First-Line Acalabrutinib Plus BR Receives CHMP Recommendation for Mantle Cell Lymphoma

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The European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending the approval of acalabrutinib (Calquence) in combination with bendamustine and rituximab (Rituxan; BR) for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are not candidates for autologous stem cell transplant (ASCT).1

The recommendation is supported by findings from the phase 3 ECHO trial (NCT02972840), which were presented at the 2024 EHA Congress and demonstrated a statistically significant progression-free survival (PFS) benefit with the addition of acalabrutinib to chemoimmunotherapy.

The acalabrutinib regimen reduced the risk of disease progression or death by 27% compared with BR alone (HR, 0.73; 95% CI, 0.57–0.94; P = .016). The median progression-free survival (PFS) was 66.4 months in the acalabrutinib arm vs 49.6 months in the control arm.

The safety profile of acalabrutinib in this combination was also consistent with previously reported data, and no new safety signals were observed.

If approved, this regimen would represent the first BTK inhibitor–based combination authorized for the frontline treatment of MCL in the European Union.

“Today's positive recommendation from the CHMP further reinforces the potential of [acalabrutinib] to advance first-line treatment options in MCL, with the [acalabrutinib] combination demonstrating an almost 1-and-a-half year improvement in PFS in this setting. If approved, [acalabrutinib] has the potential to transform the standard of care as the first BTK inhibitor approved for these patients in Europe,” Susan Galbraith, executive vice president of Oncology Haematology R&D at AstraZeneca, stated in a news release.

In January 2025, the FDA approved acalabrutinib plus BR for the treatment of adult patients with previously untreated MCL who are ineligible for ASCT.2

"Results from the pivotal ECHO trial demonstrated the significant benefits of the [acalabrutinib] combination in managing this rare and aggressive cancer. Today’s [CHMP] recommendation is an important advance within the MCL first-line treatment landscape, especially for older patients who need a balance of efficacy and tolerability,” Martin Dreyling, MD, of the Department of Medicine at University Hospital LMU Munich and investigator in the trial, added in a news release.1

ECHO Study Design

The ECHO study was a randomized, double-blind, placebo-controlled, multicenter, phase 3 trial evaluating the efficacy and safety of acalabrutinib plus BR compared with BR alone in adult patients at or over 65 years of age with previously untreated MCL.3

Eligible participants were required to have histologically confirmed MCL with documentation of the t(11;14)(q13;q32) chromosomal translocation and/or overexpression of cyclin D1 in association with other relevant markers such as CD5, CD19, CD20, and PAX5. Patients needed to require treatment for MCL and naive to prior systemic anticancer therapy. Additional inclusion criteria included an ECOG performance status of 0 to 2. .

Key exclusion criteria included significant cardiovascular disease—such as uncontrolled arrhythmias, recent myocardial infarction (within 6 months), or class 3/4 heart failure—and a corrected QT interval of greater than 480 msec. Patients with poorly controlled gastrointestinal disorders that could affect drug absorption, active malignancies involving the gastrointestinal tract, or previous resection of the stomach or small bowel likely to impair drug bioavailability were also excluded.

Patients were randomly assigned 1:1 to receive either acalabrutinib or placebo administered orally twice per day in a continuous fashion until disease progression or unacceptable toxicity. Additionally, all patients received bendamustine on days 1 and 2 and rituximab on day 1 of each cycle 28-day cycle for 6 cycles, followed by rituximab maintenance for 2 years if patients achieved a response after induction therapy.

The primary end point was PFS assessed by an independent review committee; other efficacy end points included overall survival, overall response rate, duration of response, and time to response. The trial was conducted in 27 countries across North and South America, Europe, Asia and Oceania.

References

1. Calquence plus chemoimmunotherapy recommended for approval in the EU by CHMP as first and only BTK inhibitor for 1st-line mantle cell lymphoma. News Release. AstraZeneca. March 31, 2025. Accessed March 31, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/calquence-recommended-for-eu-approval-in-1l-mcl.html#
2. FDA approves acalabrutinib with bendamustine and rituximab for previously untreated mantle cell lymphoma. FDA. January 16, 2025. Accessed March 31, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-acalabrutinib-bendamustine-and-rituximab-previously-untreated-mantle-cell-lymphoma
3. A study of BR alone versus in combination with acalabrutinib in subjects with previously untreated MCL. ClinicalTrials.gov. Updated March 25, 2025. Accessed March 31, 2025. https://clinicaltrials.gov/study/NCT02972840