INDICATION AND USAGE CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.
This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
STRONG EFFICACY SEEN OVER TIME IN RELAPSED/REFRACTORY MCL PATIENTS
LY-004 trial: Phase 2, open-label, single-arm, multicenter trial of CALQUENCE monotherapy in 124 patients (≥18 years) with MCL who had received ≥1 prior therapy. Patients received CALQUENCE 100 mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was ORR; secondary endpoints were DoR, PFS, and OS.1,2
In the initial data analysis, 80% of patients with R/R MCL
achieved a response1-3
Response rates in R/R MCL (N=124)*,†
80% ORR (n=99) [95% CI: 72, 87]
40% CR (n=49) [95% CI: 31, 49]
40% PR (n=50) [95% CI: 32, 50]
Median follow-up of 15.2 months
Median time to best response was 1.9 months
At the time of initial analysis, DoR had not been reached
Initial data analysis: based on efficacy and safety endpoints that occurred from March 12, 2015, through approximately 14 months after the last subject was enrolled.3
Consistent response rates at 24-month update analysis (N=124)3,‡
Median DoR of more than 2 years (26 months)§
Median PFS of more than 1.5 years (20 months)
24-month update analysis: based on the cumulative efficacy and safety endpoints that occurred from March 12, 2015, until data cutoff on February 12, 2018.3
Independent Review Committee-assessed per 2014 Lugano Classification response criteria for NHL.1
Investigator-assessed response rates were ORR: 81%; CR: 40%; PR: 41%.1
Investigator-assessed per 2014 Lugano Classification response criteria for NHL.3
Median follow-up was 26 months (range: 0.3 to 35.1 months).3
IMPORTANT SAFETY INFORMATION Serious and Opportunistic Infections
Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE.
Serious or Grade 3 or higher infections (bacterial, viral, or fungal) occurred in 19% of 1029 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (11% of all patients, including pneumonia in 6%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 1.9% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jiroveci
pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML). Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat promptly.
Safety profile from initial data analysis1
Warnings and precautions include hemorrhage, infections, cytopenias, second primary malignancies, and atrial fibrillation/flutter
The most common adverse drug reactions (≥20%) were anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, and bruising
Safety profile from 24-month update analysis consistent with initial analysis3
The most common treatment-emergent adverse events (≥20%) were headache (38%), diarrhea (36%),
fatigue (28%), cough (22%), and myalgia (21.0%)
IMPORTANT SAFETY INFORMATION (Cont’d) Hemorrhage
Fatal and serious hemorrhagic events have occurred in patients with hematologic malignancies treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 3.0% of patients, with fatal hemorrhage occurring in 0.1% of 1029 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 22% of patients.
Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 2.7% of patients taking CALQUENCE without antithrombotic agents and 3.6% of patients taking CALQUENCE with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE. Monitor patients for signs of bleeding.
Consider the benefit-risk of withholding CALQUENCE for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.
Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%), developed in patients with hematologic malignancies treated with CALQUENCE. Grade 4 neutropenia developed in 12% of patients. Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted.
Second Primary Malignancies
Second primary malignancies, including skin cancers and other solid tumors, occurred in 12% of 1029 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was skin cancer, reported in 6% of patients. Monitor patients for skin cancers and advise protection from sun exposure.
Atrial Fibrillation and Flutter
Grade 3 atrial fibrillation or flutter occurred in 1.1% of 1029 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 4.1% of all patients. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (e.g., palpitations, dizziness, syncope, dyspnea) and manage as appropriate.
The most common adverse reactions (≥20%) of any grade in patients with MCL were anemia,* thrombocytopenia,* headache (39%), neutropenia,* diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%). The most common Grade ≥ 3 non-hematological adverse reaction (reported in at least 2% of patients) was diarrhea (3.2%).
*Treatment-emergent decreases (all grades) of hemoglobin (46%), platelets (44%), and neutrophils (36%) were based on laboratory measurements and adverse reactions.
Dosage reductions or discontinuations due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively.
Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.
DRUG INTERACTIONS Strong CYP3A Inhibitors: Avoid co-administration with a strong CYP3A inhibitor. If a strong CYP3A inhibitor will be used short-term, interrupt CALQUENCE.
Moderate CYP3A Inhibitors: When CALQUENCE is co-administered with a moderate CYP3A inhibitor, reduce CALQUENCE dose to 100 mg once daily.
Strong CYP3A Inducers: Avoid co-administration with a strong CYP3A inducer. If a strong CYP3A inducer cannot be avoided, increase the CALQUENCE dose to 200 mg approximately every 12 hours.
Gastric Acid Reducing Agents: If treatment with a gastric acid reducing agent is required, consider using an H2-receptor antagonist or an antacid. Take CALQUENCE 2 hours before taking an H2‑receptor antagonist. Separate dosing with an antacid by at least 2 hours.
Avoid co-administration with proton pump inhibitors. Due to the long-lasting effect of proton pump inhibitors, separation of doses may not eliminate the interaction with CALQUENCE.
Based on findings in animals, CALQUENCE may cause fetal harm and dystocia when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. Advise pregnant women of the potential risk to a fetus.
Pregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy. Advise female patients of reproductive potential to use effective contraception during treatment with CALQUENCE and for at least 1 week following the last dose of CALQUENCE.
It is not known if CALQUENCE is present in human milk. Advise lactating women not to breastfeed while taking CALQUENCE and for at least 2 weeks after the final dose.
Avoid administration of CALQUENCE in patients with severe hepatic impairment. Dose modifications are not required for patients with mild or moderate hepatic impairment.
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References: 1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019. 2. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667. 3. Wang M, Rule S, Zinzani PL, et al. Durable response with single-agent acalabrutinib in patients with relapsed or refractory mantle cell lymphoma. [published online ahead of print September 26, 2019]. Leukemia. https://doi.org/10.1038/s41375-019-0575-9.
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