On October 31, 2017, the Bruton’s tyrosine kinase (BTK) inhibitor acalabrutinib (Calquence) was granted accelerated approval for treatment of adult patients with mantle cell lymphoma who have received at least one prior therapy.1,2
Supporting Efficacy Data
Approval was based on objective response rate in a phase II trial in 124 patients who had received at least 1 prior therapy.2 Patients who had received prior treatment with BTK inhibitors were excluded. Treatment consisted of acalabrutinib at 100 mg orally twice daily until disease progression or unacceptable toxicity.
Acalabrutinib has warnings/precautions for hemorrhage; infections; cytopenias; second primary malignancies, including skin cancers and other carcinomas; as well as atrial fibrillation and atrial flutter.
The median age of patients was 68 years (range = 42–90 years), 80% were male, 74% were white, 93% had an Eastern Cooperative Oncology Group performance status of 0 or 1, the median time since diagnosis was 46.3 months, the median number of prior treatments was 2 (range = 1–5, including prior stem cell transplantation in 18%), the most common prior regimens were CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)–based (52%) and cytarabine (34%), 37% had at least 1 tumor with the longest diameter ≥ 5 cm, 73% had extranodal involvement including 51% with bone marrow involvement, and the simplified mantle cell lymphoma International Prognostic Index score was intermediate in 44% and high in 17%.
The overall response rate on investigator assessment was 81%, with a complete response in 40% of patients. On an independent review committee assessment, the response rate was 80%, with a complete response in 40%. After 15.2 months of follow-up, the median response duration had not been reached. The median time to best response was 1.9 months.
How It Works
Acalabrutinib is a small-molecule inhibitor of BTK. Acalabrutinib and its active metabolite ACP-5862 form a covalent bond with a cysteine residue in the BTK active site, resulting in inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. In preclinical studies, acalabrutinib inhibited BTK-mediated activation of downstream signaling proteins CD86 and CD69 and inhibited malignant B-cell proliferation and survival.
How It Is Used
The recommended dose of acalabrutinib is 100 mg orally approximately every 12 hours until disease progression or unacceptable toxicity.
Recommended dose modifications for grade ≥ 3 nonhematologic toxicities, grade 3 thrombocytopenia with bleeding, and grade 4 thrombocytopenia or grade 4 neutropenia lasting > 7 days are as follows: treatment should be interrupted until resolution to grade 1 or baseline levels and then resumed at 100 mg twice daily for first and second occurrences and at 100 mg once daily for a third occurrence; treatment should be discontinued for a fourth occurrence.
Concomitant use of acalabrutinib with strong CYP3A inhibitors (eg, itraconazole) should be avoided; if short-term use of an inhibitor (eg, use of an anti-infective for up to 7 days) is necessary, acalabrutinib should be interrupted. The acalabrutinib dose should be reduced to 100 mg once daily for concomitant use with a moderate CYP3A inhibitor (eg, erythromycin, fluconazole, diltiazem). Concomitant use of acalabrutinib with a strong CYP3A inducer (eg, rifampin) should be avoided; if such use cannot be avoided, the acalabrutinib dose should be increased to 200 mg twice daily. Concomitant use of acalabrutinib with proton pump inhibitors should be avoided. Acalabrutinib should be taken 2 hours before taking an H2-receptor antagonist, and dosing of acalabrutinib and an antacid should be separated by at least 2 hours.
The most common adverse events of any grade in the 124 patients receiving acalabrutinib in the phase II trial were anemia (46%), thrombocytopenia (44%), headache (39%), neutropenia (36%), diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%). The most common grade 3 or 4 adverse events were neutropenia (15%), thrombocytopenia (12%), and anemia (10%); the most common grade 3 or 4 nonhematologic adverse event was diarrhea (3.2%). Dose reductions and discontinuations due to grade 3 or 4 adverse events occurred in 1.6% and 6.5% of patients, respectively.
Acalabrutinib has warnings/precautions for hemorrhage; infections; cytopenias; second primary malignancies, including skin cancers and other carcinomas; as well as atrial fibrillation and atrial flutter. Complete blood cell counts should be monitored monthly during treatment. Patients should be monitored for bleeding and for atrial fibrillation and flutter. Women should be advised not to breastfeed. ■
1. U.S. Food and Drug Administration: DDA grants accelerated approval to acalabrutinib for mantle cell lymphoma. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm583106.htm. Accessed November 21, 2017.
2. Calquence (acalabrutinib) capsules prescribing information, AstraZeneca, October 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/210259s000lbl.pdf. Accessed November 21, 2017.
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).