Acalabrutinib, a second-generation Bruton tyrosine kinase (BTK) inhibitor, has received traditional approval from the FDA for use in combination with bendamustine and rituximab for adult patients with previously untreated mantle cell lymphoma (MCL) who are ineligible for autologous hematopoietic stem cell transplantation. This approval marks a significant advancement in the treatment landscape for MCL, a rare and aggressive form of non-Hodgkin lymphoma.
The FDA's decision was supported by data from the phase 3 ECHO trial (NCT02972840), a randomized, double-blind, placebo-controlled, multicenter study that evaluated the efficacy and safety of acalabrutinib in combination with bendamustine and rituximab compared to bendamustine and rituximab plus placebo. The trial enrolled 598 patients aged 65 years or older with previously untreated MCL who were not candidates for stem cell transplantation.
ECHO Trial Results
At a median follow-up of 49.8 months, the ECHO trial demonstrated a statistically significant improvement in progression-free survival (PFS) for patients treated with the acalabrutinib combination. The median PFS was 66.4 months (95% CI, 55.1 months-not estimable) in the acalabrutinib arm compared to 49.6 months (95% CI, 36.0-64.1 months) in the placebo arm (HR, 0.73; 95% CI, 0.57-0.94; P = .016). This represents a 27% reduction in the risk of disease progression or death with the acalabrutinib combination.
Overall survival (OS) data were not mature at the time of the analysis; however, a favorable trend was observed for patients treated with the acalabrutinib combination (HR, 0.86; 95% CI, 0.65-1.13; P = .2743). Notably, a significant proportion (69%) of patients in the chemoimmunotherapy arm received subsequent treatment with a BTK inhibitor upon relapse or disease progression.
Safety and Tolerability
The safety profile of acalabrutinib in the ECHO trial was consistent with its known safety profile. Serious adverse reactions occurred in 69% of patients treated with the acalabrutinib combination, and fatal adverse reactions occurred in 12%. Serious adverse reactions reported in at least 2% of patients included pneumonia, COVID-19, pyrexia, second primary malignancy, rash, febrile neutropenia, atrial fibrillation, sepsis, and anemia.
Clinical Implications
"Managing this aggressive cancer requires maximizing efficacy while maintaining tolerability, especially for elderly patients," said Michael Wang, MD, Puddin Clarke Endowed Professor, Director of Mantle Cell Lymphoma Program of Excellence and principal investigator in the trial. "Results from the pivotal ECHO trial highlight the promise of the acalabrutinib combination in defining a new standard of care, with today’s approval underscoring the transformative potential of this regimen as a first-line treatment for older patients with mantle cell lymphoma."
This approval also converts acalabrutinib’s accelerated approval to a full approval for adult patients with MCL treated with at least one prior therapy, as granted by the FDA in October 2017.
The recommended dose of acalabrutinib is 100 mg orally approximately every 12 hours until disease progression or unacceptable toxicity.
Regulatory Context
The FDA’s review was conducted under Project Orbis, an initiative that provides a framework for concurrent submission and review of oncology drugs among international partners. As part of Project Orbis, the application for acalabrutinib plus chemoimmunotherapy is also under review by regulatory authorities in Australia, Canada, and Switzerland. Regulatory applications are also under review in the EU, Japan, and other countries based on the ECHO results.
