On November 21, 2019, the Bruton’s tyrosine kinase (BTK) inhibitor acalabrutinib was approved for the treatment of adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).^1,2 The review resulting in approval was conducted under Project Orbis, an initiative of the U.S. Food and Drug Administration (FDA) Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. The FDA, the Australian Therapeutic Goods Administration, and Health Canada collaborated on the review.

Supporting Efficacy Data

Approval was based on the findings from two phase III trials assessing acalabrutinib in previously untreated and relapsed or refractory CLL.^3,4 In both trials, progression-free survival was assessed by an independent review committee.

In the ELEVATE-TN trial (ClinicalTrials.gov identifier NCT02475681),³ 535 patients with previously untreated CLL were randomly assigned to receive acalabrutinib monotherapy (n = 179), acalabrutinib plus obinutuzumab (n = 179), or obinutuzumab plus chlorambucil (n = 177). Acalabrutinib was given at 100 mg approximately every 12 hours until disease progression or unacceptable toxicity. The median follow-up was 28.3 months. Progression-free survival events occurred in 15% of the acalabrutinib monotherapy group, 8% of the acalabrutinib/obinutuzumab group, and 53% of the obinutuzumab/chlorambucil group; the median progression-free survival was not reached (hazard ratio [HR] = 0.20, P < .0001) in the acalabrutinib monotherapy group, vs not reached (HR = 0.10, P < .0001) in the acalabrutinib/obinutuzumab group, vs 22.6 months in the obinutuzumab/chlorambucil group.

In the ASCEND trial (NCT02970318),⁴ 310 patients with relapsed or refractory CLL after at least one prior systemic therapy were randomly assigned to receive acalabrutinib alone (n = 155) or investigator’s choice of idelalisib plus a rituximab product or bendamustine plus a rituximab product (n = 155). The median follow-up was 16.1 months. The median progression-free survival was not reached in the acalabrutinib group (17% of patients with events) vs 16.5 months in the control group (HR = 0.31, P < .0001).

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 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 tumor growth in mouse xenograft models.

How It Is Used

For patients with CLL or SLL, the recommended dose of acalabrutinib monotherapy is 100 mg orally approximately every 12 hours until disease progression or unacceptable toxicity. For patients with previously untreated CLL or SLL receiving acalabrutinib plus obinutuzumab, the recommended dose of acalabrutinib is 100 mg orally approximately every 12 hours until disease progression or unacceptable toxicity; acalabrutinib should be started at cycle 1 and obinutuzumab at cycle 2 for a total of six 28-day cycles. Acalabrutinib is given before obinutuzumab when both are given on the same day.

Full prescribing information for acalabrutinib provides instructions on dose modifications for hepatic impairment, strong and moderate CYP3A inhibitors and strong CYP3A inducers, and gastric acid-reducing agents. Full prescribing information provides instructions on dose modification for adverse reactions.

Safety Profile

The most common adverse events of any grade in patients receiving acalabrutinib in clinical trials (incidence ≥ 30%) have been anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache, diarrhea, and musculoskeletal pain. In the ELEVATE-TN trial in 535 patients with previously untreated CLL, the most common grade ≥ 3 adverse events with acalabrutinib monotherapy were lymphocytosis, infection, neutropenia, and anemia. The most common grade ≥ 3 adverse events with acalabrutinib/obinutuzumab were neutropenia, infection, anemia, thrombocytopenia, and lymphocytosis. Among both groups, second primary malignancy occurred in 10% of patients and nonmelanoma skin cancer, in 5%.Serious adverse events occurred in 32% and 39% of the two groups, with the most common being pneumonia (7% and 3%). Adverse events led to treatment discontinuation in 10% and 11% of patients. Fatal adverse events occurring in the absence of disease progression and with onset within 30 days of the last study treatment were reported in 2% of each group.

In the ASCEND trial, in 310 patients with relapsed or refractory CLL after at least one prior systemic therapy, the most common grade ≥ 3 adverse events with acalabrutinib were neutropenia, lymphocytosis, infection, and anemia. Second primary malignancy occurred in 12% of patients and nonmelanoma skin cancer, in 6%. Serious adverse events occurred in 29%, with the most common being lower respiratory tract infection. Permanent treatment discontinuation due to adverse events occurred in 10% of patients, most commonly due to second primary malignancies and infection. Fatal adverse events within 30 days of the last dose occurred in 2.6% of patients, including from second primary malignancies and infection.

Acalabrutinib has warnings/precautions for serious and opportunistic infections; hemorrhage; cytopenias; second primary malignancies, including skin cancers and other solid tumors; and atrial fibrillation and atrial flutter. Complete blood cell counts should be monitored regularly. Patients should be monitored for the signs and symptoms of infection, bleeding, and arrhythmia. The agent may cause fetal harm and dystocia during pregnancy. Patients should be advised not to breastfeed while receiving acalabrutinib. ■

REFERENCES

1. U.S. Food and Drug Administration: Project Orbis : FDA approves acalabrutinib for CLL and SLL. Available at www.fda.gov/drugs/resources-information-approved-drugs/project-orbis-fda-approves-acalabrutinib-cll-and-sll. Accessed December 10, 2019.

2. U.S. Food and Drug Administration: Calquence (acalabrutinib) capsules prescribing information, AstraZeneca, November 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/210259s006s007lbl.pdf. Accessed December 10, 2019.

3. Sharman JP, et al: ELEVATE TN : Phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil in patients with treatment-naive chronic lymphocytic leukemia. Blood 134(suppl 1):31, 2019.

4. Ghia P, et al: ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelalisib or bendamustine in patients with relapsed/refractory chronic lymphocytic leukemia. 2019 EHA Congress. Abstract LB2606. Presented June 16, 2019.