AstraZeneca's CALQUENCE (acalabrutinib) combination therapy has demonstrated significant clinical benefits for patients with previously untreated mantle cell lymphoma (MCL), according to new data presented at the European Hematology Association (EHA) 2024 Hybrid Congress in Madrid, Spain.
The late-breaking results from the ECHO Phase III trial showed that CALQUENCE in combination with bendamustine and rituximab 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).
Significant Improvement in Progression-Free Survival
Patients treated with the CALQUENCE combination (n=299) achieved a median progression-free survival (PFS) of 66.4 months compared to 49.6 months for those receiving standard-of-care chemoimmunotherapy (n=299). This represents an additional 16.8 months that patients could live without their disease progressing – a clinically meaningful improvement for this patient population.
The trial also showed a favorable trend in overall survival (OS) for the CALQUENCE combination compared to standard-of-care (HR 0.86; 95% CI 0.65-1.13; p=0.2743), though these data were not mature at the time of analysis. The trial will continue to assess OS as a key secondary endpoint.
Dr. Michael Wang, Puddin Clarke Endowed Professor and Director of the Mantle Cell Lymphoma Program of Excellence at MD Anderson Cancer Center, who served as principal investigator in the trial, emphasized the significance of these findings: "For people living with mantle cell lymphoma, 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."
COVID-19 Impact Analysis
The ECHO trial enrolled patients from May 2017 to March 2023, spanning the COVID-19 pandemic period. A pre-specified analysis censoring for COVID-19-related deaths showed even more pronounced benefits, with the CALQUENCE combination reducing the risk of disease progression or death by 36% (HR 0.64; 95% CI 0.48-0.84; p=0.0017).
In this analysis, median PFS was not reached among patients treated with the CALQUENCE combination versus 61.6 months for standard-of-care chemoimmunotherapy. A favorable trend was also observed for OS (HR 0.75; 95% CI 0.53-1.04; p=0.0797).
Safety and Tolerability Profile
The safety and tolerability of CALQUENCE was consistent with its known profile, with no new safety signals identified. Grade 3 or higher adverse events (AEs) due to any cause occurred in 88.9% (n=264) of patients treated with the CALQUENCE combination and 88.2% (n=262) of patients treated with standard-of-care chemoimmunotherapy.
Specific Grade 3 or higher adverse events included:
- Atrial fibrillation: 3.7% (n=11) in the CALQUENCE arm vs. 1.7% (n=5) in the control arm
- Hypertension: 5.4% (n=16) vs. 8.4% (n=25)
- Major bleeding: 2.0% (n=6) vs. 3.4% (n=10)
- Infections: 41.1% (n=122) vs. 34.0% (n=101)
Serious AEs and Grade 5 events were balanced across arms (69% [n=205] versus 62% [n=184], and 12.1% [n=36] versus 10.1% [n=30], respectively). AEs leading to discontinuation were observed in 10.4% (n=31) of patients in the CALQUENCE combination arm and 6.4% (n=19) in the placebo arm.
COVID-19-related adverse events, including Grade 5 events, occurred in 9.4% (n=28) of patients treated with the CALQUENCE combination and 6.7% (n=20) of patients treated with standard-of-care chemoimmunotherapy.
First BTK Inhibitor to Show Benefits in First-Line Setting
Susan Galbraith, Executive Vice President of Oncology R&D at AstraZeneca, highlighted the significance of these results: "The ECHO trial data demonstrate important progress in improving outcomes for patients with mantle cell lymphoma. 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 overall survival. We therefore believe CALQUENCE plus chemoimmunotherapy will be an important new option for patients living with this disease."
CALQUENCE is the first and only Bruton's tyrosine kinase (BTK) inhibitor to demonstrate a favorable overall survival trend versus standard-of-care chemoimmunotherapy in the first-line MCL setting.
About Mantle Cell Lymphoma
Mantle cell lymphoma is a rare and typically aggressive form of non-Hodgkin lymphoma, often diagnosed as a late-stage disease. It occurs when B-lymphocytes mutate into malignant cells within a region of the lymph node known as the mantle zone.
MCL comprises about 3-6% of non-Hodgkin lymphomas, with an annual incidence of 0.5 per 100,000 population in Western countries. In the US, approximately 4,000 new patients are diagnosed with MCL each year, and it is estimated that more than 27,500 people are living with MCL worldwide.
While MCL patients initially respond to treatment, they tend to relapse, highlighting the need for more effective therapeutic options.
About the ECHO Trial
ECHO is a randomized, double-blind, placebo-controlled, multi-center Phase III trial evaluating the efficacy and safety of CALQUENCE plus bendamustine and rituximab compared to standard-of-care chemoimmunotherapy in adult patients aged 65 or older (n=635) with previously untreated MCL.
Patients were randomized 1:1 to receive either CALQUENCE or placebo administered orally twice per day, on 28-day treatment cycles, plus bendamustine on days 1 and 2 and rituximab on day 1 of each cycle. After six cycles of induction therapy, patients received CALQUENCE or placebo plus maintenance rituximab for two years and then either CALQUENCE or placebo only until disease progression.
The primary endpoint was PFS assessed by an Independent Review Committee, with key secondary endpoints including OS, overall response rate, duration of response, and time to response. The trial included 27 countries across North and South America, Europe, Asia, and Oceania.
CALQUENCE Mechanism and Indications
CALQUENCE (acalabrutinib) is a next-generation, selective inhibitor of Bruton's tyrosine kinase (BTK). It binds covalently to BTK, thereby inhibiting its activity. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.
The drug has been used to treat more than 80,000 patients worldwide and is approved for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) in the US and Japan, as well as for CLL in the EU and many other countries. It is also approved in the US, China, and several other countries for the treatment of adult patients with MCL who have received at least one prior therapy.
These new findings from the ECHO trial may potentially expand CALQUENCE's indications to include first-line treatment of MCL in combination with chemoimmunotherapy, pending regulatory approvals.
