INITIAL DATA ANALYSIS

EFFICACY

RESPONSE RATES IN PATIENTS WITH RELAPSED/REFRACTORY MCL

INITIAL DATA ANALYSIS

March 12, 2015, to January 5, 20161

80% OF PATIENTS WITH RELAPSED/REFRACTORY MCL ACHIEVED A RESPONSE (N=124)1,2

80% ORR1,2,* (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 MONTHS2

  • Median time to best response was 1.9 months2
  • At the time of initial analysis, median DoR had not been reached1

LY-004 trial: Phase 2, open-label, single-arm, multicenter trial of CALQUENCE monotherapy in 124 patients (>18 years) with MCL who had received at least 1 prior therapy. Patients received CALQUENCE 100 mg approximately every 12 hours until disease progression or unacceptable toxicity. The primary endpoint was ORR; secondary endpoints were DoR, PFS, and OS.1,2

*Independent Review Committee-assessed per 2014 Lugano Classification.2

lnvestigator-assessed response rates were ORR: 81%; CR: 40%; PR: 41%.2

CI=confidence interval; CR=complete response; DoR=duration of response; MCL=mantle cell lymphoma; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; PR=partial response.

24-MONTH UPDATE ANALYSIS

Median follow-up: 26 months3

RESPONSE RATES AT 24-MONTH UPDATE CONSISTENT WITH INITIAL ANALYSIS (N=124)3,*

ORR at 24-Month Update Analysis
  • Of those patients who responded to CALQUENCE, 53% (53/100) achieved a complete response3

*Investigator-assessed per 2014 Lugano Classification.3

MEDIAN PROGRESSION-FREE SURVIVAL

MEDIAN PROGRESSION-FREE SURVIVAL WAS 20 MONTHS (MORE THAN 1.5 YEARS)3

PFS FOR PATIENTS WITH RELAPSED/REFRACTORY MCL (N=124)3,*

Median PFS was more than 1.5 Years for Relapsed/Refractory MCL Patients

Median OS not reached at median follow-up of 26 months3

  • At the time of PFS analysis, 66 events (53.2%) had occurred4
  • At the time of OS analysis, 41 events (33.1%) had occurred4
  • Further follow-up analyses may be conducted when more mature data become available4

*Investigator-assessed per 2014 Lugano Classification.3

CALQUENCE DELIVERED A MEDIAN DURATION OF RESPONSE OF 26 MONTHS (MORE THAN 2 YEARS)3

DoR IN RELAPSED/REFRACTORY MCL3,*

CALQUENCE Delivered Median DoR of more than 2 Years for Relapsed/Refractory MCL Patients
  • Median follow-up was 26 months (range: 0.3 to 35.1 months)3

*Investigator-assessed per 2014 Lugano Classification.3

DoR was measured in the 100 subjects who achieved a CR or PR.3

Trial Design

FDA ACCELERATED APPROVAL BASED ON OVERALL RESPONSE RATE IN THE PHASE 2 LY-004 STUDY1,2

  • Phase 2, open-label, single-arm, multicenter trial of CALQUENCE monotherapy in patients (≥18 years) with MCL who had received at least 1 prior therapy (N=124)1,2
  • Patients received CALQUENCE 100 mg approximately every 12 hours until disease progression or unacceptable toxicity1

INITIAL DATA ANALYSIS

  • Efficacy and safety endpoints from March 12, 2015, to January 5, 2016. The median study follow-up time was 15.2 months1
  • Independent Review Committee (IRC) and investigator assessments conducted on primary and secondary endpoints per 2014 Lugano Classification1,2

24-MONTH UPDATE ANALYSIS

  • Cumulative efficacy and safety endpoints that occurred from March 12, 2015, until data cutoff on February 12, 20183
  • Investigator assessments were conducted on primary and secondary endpoints per Lugano Classification1,3
  • IRC-endpoint analyses were not conducted in 24-month data update. High concordance was observed between investigator-assessed and IRC-assessed ORR (91%) and CR (94%) in the initial analysis1

Patients typically seen in your practice

KEY EFFICACY ENDPOINTS AND STUDY CRITERIA

KEY INCLUSION CRITERIA1

  • Relapsed/refractory disease, defined as achieving less than partial response with the most recent treatment
  • Confirmed mantle cell lymphoma with translocation t(11;14)(q13;q32), overexpressed cyclin D1, or both
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

KEY EXCLUSION CRITERIA1,5

  • Prior treatment with a BTK inhibitor
  • Significant cardiovascular disease
    • Uncontrolled or symptomatic arrhythmias
      • Patients with prior or concurrent controlled atrial fibrillation were not excluded
    • 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
  • Anticoagulation with warfarin or equivalent vitamin K antagonists
Key Efficacy Endpoints

*Complete response 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; partial response is defined as a reduction of measurable or metabolic disease and no new lesions, as defined by PET-CT scan. Efficacy endpoints were assessed by the investigator and by an Independent Review Committee.2,6

BASELINE PATIENT CHARACTERISTICS (N=124)1,2,7

Baseline Patient Characteristics

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).1

MIPI=Mantle Cell Lymphoma International Prognostic Index.1

§Alone or as part of a combination regimen.1

CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone; CVAD=cyclophosphamide, vincristine, doxorubicin, and dexamethasone.

Investigator-assessed overall response in LY-004 was consistent across prespecified subgroups, including age and number of prior therapies1

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IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE® (acalabrutinib) capsules

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.

IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE® (acalabrutinib) capsules

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.

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.

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.

ADVERSE REACTIONS

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.

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 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.

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.

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Reference: 1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.

References: 1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019. 2. Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017;363(2):240-252. 3. Hendriks RW, Yuvaraj S, Kil LP. Targeting Bruton’s tyrosine kinase in B cell malignancies. Nat Rev Cancer. 2014;14(4):219-232.

References: 1. 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. 2. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019. 3. 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. 4. Data on File, REF-43179. AstraZeneca Pharmaceuticals LP. 5. Wang M, Rule S, Zinzani PL, et al. Long-term follow-up of acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma. Poster presented at: 60th Annual Meeting of the American Society of Hematology; December 1-4, 2018; San Diego, CA. 6. 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. 7. Data on File, REF-18540. AstraZeneca Pharmaceuticals LP.

References: 1. 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. 2. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019. 3. 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. 4. Badillo M, Nava D, Dela Rosa M, Rodriguez S, Xu J, Wang M. Managing adverse events in patients with relapsed/refractory mantle cell lymphoma treated with acalabrutinib: clinical experience from the MD Anderson Center. Poster presentation at: Oncology Nursing Society 44th Annual Congress; April 11-14, 2019; Anaheim, CA. 5. Data on File, REF-43179. AstraZeneca Pharmaceuticals LP.

References: 1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019. 2. Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017;363(2):240-252.