What is acalabrutinib?
Acalabrutinib is a second-generation inhibitor of Bruton's tyrosine kinase (BTK).
How does acalabrutinib work?
BTK is a crucial component of B-cell receptor (BCR) signaling and downstream survival. Acalabrutinib irreversibly binds to BTK, inhibiting aberrant BCR signaling and malignant B-cell proliferation, adhesion, and survival.
What is this approved for?
Acalabrutinib is approved for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least one prior treatment.
Acalabrutinib received accelerated FDA approval in October 2017 based on results of a phase II, single-arm, open-label study of 124 relapsed/refractory MCL patients. Acalabrutinib 100 mg orally twice daily was given until progressive disease or unacceptable toxicity. The primary endpoint was overall response rate [ORR, partial response + complete response (CR)]. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Median age was 68 years and 80 percent were male. The ORR was 81 percent (95% CI, 73-87). CR occurred in 49 patients (40%). The median time to best response was 1.9 months. Median DOR, PFS, and OS were not reached. At 1-year, DOR was 72 percent, PFS 67 percent, and OS 87 percent (Lancet 2017; http://dx.doi.org/10.1016/S0140-6736(17)33108-2).
How do you administer this drug?
Acalabrutinib is administered at 100 mg orally every 12 hours with or without food. Swallow capsules whole with water. Acalabrutinib may be dose modified to 100 mg capsules daily for toxicity or drug interactions.
Are there any pre-medications needed?
None required.
What are the common side effects associated with acalabrutinib (> or =10%)?
Acalabrutinib toxicities were primarily grade 1/2 and resulted in dose modifications or discontinuation in 1.6 percent and 6.5 percent, respectively. The most common any grade adverse events include anemia (46%), thrombocytopenia (44%), headache (39%), neutropenia (grade 3 of greater: 10%), diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%).
What are the uncommon side effects associated with acalabrutinib (less than 10%)?
Less common toxicities include hemorrhage/hematoma (8%) and epistaxis (6%).
Are there any important drug interactions I should be aware of?
Acalabrutinib is metabolized by cytochrome P450 CYP3A4. Co-administration of itraconazole, a strong CYP3A inhibitor, increased acalabrutinib Cmax and AUC 3.9- and 5.1-fold. Concomitant erythromycin, a moderate CYP3A inhibitor, increased acalabrutinib exposure 2- to 3-fold. Avoid concurrent use of strong CYP3A inhibitors with acalabrutinib. Reduce acalabrutinib dosing to 100 mg daily with concomitant moderate CYP3A inhibitors. Co-administration with rifampin, a strong CYP3A inducer, decreased acalabrutinib Cmax and AUC 68 percent and 77 percent. Avoid concurrent use of strong CYP3A inducers. If concomitant use is required, escalate acalabrutinib to 200 mg every 12 hours.
Acalabrutinib has pH dependent-solubility. Co-administration of proton pump inhibitors should be avoided. Separate acalabrutinib and H2-receptor antagonists or antacids by 2 hours.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
Acalabrutinib is metabolized in the liver. Excretion is primarily via the biliary tract with 12 percent renal elimination. No dose modification is required in patients with mild to moderate hepatic impairment or renal impairment. Acalabrutinib has not been studied in patients with severe renal impairment (GFR < 30 mL/min), dialysis, or severe hepatic dysfunction (total bilirubin 3-10 times upper limit of normal and any AST).
Practical tips
Bruising and petechiae occurred in ~50 percent of patients. Grade 3 or higher bleeding events (gastrointestinal, intracranial, and epistaxis) were reported in 2 percent. Concurrent anticoagulant or antiplatelet medications may increase bleeding risk. Consider holding acalabrutinib for 3-7 days pre- and post-surgery, depending on surgery bleeding risk.
Grade 3 or higher neutropenia and infections occurred in 23 percent and 18 percent, respectively. Assess complete blood count monthly and treat infection as appropriate. Reactivation of hepatitis B virus and progressive multifocal leukoencephalopathy have been reported.
What should my patients know about acalabrutinib?
Patients should contact their health care provider if they experience any of the following: bleeding (blood in the stool; pink or brown urine; coughing up blood; bleeding that won't stop; or coffee ground emesis); headache; fever, chills, flu-like symptoms; irregular heartbeat; unusual tiredness; diarrhea; and muscle aches.
What else should I know about acalabrutinib?
Acalabrutinib is more selective than ibrutinib with higher potency and fewer off-target effects. Because of this, acalabrutinib is associated with fewer grade 3 and higher toxicities (atrial fibrillation, infection, bleeding).
What useful links are available regarding acalabrutinib?
* https://www.calquence.com/
* https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm583106.htm
Any ongoing clinical trials related to acalabrutinib?
Acalabrutinib is being studied in other B-cell hematologic malignancies, including relapsed/refractory chronic lymphocytic leukemia and non-Hodgkin lymphoma. More information is available about these clinical trials at https://clinicaltrials.gov.
HEIDI D. FINNES, PHARMD, BCOP, is Senior Manager, Pharmacy Cancer Research, and Assistant Professor of Pharmacy, College of Medicine, Mayo Clinic, Rochester, Minn. RAMASWAMY GOVINDAN, MD, Co-Director, Section of Medical Oncology, Professor of Medicine, Washington University School of Medicine, Alvin J. Siteman Cancer Center, serves as the Pharmacy Forum column physician advisor. JANELLE E. MANN, PHARMD, BCOP, is an Investigational Drug Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column co-editor.