Early Data Suggest Acalabrutinib May Benefit Patients With Advanced COVID-19

Treatment with the BTK inhibitor acalabrutinib (Calquence) resulted in decreased inflammation and improve outcomes in patients with severe coronavirus disease 2019 (COVID-19), according to exploratory research published in Science Immunology.¹

A total of 19 patients with acute respiratory distress syndrome caused by COVID-19 received treatment with acalabrutinib for 10 to 14 days. Results showed that most patients experienced measurable improvements in oxygenation within just 1 to 3 days with the BTK inhibitor.

Additionally, 73% of patients who had been receiving supplemental oxygen when treated with acalabrutinib were discharged from the hospital having no longer required that oxygen (n = 9/11). Moreover, half of patients who had been receiving invasive mechanical ventilation before treatment with acalabrutinib were extubated (n = 4/8) and 2 were discharged (n = 2/4) without the need of supplemental oxygen.

Notably, investigators also observed improvement in disease progression, including C-reactive protein (CRP) level and lymphocyte levels. No toxicities associated with the BTK inhibitor were observed.

Oncologists from The US Oncology Network were asked to participate in this research effort because of their knowledge of, and active participation in, the development of several BTK inhibitors, specifically acalabrutinib. Due to this experience, they were asked to provide insight at select hospitals to advise colleagues on how to optimally administer the agent and further investigate its potential to address the body’s reaction to COVID-19, according to a recent press release issued by the network.²

The rationale for examining acalabrutinib in this space is that BTK inhibitors are known to modify immunologic signaling pathways in patients with chronic lymphocytic leukemia. As such, investigators hypothesized that the agent might also aid in the treatment of COVID-19 cases by reducing hyperinflammatory immune responses commonly observed within the respiratory pathways.

“[Cytokine storms, which result in an inflammatory condition], appear to be driven specifically by macrophages,” co-author of the manuscript Jeff Sharman, MD, the medical director of hematology research at The US Oncology Network and director of research at Willamette Valley Center Institute, told OncLive.

“When a macrophage ingests a viral particle, it triggers a signaling pathway which proceeds through an enzyme known as BTK. We have been using inhibitors of this enzyme to treat leukemia and it has been very effective in that setting, with a good safety profile—even amongst patients who take [these agents] chronically for years,” Sharman explained. “The hypothesis was that by inhibiting this enzyme, we could turn off the cytokine storm and improve the inflammatory balance within the lungs, thus allowing patients to breathe better.”

When evaluating the BTK inhibitor ibrutinib (Imbruvica) in patients with lymphoma, investigators noted that a handful of patients developed aspergillosis, an invasive fungal infection, during treatment. When similar infections were observed in BTK-deficient mice, investigators realized that the infection was not able to be controlled by monocytes/macrophages and neutrophils. Although this complication was considered to be uncommon, it suggested that BTK inhibitors such as acalabrutinib might help control macrophage-dominated inflammatory responses, as is the case in COVID-19 cases.

Based on these findings, investigators hypothesized that dysregulated macrophage signaling that is dependent on BTK is crucial to the exaggerated inflammatory responses and pulmonary conditions associated with COVID-19 infection. In an effort to decrease that inflammation, and thus improve patient outcomes, investigators examined the use of acalabrutinib in 19 hospitalized patients with COVID-19.

Study participants received off-label acalabrutinib from March 30, 2020 through April 10, 2020. To be eligible for enrollment, patients had to have confirmed infection with the virus and have required hospitalization for hypoxemia; they also had to demonstrate evidence of inflammation and/or lymphopenia. The majority of participants were male (68%) and the median age was 61 years.

Fifty-eight percent of patients had been receiving supplemental oxygen for a median of 2 days; 64% of these patients were on high-flow nasal cannula when they started treatment with the BTK inhibitor; these patients comprised the supplemental oxygen cohort of the trial. At the time of treatment initiation, all patients except for 1 had an increasing oxygen demand. Just under half, or 42%, had been receiving invasive mechanical ventilation for a median of 1.5 days prior to receiving acalabrutinib; these patients comprised the mechanical ventilation cohort. Eighty-four percent of patients (n = 16/19) also had hypertension, 68% (n = 13/19) were obese, and 37% (n = 7/19) had diabetes mellitus.

Five of 11 patients in the supplemental oxygen arm also received steroids and/or hydroxychloroquine (45% each). Seventy-five percent of patients on the mechanical ventilation arm received steroids and 38% received hydroxychloroquine for COVID-19. Notably, no patients on either arm had been given an anti–IL-6 receptor monoclonal antibody or remdesivir (Veklury).

Inflammation, accompanied by elevated CRP and/or ferritin, was observed in 95% of the patient population with elevated laboratory abnormalities at baseline prior to treatment with acalabrutinib. The median follow-up post-acalabrutinib was 12 days for patients within both the supplemental oxygen cohort (n = 11) and the mechanical ventilation cohort (n = 8).

Investigators also evaluated laboratory measures of inflammation during treatment with the BTK inhibitor, and the biggest indicator for decreased inflammation was CRP level. While monitoring inflammation in the supplemental oxygen cohort, it was noted that 91% of patients had their CRP return to normal levels, with 1 additional patient (9%) showing decreasing levels. Normalized IL-6 levels were observed in 60% of, or 3 of 5 patients in, this cohort. Of 10 patients for whom A1C was determined to be evaluable, 70% of patients (n = 7) had increased levels on the BTK inhibitor; 6 patients experienced normalization of those levels, and 3 patients experienced a decrease in their levels.

“We observed fairly rapid improvements amongst those patients treated with BTK inhibitors, saw markers of inflammation go down, and [observed] a very tight correlation between improvement in inflammation and respiratory function,” Sharman noted.

Those on the mechanical ventilation cohort saw more varied and blunted change in regard to laboratory values versus the supplemental oxygen cohort. Two extubated patients (25%) experienced normalized CRP, while an additional 3 patients (37%) saw decreased levels. Among 3 patients who experienced oscillating CRP levels, 1 was extubated, while the others experienced multiorgan failure. The majority of this cohort experienced a normalization of A1C values (63%), while the remainder (37%) experienced oscillating values.

AstraZeneca, the manufacturer of acalabrutinib, has launched research efforts to explore the efficacy of acalabrutinib in patients with severe COVID-19 infections based on the findings from this trial. These efforts include 2 phase 2 studies that are comparing acalabrutinib with the current best supportive care for hospitalized patients with COVID-19, 1 of which includes the CALAVI trial (NCT04346199).

“Our early data is best considered pilot data. Although it is exciting to see what appears to be a treatment effect, this needs to be validated in subsequent studies,” Sharman concluded. “This enthusiasm is reflected in several studies being launched to do just that. Three different FDA-approved BTK inhibitors, including acalabrutinib, ibrutinib, and zanubrutinib (Brukinsa). Each of these are moving forward with clinical trials to further explore this hypothesis, and phase 3 studies are being initiated, as well.”

References

1. Roschewski M, Lionakis MS, Sharman JP, et al. Inhibition of Bruton tyrosine kinase in patients with severe COVID-19. Science Immunology. Published online June 5, 2020. doi:10.1126/sciimmunol.abd0110
2. Preliminary research involving members of The US Oncology Network finds cancer drug may benefit advanced COVID-19 patients. News release. The US Oncology Network. June 5, 2020. Accessed June 12, 2020. bit.ly/30bFcus.