November 18, 2020 - The addition of the oral BTK inhibitor acalabrutinib to best supportive care in patients with respiratory symptoms from coronavirus disease 2019 infection failed to increase the proportion of patients who remained alive and free of respiratory failure, missing the primary efficacy end points of the 2 phase 2 CALAVI trials.
The addition of the oral BTK inhibitor acalabrutinib (Calquence) to best supportive care (BSC) in patients with respiratory symptoms from coronavirus disease 2019 (COVID-19) infection failed to increase the proportion of patients who remained alive and free of respiratory failure, missing the primary efficacy end points of the 2 phase 2 CALAVI trials (NCT04380688; NCT04346199).1
However, no new safety signals with the drug were reported in the trials, according to AstraZeneca; The data are expected to be presented in the future.
“The CALAVI trials were launched based on preclinical and early clinical evidence that [acalabrutinib] could decrease the hyperinflammatory immune response and improve clinical outcomes in patients hospitalized with respiratory symptoms of COVID-19,” José Baselgá, executive vice president of Oncology R&D at AstraZeneca, stated in a press release. “While the CALAVI results are disappointing, we remain committed to advancing science that helps patients during this unprecedented global pandemic, including clinical trials for the AstraZeneca Oxford coronavirus vaccine and our long-acting antibody combination.”
Patients with severe COVID-19 infection are known to have hyperinflammatory immune response that is thought to be indicative of macrophage activation. Because BTK inhibitors are known to regulate such activation, acalabrutinib was previously evaluated off label in 19 hospitalized patients with severe COVID-19 infection; 11 of these patients were on supplemental oxygen, while 8 were on mechanical ventilation.2 The overwhelming majority of these patients (n = 18) were noted to have had increasing oxygen requirements at baseline.
Results showed that the majority of patients who received a 10- to 14-day course of acalabrutinib experienced improvement in oxygenation that was found to occur within 1 to 3 days of treatment. Moreover, measures of C-reactive protein and interleukin-6 and lymphopenia were found to normalize in most patients fairly quickly, as oxygenation improved.
Once treatment with the BTK inhibitor was completed, 72.7% (n = 8/11) of the patients who were on supplemental oxygen had been discharged on room air and 50% (n = 4/8) of those who were on mechanical ventilation were able to be extubated and 25% (n = 2/8) were discharged on room air.
Investigators concluded that using a BTK inhibitor to target inflammation in patients with severe COVID-19 can be an effective treatment approach.
The phase 2 CALAVI program was comprised of 2 randomized, open-label, multicenter trials that examined the safety and efficacy of acalabrutinib plus BSC compared with BSC alone in hospitalized patients with COVID-19–related respiratory complications.
In both trials, patients were randomized in a 1:1 fashion to either treatment arm. To be eligible for inclusion, patients had to be hospitalized, but they could not be on mechanical ventilation or within the intensive care unit. The primary objective of these efforts focused on respiratory failure or death. This research was conducted in the United States and several other countries around the globe.
In November 2019, the FDA approved acalabrutinib for use in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma, based on findings from the phase 3 ELEVATE-TN (NCT02475681) and ASCEND (NCT02970318) trials. Results from ELEVATE-TN trial showed that acalabrutinib as a monotherapy or in combination with obinutuzumab (Gazyva) significantly improved progression-free survival (PFS) versus obinutuzumab/chlorambucil in treatment-naïve patients with CLL.3
At a median follow-up of 28.3 months, acalabrutinib plus obinutuzumab resulted in a 90% reduction in the risk of disease progression or death versus obinutuzumab/chlorambucil (HR, 0.10; 95% CI, 0.06-0.17; P <.0001). When used as a single agent, acalabrutinib also demonstrated a statistically significant PFS benefit (HR, 0.20; 95% CI, 0.13-0.30; P <.0001).
Previously, in October 2017, acalabrutinib was granted an accelerated approval from the FDA for use as a treatment in adult patients with mantle cell lymphoma following at least 1 previous therapy. The regulatory decision was based on data from the ACE-LY-004 study (NCT02213926), which showed that the agent elicited an objective response rate of 81% (95% CI, 73-87) per investigator assessment.4