Acalabrutinib Plus BR Wins EU Approval for Previously Untreated, Transplant-Ineligible Mantle Cell Lymphoma

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The European Commission has approved acalabrutinib (Calquence) in combination with bendamustine and rituximab (Rituxan; BR) for patients with previously untreated mantle cell lymphoma (MCL) who are not eligible for autologous stem cell transplant.¹

The regulatory decision was supported by data from the phase 3 ECHO trial (NCT02972840), which showed that at a median follow-up of 49.8 months, patients treated with acalabrutinib plus BR (n = 299) achieved a median progression-free survival (PFS) of 66.4 months (95% CI, 55.1-not evaluable [NE]) compared with 49.6 months (95% CI, 36.0-64.1) for patients treated with placebo plus BR (n = 299; HR, 0.73; 95% CI, 0.57-0.94; P = . 0160).²

“This approval provides a new first-line treatment option for patients in the European Union [EU] with MCL, an aggressive lymphoma with a dismal long-term outcome still today,” Martin Dreyling, MD, of the Department of Medicine at University Hospital LMU Munich and investigator of the ECHO trial, stated in a news release.¹ “With a PFS improvement of more than 16 months for these patients, the acalabrutinib combination is a much-needed advance in this challenging disease.”

In January 2025, the FDA approved acalabrutinib plus BR for adult patients with previously untreated MCL who are ineligible for ASCT, based on data from ECHO.³

ECHO was a randomized, multicenter, double-blind, placebo-controlled study that enrolled patients at least 65 years of age with pathologically confirmed MCL requiring treatment.² Patients were required to be naive to systemic therapy for MCL, and an ECOG performance status of 0 to 2 was also required. Patients who planned to undergo ASCT were excluded from enrollment.

Patients were randomly assigned 1:1 to receive acalabrutinib at 100 mg twice per day or placebo in combination with BR. In both arms, bendamustine was administered at 90 mg/m² on days 1 and 2 of each 28-day cycle for 6 cycles plus rituximab at 375 mg/m² on day 1 of each cycle of 6 cycles. Treatment with acalabrutinib or placebo continued until disease progression or unacceptable toxicity.

Stratification factors included region (North America vs Western Europe vs other) and simplified MCL International Prognostic Index score (low vs intermediate vs high).

PFS per independent review committee assessment served as the trial’s primary end point. Secondary end points included overall response rate (ORR), overall survival (OS), and safety.

Additional data showed that acalabrutinib plus BR generated an ORR of 91.0% (95% CI, 87.3%-93.8%) vs 88.0% (95% CI, 83.9%-91.3%) for placebo plus BR. The complete response rates were 66.6% and 53.5%, respectively. The median duration of response was 63.5 months (95% CI, 52.5-NE) in the acalabrutinib arm compared with 53.8 months (95% CI, 37.6-66.1) in the placebo arm.

At data cutoff, the median OS was not reached in both arms, and differences were not observed between the two groups (HR, 0.86; 95% CI, 0.65-1.13; P = .2743).

Regarding safety, any-grade adverse effects (AEs) occurred in 99.7% of patients in the acalabrutinib arm vs 99% of those in the placebo arm. The rates of grade 3 or higher AEs were 88.9% and 88.2%, respectively. The most common AEs reported in more than 30% of patients include nausea (acalabrutinib arm, 42.8%; placebo arm, 37.7%), neutropenia (40.1%; 41.4%), diarrhea (37.4%; 27.9%), COVID-19 (30.6%; 20.9%), and headache (30.3%; 14.1%).

“Treatment with the [acalabrutinib] combination in first-line MCL demonstrated a significant improvement in PFS and a consistent safety profile for patients in the pivotal ECHO trial,” Dave Fredrickson, executive vice president of the Oncology Hematology Business Unit at AstraZeneca, added in a news release.¹ “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."

References

1. Calquence plus chemoimmunotherapy approved in the EU as first and only BTK inhibitor for 1st-line mantle cell lymphoma. News release. AstraZeneca. May 6, 2025. Accessed May 6, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/calquence-combination-approved-in-eu-for-1l-mcl.html#!
2. Wang M, Salek D, Belada D, et al. Acalabrutinib plus bendamustine-rituximab in untreated mantle cell lymphoma. J Clin Oncol. Published online May 1, 2025. doi:10.1200/JCO-25-00690
3. FDA approves acalabrutinib with bendamustine and rituximab for previously untreated mantle cell lymphoma. FDA. January 16, 2025. Accessed May 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-acalabrutinib-bendamustine-and-rituximab-previously-untreated-mantle-cell-lymphoma