LY-004 Efficacy

Accelerated approval of CALQUENCE for R/R MCL was based on overall response rate in the pivotal LY-004 study. 

CALQUENCE: A BTKi for adult patients with MCL after at least one prior therapy1

Continued approval of this indication may be contingent upon verification and description of clinical benefit in confirmatory clinical trials.

Study design1

A Phase 2, open-label, single-arm, multicenter trial of CALQUENCE monotherapy in patients (≥18 years) with MCL who had received at least one prior therapy (N=124).1,2

Patients received CALQUENCE 100 mg approximately every 12 hours until disease progression or unacceptable toxicity.1

Investigator-assessed ORR was the primary endpoint; secondary endpoints included DoR, PFS, and OS. IRC-assessed ORR was a secondary endpoint.2

Data at initial analysis

  • Efficacy and safety endpoints measured from March 12, 2015, to January 5, 2016; the median study follow-up time was 15.2 months2
  • Independent Review Committee (IRC) and investigator assessments conducted on primary and secondary efficacy endpoints per 2014 Lugano Classification response criteria for NHL1,2
  • Investigator-assessed ORR was the primary endpoint; secondary endpoints included DoR, PFS, and OS. IRC-assessed ORR was a secondary endpoint2

Long-term follow-up data

  • Efficacy and safety endpoints from an additional year of follow-up representing a 38-month median follow-up3,4
  • Investigator assessments were conducted on primary and secondary efficacy endpoints per 2014 Lugano Classification response criteria for NHL3
  • IRC–endpoint analyses were not conducted in long-term data update2

INITIAL ANALYSIS (15.2-MONTH MEDIAN FOLLOW-UP)

  • Efficacy and safety endpoints measured from March 12, 2015 to January 5, 20162
  • Independent Review Committee (IRC) and investigator assessments conducted on primary and secondary efficacy endpoints per 2014 Lugano Classification1,2

LONG-TERM ANALYSIS (38-MONTH MEDIAN FOLLOW-UP)

  • Investigator assessments were conducted on primary and secondary efficacy endpoints per 2014 Lugano Classification response criteria3
  • IRC–endpoint analyses were not conducted in long-term data update2

Long-term follow-up

  • Efficacy and safety endpoints from an additional year of follow-up representing a 38-month median follow-up3,4
  • Investigator assessments were conducted on primary and secondary efficacy endpoints per 2014 Lugano Classification response criteria for NHL3
  • IRC–endpoint analyses were not conducted in long-term data update2

BTKi=Bruton tyrosine kinase inhibitor; DoR=duration of response; IRC=Independent Review Committee; MCL=mantle cell lymphoma; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; R/R=relapsed/refractory.

More Than Three Thousand Patients

More than 3000 patients with R/R MCL have been prescribed CALQUENCE since launch*5

Key efficacy endpoints and study criteria in LY-004

Primary endpoint

  • ORR by investigator assessment per 2014 Lugano Classification1,2
    • Defined as the proportion of subjects who achieve a CR† or PR†2

Secondary endpoints2

  • Duration of response
  • Progression-free survival
  • Overall survival

Key inclusion criteria2

  • Confirmed MCL with translocation t(11;14)(q13;q32), overexpressed cyclin D1, or both, and measurable disease (one or more lesions measuring ≥2 cm in the longest diameter)
  • Relapsed or refractory (R/R) disease to at least one previous treatment
  • ECOG performance status of 0-2

Key EXCLUSION criteria2

  • Prior treatment with a BTKi , PI3K, SYKi, or BCL-2i
  • Significant cardiovascular disease
    • Uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening
    • Any Class 3 or 4 cardiac disease per New York Heart Association functional classification
    • Corrected QT interval >480 milliseconds

PATIENTS WHO RECEIVED ANTITHROMBOTIC AGENTS OTHER THAN WARFARIN OR EQUIVALENT VITAMIN K ANTAGONISTS WERE ALLOWED2

Patients with controlled, asymptomatic arrhythmias were allowed; Patients with significant cardiovascular disease were excluded2

Baseline patient characteristics (N=124)1,2,4,6

CHARACTERISTICS
 SUBJECTS, n
(% or range)
Median age, years 68 (42-90)
Sex, male 99 (80)
ECOG performance status  
0 or 1 115 (93)
2‡ 9 (7)
Ann Arbor Stage IV 93 (75)
Median time from initial diagnosis, months 46.3 (2.5-170.1)
Simplified MIPI score  
Low risk 48 (39)
Intermediate risk 54 (44)
High risk 21 (17)
Missing 1 (1)
Bulky disease  
≥5 cm 46 (37)
≥10 cm 10 (8)
Extranodal disease 89 (72)§
Bone marrow 63 (51)
Gastrointestinal 13 (10)
Lung 12 (10)
Blastoid/pleomorphic MCL 26 (21)
Ki-67 proliferation index  
<50% 64 (52)
≥50% 32 (26)
Missing 28 (22)
Median number of prior therapies 2 (1-5)
Prior therapies  
Rituximab|| 118 (95)
CHOP-based regimen 64 (52)
Bendamustine and rituximab-based regimen 27 (22)
Hyper-CVAD 26 (21)
Bortezomib or carfilzomib 24 (19)
Stem cell transplant 22 (18)
Lenalidomide 9 (7)
Overall Response Rate >

*Launch date: October 2017.5

†CR is defined as the disappearance of evidence of disease, including extranodal disease (if present at baseline), and/or PET negativity based on FDG uptake less than or equal to the liver by PET-CT scan; PR is defined as a reduction of measurable or metabolic disease and no new lesions, as identified by PET-CT scan. Efficacy endpoints were assessed by the investigator and by an Independent Review Committee at initial analysis.1,7

‡One patient with an ECOG performance status of 1 at screening had an ECOG performance status of 3 at the baseline assessment (cycle 1, day 1).2

§The site of disease for 1 patient was changed from osseous/bone to none after the original cutoff date that was previously published.4

||Alone or as part of a combination regimen.2

CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone; CR=complete response; CVAD=cyclophosphamide, vincristine, doxorubicin, and dexamethasone; ECOG=Eastern Cooperative Oncology Group; FDG=fluorine-18-fluorodeoxy-D-glucose; MIPI=Mantle Cell Lymphoma International Prognostic Index; PET-CT=Positron emission tomography-computed tomography; PR=partial response.

 

  • CALQUENCE® (acalabrutinib) tablets [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2024.
  • 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.
  • Wang M, Rule S, Zinzani PL, et al. Acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study. Poster presented at: American Society of Hematology (ASH) Annual Meeting and Exposition; December 5-8, 2020 (Virtual Meeting). Abstract 2040.
  • Wang M, Rule S, Zinzani PL, et al. Durable response with single-agent acalabrutinib in patients with relapsed or refractory mantle cell lymphoma. Leukemia. 2019;33(11):2762-2766.
  • Data on File. US-74808. AstraZeneca Pharmaceuticals LP.
  • Data on File. REF-18540. AstraZeneca Pharmaceuticals LP.
  • Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
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INDICATION AND IMPORTANT SAFETY INFORMATION

IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE® (acalabrutinib) tablets

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 jirovecii 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.

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.

Cytopenias

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.

Cardiac Arrhythmias

Serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. 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. Grade 3 or higher ventricular arrhythmia events were reported in 0.9% of patients. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (eg, palpitations, dizziness, syncope, dyspnea) and manage as appropriate.

Hepatotoxicity, Including Drug-Induced Liver Injury

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including CALQUENCE.

Evaluate bilirubin and transaminases at baseline and throughout treatment with CALQUENCE. For patients who develop abnormal liver tests after CALQUENCE, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold CALQUENCE. Upon confirmation of DILI, discontinue CALQUENCE.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) of any grade in patients with relapsed or refractory 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.

Dose reductions or discontinuations due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively. Increases in creatinine to 1.5 to 3 times the upper limit of normal (ULN) occurred in 4.8% of patients.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Avoid co-administration of CALQUENCE with a strong CYP3A inhibitor. If these inhibitors will be used short-term, interrupt CALQUENCE. After discontinuation of strong CYP3A inhibitor for at least 24 hours, resume previous dosage of CALQUENCE.

Moderate CYP3A Inhibitors: Reduce the dosage of CALQUENCE to 100 mg once daily when co-administered with a moderate CYP3A inhibitor.

Strong CYP3A Inducers: Avoid co-administration of CALQUENCE with a strong CYP3A inducer. If co-administration is unavoidable, increase the dosage of CALQUENCE to 200 mg approximately every 12 hours.

SPECIFIC POPULATIONS

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 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 2 weeks after the last dose.

Avoid use of CALQUENCE in patients with severe hepatic impairment (Child-Pugh class C). No dosage adjustment of CALQUENCE is recommended in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.

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.

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.

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.

Please see full Prescribing Information, including Patient Information.

You may report side effects related to AstraZeneca products .

INDICATION AND IMPORTANT SAFETY INFORMATION

IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE® (acalabrutinib) tablets

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 jirovecii 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.

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.

Cytopenias

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.

Cardiac Arrhythmias

Serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. 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. Grade 3 or higher ventricular arrhythmia events were reported in 0.9% of patients. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (eg, palpitations, dizziness, syncope, dyspnea) and manage as appropriate.

Hepatotoxicity, Including Drug-Induced Liver Injury

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including CALQUENCE.

Evaluate bilirubin and transaminases at baseline and throughout treatment with CALQUENCE. For patients who develop abnormal liver tests after CALQUENCE, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold CALQUENCE. Upon confirmation of DILI, discontinue CALQUENCE.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) of any grade in patients with relapsed or refractory 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.

Dose reductions or discontinuations due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively. Increases in creatinine to 1.5 to 3 times the upper limit of normal (ULN) occurred in 4.8% of patients.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Avoid co-administration of CALQUENCE with a strong CYP3A inhibitor. If these inhibitors will be used short-term, interrupt CALQUENCE. After discontinuation of strong CYP3A inhibitor for at least 24 hours, resume previous dosage of CALQUENCE.

Moderate CYP3A Inhibitors: Reduce the dosage of CALQUENCE to 100 mg once daily when co-administered with a moderate CYP3A inhibitor.

Strong CYP3A Inducers: Avoid co-administration of CALQUENCE with a strong CYP3A inducer. If co-administration is unavoidable, increase the dosage of CALQUENCE to 200 mg approximately every 12 hours.

SPECIFIC POPULATIONS

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 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 2 weeks after the last dose.

Avoid use of CALQUENCE in patients with severe hepatic impairment (Child-Pugh class C). No dosage adjustment of CALQUENCE is recommended in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.

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.

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.

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.

Please see full Prescribing Information, including Patient Information.

You may report side effects related to AstraZeneca products .

Read More