Updated Results Indicate Long-Term Efficacy of Acalabrutinib in Treatment-Naïve Patients with CLL

Targeted therapy with the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib (Calquence), which is currently approved for the treatment of patients with non-Hodgkin lymphoma, has demonstrated durable remissions in treatment-naïve patients with chronic lymphocytic leukemia (CLL), according to the long-term data from the phase 2 CLL-001 study, which were presented at the ASCO 2020 virtual annual meeting.

The study results of monotherapy with acalabrutinib showed an overall response rate of 97% in treatment-naïve patients with CLL, according to lead investigator, John C. Byrd, MD, D. Warren Brown Chair of Leukemia Research, the Ohio State University Comprehensive Cancer Center, Columbus, who presented the results.

Of note, the responses were durable, with 86% of patients still receiving treatment after almost 2.5 years. The treatment was also well tolerated, with no long-term safety issues. Collectively, these data support the use of acalabrutinib in the upfront treatment of CLL, Dr Byrd said.

“Acalabrutinib monotherapy produced a very high and durable response, regardless of high-risk genomic characteristics seen in previously untreated CLL,” he said. “The toxicity associated with acalabrutinib was generally mild, with only a small subset of patients discontinuing therapy due to adverse events.”

The targeted inhibition of BTK has improved clinical outcomes in treatment-naïve patients with relapsed or refractory CLL, Dr Byrd said. Acalabrutinib is a selective second-generation BTK inhibitor that has demonstrated less off-target activity in nonhuman studies compared with first-generation BTK inhibitors, such as ibrutinib (Imbruvica).

In late 2019, acalabrutinib was approved for the treatment of treatment-naïve patients with relapsed or refractory CLL and for small lymphocytic lymphoma based on results from 2 complementary phase 3 studies.

CLL-001 Phase 2 Study Results

At ASCO 2020, Dr Byrd reported the mature results of CLL-001, the first phase 2 study of acalabrutinib in treatment-naïve patients with CLL. In the expansion of the study, 99 treatment-naïve patients with CLL were enrolled and received acalabrutinib until disease progression or unacceptable toxicity.

The treatment with acalabrutinib was initiated at a dose of 100 mg twice daily or 200 mg once daily. Later in the study, when it was identified that twice-daily dosing was potentially better, all patients were converted to the 100-mg twice-daily dosing regimen. In addition to assessing tolerability, the efficacy end points included investigator-assessed response, time to response, duration of response, and event-free survival.

The demographics of the study patients matched most CLL trials that have been performed, said Dr Byrd, who reported that enrolled patients had a median age of 64 years, and nearly 50% of the patients had stage III or IV disease. In addition, 10% of the patients had deletion 17p, and almost 66% had no IGVH mutation, another genomic aberration often associated with CLL.

After a median follow-up of 53 months, 86% of the patients in the study continued to receive therapy with acalabrutinib, and 14 patients discontinued treatment. Of these treatment discontinuations, 6 resulted from adverse events and 3 patients had progressive disease.

The results of the study showed an overall response rate of 97%, including 7% complete responses and 90% partial responses. Of note, the median time to response was 3.7 months.

“Median duration of response and event-free survival median response have not yet been reached with extended follow-up, and the estimated 48-month duration of response is 97%,” Dr Byrd concluded.

Adverse Events

The most common adverse events of any grade were diarrhea, headache, upper respiratory tract infection, arthralgia, and contusion or bruising. Dr Byrd noted that most of these adverse events were grade 1 or 2, and that adverse events with acalabrutinib generally reversed with continuing use of therapy.

Serious adverse events were reported in 38% of patients, with pneumonia and sepsis the only 2 events that occurred in ≥2 patients.

A total of 2 deaths were reported with the study, 1 of which resulted from multiorgan dysfunction in the setting of pneumonia and the other from cardiac failure; both of these deaths were unrelated to treatment with acalabrutinib.

“High-grade hematologic adverse events were very uncommon, and no patients discontinued acalabrutinib due to hypertension, bleeding events, or atrial fibrillation,” said Dr Byrd.

According to Dr Byrd, of the 6 patients who discontinued because of adverse events, 4 were a result of secondary cancers and 2 were because of infections.

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