Acalabrutinib Combination Treatment Improves Progression-Free Survival in Patients With Previously Untreated MCL


Compared with standard of care chemoimmunotherapy, acalabrutinib with bendamustine and rituximab reduced risk of death or disease by approximately 27%.

According to positive results from the phase 3 ECHO trial (NCT02972840), acalabrutinib (Calquence; AstraZeneca) in combination with bendamustine and rituximab, compared with standard of care chemoimmunotherapy, demonstrated both statistically significant and clinically meaningful improvement in progression-free survival (PFS) and a favorable trend in overall survival (OS) in patients with previously untreated mantle cell lymphoma (MCL).1

Mantle cell lymphoma -- Image credit: Zhanna |

Image credit: Zhanna |

Acalabrutinib is a next-generation, selective Bruton tyrosine kinase (BTK) inhibitor that binds covalently to BTK to inhibit its activity. BTK signaling results in the activation of pathways that are necessary for the proliferation, trafficking, chemotaxis, and adhesion in B-cells. Currently, acalabrutinib is approved in the US for the treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL), as well as adult patients with MCL who received at least 1 prior therapy. Additionally, the BTK inhibitor is currently being evaluated as a single treatment and combination treatment with standard of care chemoimmunotherapy for patients with multiple B-cell blood cancers, such as CLL, MCL, follicular lymphoma, and diffuse large B-cell lymphoma.1

The ECHO trial (NCT02972840) is a randomized, double-blind, placebo-controlled, multicenter phase 3 trial that evaluated the safety and efficacy of acalabrutinib with bendamustine and rituximab compared to standard of care chemoimmunotherapy in 635 adult patients with previously untreated MCL who are 65 years of age are or older. Patients were randomly assigned to receive either acalabrutinib or placebo administered orally twice per day on 28-day treatment cycles, plus intravenous (IV) bendamustine on days 1 and 2 and IV rituximab on day 1 of each cycle. Following 6 induction therapy cycles, all patients continued acalabrutinib or placebo in combination with bendamustine and rituximab, patients receive acalabrutinib or placebo plus maintenance rituximab for 2 years, and the patients receive either acalabrutinib or placebo alone until disease progression.1,2

About the Trial

Trial Name: A Study of BR Alone Versus in Combination With Acalabrutinib in Subjects With Previously Untreated MCL ID: NCT02972840

Sponsor: Acerta Pharma BV

Completion Date (Estimated): October 28, 2025

The trial’s primary end point is PFS, and key secondary end points include OS, overall response rate, duration of response, and time to response. All end points are assessed up to 6 years.1,2

According to the trial findings, the acalabrutinib combination regimen had decreased the risk of disease progression or death by approximately 27%. For patients treated with the acalabrutinib combination regimen, the median PFS was 66.4 months compared with 49.6 months in the placebo group. In addition, OS also demonstrated a favorable trend for the patients treated with acalabrutinib (HR 0.86; 95% CI 0.65-1.13; p = .2743); however, OS data were immature at the time of the analysis and the trial will continue to assess this secondary end point.1

Further, the ECHO trial also enrolled during the COVID-19 pandemic, and a pre-specified analysis that censored for deaths due to the virus was conducted to assess its impact. In both treatment groups, PFS was improved, with acalabrutinib decreasing the risk of death or disease progression by approximately 36% (HR 0.64; 95% CI; 0.48-0.84; p = .0017). Additionally, median PFS was not reached among those treated with the acalabrutinib regimen versus 61.6 months for standard of care chemoimmunotherapy (HR 0.64, 95% CI, 0.48-0.84; p = .0017), and a favorable trend in OS was observed for the acalabrutinib combination regimen (HR 0.75; 95% CI 0.53-1.04; p = .0797).1

“For people living with MCL, a typically aggressive form of non-Hodgkin's lymphoma, the ECHO results offer promise of a new, effective treatment option for adults older than 65, who represent the majority of MCL patients,” said principal investigator Michael Wang, MD, professor at Puddin Clarke Endowed, director of Mantle Cell Lymphoma Program of Excellence, co-director of clinical trials at MD Anderson Cancer Center in Houston, US, in a news release. “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.”1

According to the investigators, the safety and tolerability of acalabrutinib demonstrated in ECHO was consistent with its known safety profile, with no new safety signals observed. Grade 3 or higher adverse events (AEs) resulting from any cause occurred in 264 patients (88.9%) who were treated with the acalabrutinib combination regimen, and 262 patients (88.2%) treated with standard of care chemoimmunotherapy. These AEs included grade 3 or higher atrial fibrillation (acalabrutinib: 3.7%, n = 11; standard of care: 1.7%, n = 5) hypertension (acalabrutinib: 5.4%, n = 16; standard of care: 8.4%, n = 25), major bleeding (acalabrutinib: 2.0%, n = 6; standard of care: 3.4%, n = 10), and infections (acalabrutinib: 41.1%, n = 122; standard of care: 34.0%, n = 101).1

Further, AEs that led to discontinuation of treatment were observed in 31 (10.4%) and 19 (6.4%) patients in the acalabrutinib and standard of care groups, respectively. COVID-19-related AEs were also observed, and included grade 5 events that were present in 28 (9/4%) and 20 (6.7%) patients in the acalabrutinib and standard of care groups, respectively.1

“The ECHO trial data demonstrate important progress in improving outcomes for patients with MCL. The 16.8 months of additional time patients can live without their disease progressing is highly clinically meaningful, together with a trend to improvement in OS. We therefore believe [acalabrutinib] plus chemoimmunotherapy will be an important new option for patients living with this disease,” said Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca, in the news release.1


1. AstraZeneca. Calquence 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. June 16, 2024. Accessed June 17, 2024.
2. A Study of BR Alone Versus in Combination With Acalabrutinib in Subjects With Previously Untreated identifier: NCT02972840. Updated March 8, 2024. Accessed June 17, 2024.
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