New BTK Inhibitor Leads to Durable Responses in Relapsed or Refractory Chronic Lymphocytic LeukemiaLeukemia, Web Exclusives
Atlanta, GA—More than 90% of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) achieved objective responses with the new Bruton’s tyrosine kinase (BTK) inhibitor acalabrutinib (Calquence), updated data from an ongoing study showed. In most cases, the responses were durable, reported John C. Byrd, MD, Director, Division of Hematology, the Ohio State University Comprehensive Cancer Center, Columbus, at ASH 2017.
Including partial response with lymphocytosis, 93% of 134 treated patients had objective responses to single-agent acalabrutinib. Complete responses accounted for 3% of the total response rate.
“This updated analysis of an ongoing phase 1/2 showed that acalabrutinib is associated with a high response rate and durable remissions in patients with relapsed or refractory CLL or small-lymphocytic lymphoma” (SLL), said Dr Byrd. “The reported adverse events are consistent with a tolerable safety profile, including a low rate of grade 3 or higher bleeding or cardiac events.”
Acalabrutinib received FDA approval on October 31, 2017, for patients with mantle-cell lymphoma but not for patients with CLL. It is only the second BTK inhibitor to receive approval by the FDA.
Ibrutinib (Imbruvica), the first BTK inhibitor approved by the FDA, is approved for several indications, including CLL, SLL, and mantle-cell lymphoma, among others. Ibrutinib has resulted in objective responses in a high percentage of patients with CLL.
Acalabrutinib exhibits greater selectivity and potency of BTK inhibition. Preliminary data from a phase 1/2 trial involving 61 patients with relapsed or refractory CLL/SLL showed an objective response rate (ORR) of 95% and stable disease in the remaining 5%. A safety analysis showed that most adverse events were grade 1 or 2 in severity (Byrd JC, et al. N Engl J Med. 2016;374:323-332).
Dr Byrd presented findings from an updated analysis of the phase 1/2 trial, which included more than twice as many patients as the original report. Eligible patients had CLL/SLL that relapsed after or proved refractory to at least 1 previous therapy. Treatment started with acalabrutinib 100 to 400 mg once daily or 100 to 200 mg twice daily during the dose-escalation phase, and 100 mg twice daily during the expansion phase. Treatment continued until disease progression or unacceptable toxicity.
Safety was the study’s primary objective, and investigator-assessed ORR was a key secondary end point. The updated analysis showed an ORR of 87%, including complete responses in 2% of patients. Including response with lymphocytosis pushed the ORR to 93%.
A subgroup analysis showed consistent efficacy, including in high-risk groups, such as in 23 of 27 (85%) patients with deletion 17(p13.1), 18 of 21 (86%) patients with del(11)(q22.3), and 71 of 81 (88%) patients with immunoglobulin VH without mutation. The median progression-free survival (PFS) had not yet been reached; the 18-month PFS was 88%. Similarly, the median PFS had not yet been reached in high-risk subgroups; the 18-month PFS rates for del(11)(q22.3) and del(17)(p13.1) were 100% and 78%, respectively.
“The response rate and progression-free survival were consistent across all subgroups, including high-risk subgroups,” said Dr Byrd. “The 18-month PFS was above 80% in all subgroups.” The responses tended to be durable, which was reflected in the median response duration of 24.5 months.
Consistent with the earlier report, most adverse events were grade 1/2 in severity. The most common events (all grades) were headache (46%), diarrhea (43%), upper respiratory tract infection (28%), fatigue (27%), nausea (27%), arthralgia (23%), pyrexia (23%), contusion (22%), petechiae (21%), and weight gain (21%). The most common grade 3/4 adverse events were neutropenia (11%) and pneumonia (11%).
Based on these results, 3 phase 3 clinical trials of acalabrutinib in CLL/SLL have begun to enroll patients.
On December 12, 2019, the FDA issued draft guidance to implement amendments to the Federal Food, Drug, and Cosmetic (FD&C) Act that will facilitate early assessment of studies of molecularly targeted oncology drugs that may be effective in the treatment of pediatric cancers.
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