CHMP Recommends Acalabrutinib Combo Approval in Untreated MCL

Acalabrutinib improved PFS and OS compared with standard of care in the first-line treatment of mantle cell lymphoma.

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for acalabrutinib (Calquence) plus bendamustine (Treanda) and rituximab (Rituxan) in the first-line treatment of adult patients with mantle cell lymphoma (MCL) who are ineligible for autologous hematopoietic stem cell transplantation, according to a press release from the developer, AstraZeneca.¹

Supporting results for the recommendation came from the randomized, double-blind phase 3 ECHO trial (NCT02972840) that evaluated the efficacy and safety of acalabrutinib plus bendamustine/rituximab compared with placebo plus bendamustine/rituximab in untreated MCL. Updated results were shared at the 2024 European Hematology Association Congress.²

The combination led to a 27% reduction in the risk of disease progression or death compared with standard-of-care therapy (HR, 0.73; 95% CI, 0.57-0.94; P = .016); the median progression-free survival (PFS) was 66.4 months vs 49.6 months, respectively.

Although overall survival (OS) data were not fully mature at the time of analysis, favorable trends were observed with the acalabrutinib combination vs the standard-of-care treatment (HR, 0.86; 95% CI, 0.65-1.13; P = .2743).

In January 2025, the treatment combination was approved by the FDA in the same population.³ In February 2025, the CHMP recommended approval for acalabrutinib in relapsed or refractory MCL.⁴

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

The trial enrolled a total of 635 patients with untreated MCL who were randomly assigned, in a 1:1 ratio, to receive oral acalabrutinib or placebo given twice daily until disease progression or unacceptable toxicity, as well as 6 cycles of bendamustine on days 1 and 2 and rituximab on day 1 on each 28-day cycle. Patients also received rituximab maintenance therapy for 2 years if they achieved a response with induction therapy.

Eligible patients were 65 years or older, had an ECOG performance status of 2 or less, and had MCL without prior systemic anticancer therapy.⁵ Those with significant cardiovascular disease, malabsorption syndrome, resection of the stomach, uncontrolled active systemic infection, and concurrent participation in another clinical trial were ineligible for participation.

The trial’s primary end point was PFS per independent review committee assessment. Secondary end points included OS, overall response rate, duration of response, and time to response.

A prespecified analysis that censored for COVID-19–related deaths showed additional PFS improvements, demonstrating a 36% reduction in the risk of disease progression or death with the acalabrutinib treatment (HR, 0.64; 95% CI, 0.48-0.84; P = .0017); the median PFS was not reached with acalabrutinib vs 61.6 months with standard of care. OS was also further improved, demonstrating a favorable trend with acalabrutinib (HR, 0.75; 95% CI, 0.53-1.04; P = .0797).

No new safety signals were observed with the treatment combination. Grade 3 or higher adverse events (AEs) occurred in 88.9% of patients who received acalabrutinib and 88.2% who received standard of care.² They included atrial fibrillation (3.7% vs 1.7%, respectively), hypertension (5.4% vs 8.4%), major bleeding (2.0% vs 3.4%), and infections (41.1% vs 34.0%). Grade 5 AEs occurred in 12.1% vs 10.1%, respectively, and serious AEs occurred in 69% vs 62%; AEs led to discontinuation in 10.4% and 6.4%. Grade 5 AEs related to COVID-19 occurred in 9.4% and 6.7%, respectively.

“For people living with [MCL], a typically aggressive form of non-Hodgkin lymphoma, the ECHO results offer promise of a new, effective treatment option for adults older than 65, who represent the majority of [patients with] MCL,” Michael Wang, MD, Puddin Clarke Endowed Professor, director of the Mantle Cell Lymphoma Program of Excellence, co-director of Clinical Trials at the University of Texas MD Anderson Cancer Center, and principal investigator in the trial, stated.² “The improved [PFS] seen in patients treated with the [acalabrutinib] combination compared to chemoimmunotherapy demonstrate its potential to change the standard of care as the only BTK inhibitor in this first-line setting.”

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://tinyurl.com/59we5a28
2. CALQUENCE® (acalabrutinib) plus chemoimmunotherapy reduced the risk of disease progression or death by 27% vs. standard of care in patients with untreated mantle cell lymphoma in ECHO Phase III trial. News release. AstraZeneca. June 16, 2024. Accessed March 31, 2025. https://tinyurl.com/bdeb2kze
3. FDA approves acalabrutinib with bendamustine and rituximab for previously untreated mantle cell lymphoma. January 16, 2024. Accessed March 31, 2025. https://shorturl.at/fTW0O
4. Calquence – opinion on variation to marketing authorization. News release. European Medicines Agency. February 27, 2025. Accessed March 31, 2025. https://tinyurl.com/yty6jd7e
5. 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://tinyurl.com/2r8dzpwr