated a significant improvement in progression free survival and a consistent safety profile for patients in the pivotal ECHO trial. As the first and only BTK inhibitor approved in this indication in the EU, we are proud to provide a much-needed new option to patients living with this difficult disease,” added Dave Fredrickson, Executive Vice President, Oncology Haematology Business Unit, AstraZeneca.

Safety and Tollerability
The safety and tolerability of acalabrutinib  was consistent with its known safety profile, and no new safety signals were identified.

Acalabrutinib plus bendamustine and rituximab is approved in the US and several other countries in this setting based on the ECHO results. Regulatory applications are currently under review in Japan and several other countries in this indication.

This approval follows the recent approval for acalabrutinib  monotherapy for the treatment of adult patients with relapsed or refractory MCL in the EU.

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Clinical trials
A Study of BR Alone Versus in Combination With Acalabrutinib in Subjects With Previously Untreated MCL – ClinicalTrials.gov ID NCT02972840

Highlights of Prescribing Information
Acalabrutinib (Calquence®; AstraZeneca) [Prescribing Information]
Bendamustine (Treanda®; Cephalon, a subsidiary company of Teva Pharmaceutical) [Prescribing Information]
Rituximab (Rituxan® / MabThera®; Genentech/Roche)[Prescribing Information]

Reference
[1] Lymphoma Research Foundation. Mantle Cell Lymphoma. Online. Last accessed in April 2025.
[2] National Organization for Rare Disorders. Mantle Cell Lymphoma. Online. Last accessed in April 2025.
[3] AstraZeneca 2024. Q3 2024 Financial Results.  Online. Last accessed in April 2025.
[4] Cheah CY, Seymour JF, Wang ML. Mantle Cell Lymphoma. J Clin Oncol. 2016 Apr 10;34(11):1256-69. doi: 10.1200/JCO.2015.63.5904. Epub 2016 Jan 11. PMID: 26755518.4.
[5] Lynch DT, Koya S, Dogga S, et al. Mantle Cell Lymphoma. [Updated 2023 Jul 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK536985/. Last accessed in April 2025.
[6] Wu J, Zhang M, Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016 Mar 9;9:21. doi: 10.1186/s13045-016-0250-9. PMID: 26957112; PMCID: PMC4784459.

Featured image: R&D at AstraZeneca. Photo courtes: © 2026 – 2025 AstraZeneca. Used with permission.

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