Previously Untreated CLL

EFFICACY

Previously Untreated CLL

PFS

UNPRECEDENTED PFS: 90% RISK REDUCTION IN DISEASE PROGRESSION OR DEATH WITH CALQUENCE + OBINUTUZUMAB vs GClb

At median 28.3-month follow-up (range: 0.0 to 40.8 months), median PFS was not reached with CALQUENCE + obinutuzumab vs 22.6 months (95% CI: 20-28) with GClb*1

IRC-assessed progression-free survival†1,2

Progression Free Survival PFS Progression Free Survival PFS

93% ESTIMATED PFS AT 24 MONTHS FOR CALQUENCE + OBINUTUZUMAB||2

CALQUENCE monotherapy1:

  • 80% relative risk reduction in disease progression or death vs GClb (HR=0.20 [95% CI: 0.13-0.30], P<0.0001§)
  • Median PFS was not reached (95% CI: 34-NE) vs 22.6 months (95% CI: 20-28) with GClb

*Per 2008 International Workshop on CLL (IWCLL) criteria.1

At the time of analysis, the number of events in each arm was 14 (8%) for CALQUENCE + obinutuzumab, 26 (15%) for CALQUENCE monotherapy, and 93 (53%) for GClb.1

Based on a stratified Cox proportional-hazards model. Both hazard ratios are compared with the GClb arm.1

§Based on a stratified log-rank test, with an alpha level of 0.012 derived from alpha spending function by the O'Brien-Fleming method.1

||Confidence intervals for estimated 24-month PFS: CALQUENCE + obinutuzumab (95% CI: 87-96); CALQUENCE monotherapy (95% CI: 81-92); and GClb (95% CI: 39-55).2

CI=confidence interval; GClb=obinutuzumab + chlorambucil; HR=hazard ratio; IRC=Independent Review Committee; NE=not estimable; PFS=progression-free survival.

ORR

94% ORR IN THE CALQUENCE + OBINUTUZUMAB ARM1

IRC-assessed overall response rate

Overall Response Rate - ORR Overall Response Rate - ORR

Based on a stratified Cochran-Mantel-Haenszel test for the comparison with the GClb arm.1

CR=complete response; CRi=complete response with incomplete blood count recovery; ORR=overall response rate; nPR=nodular partial response; PR=partial response.

SUBGROUP ANALYSIS

CALQUENCE + OBINUTUZUMAB DELIVERED CONSISTENT PFS RESULTS ACROSS SUBGROUPS#2

CALQUENCE PFS Results Across Subgroups

#Exploratory analysis of prespecified subgroups. Study not powered to show statistical significance across subgroups.

ECOG=Eastern Cooperative Oncology Group.

STUDY DESIGN

ELEVATE-TN: A PHASE 3, OPEN-LABEL, RANDOMIZED, MULTICENTER TRIAL IN PATIENTS WITH PREVIOUSLY UNTREATED CLL1,3

Multicenter Trial in Patients with PREVIOUSLY UNTREATED CLL Multicenter Trial in Patients with PREVIOUSLY UNTREATED CLL

Patients received CALQUENCE 100 mg approximately every 12 hours until disease progression or unacceptable toxicity for either CALQUENCE + obinutuzumab or CALQUENCE monotherapy.1

**For CALQUENCE + obinutuzumab, obinutuzumab was given 28 days after the first dose of CALQUENCE (Cycle 2, Day 1), and was given for up to 6 cycles.1

Key inclusion criteria1,3:

  • Age:
    • ≥65 years or
    • 18 to <65 years and ≥1 of the following criteria:
      • CrCL 30-69 mL/min
      • CIRS-G >6

Key exclusion criteria1,3:

  • Any prior systemic treatment for CLL
  • Required or was receiving anticoagulation with warfarin or equivalent vitamin K antagonists within 7 days of first dose of study drug
    • Novel antithrombotic treatments were allowed

CIRS-G=Cumulative Illness Rating Scale–Geriatric; CrCL=creatinine clearance.

PATIENT CHARACTERISTICS WERE GENERALLY WELL BALANCED ACROSS ALL 3 ARMS OF THE CLINICAL TRIAL

Select demographics and baseline characteristics in ELEVATE-TN2

Patients characteristics ELEVATE-TN study

FISH=fluorescence in situ hybridization.

RELAPSED/REFRACTORY CLL

PFS

69% RISK REDUCTION IN DISEASE PROGRESSION OR DEATH WITH CALQUENCE vs IR OR BR

At median 16.1-month follow-up (range: 0.03 to 22.4 months), median PFS was not reached with CALQUENCE vs 16.5 months (95% CI: 14.0-17.1) with IR or BR*1

IRC-assessed progression-free survival†1,2

CALQUENCE PFS ASCEND STUDY CALQUENCE PFS ASCEND STUDY
  • CALQUENCE: 81% ORR (95% CI: 74-87; CR/CRi: 0%; PR/nPR: 81%)||1
  • IR or BR: 75% ORR (95% CI: 68-82; CR/CRi: 1%; PR/nPR: 74%)||1

CALQUENCE IS THE FIRST AND ONLY BTKI MONOTHERAPY TO DEMONSTRATE SUPERIOR PFS AGAINST STANDARD-OF-CARE COMBINATIONS, INCLUDING NOVEL AGENTS, IN RELAPSED/REFRACTORY CLL1

*Per 2008 IWCLL criteria.1

At the time of analysis, the number of events in each arm was 27 (17%) for CALQUENCE and 68 (44%) for IR or BR.1

Based on a stratified Cox proportional-hazards model.1

§Based on a stratified log-rank test. The prespecified type I error rate (α) for this interim analysis is 0.012 derived from a Lan-DeMets alpha spending function with O’Brien-Fleming boundary.1

||There was no statistically significant difference in overall response rates between the two treatment arms.1

BR=bendamustine + rituximab; BTKi=Bruton tyrosine kinase inhibitor; IR=idelalisib + rituximab.

SUBGROUP ANALYSIS

CALQUENCE DELIVERED CONSISTENT PFS RESULTS ACROSS SUBGROUPS, INCLUDING IN PATIENTS WITH HIGH-RISK FEATURES¶2

Subgroup Analysis in Ascend Study

Exploratory analysis of prespecified subgroups. Study not powered to show statistical significance across subgroups.

STUDY DESIGN

ASCEND: A PHASE 3, OPEN-LABEL, RANDOMIZED, MULTICENTER TRIAL IN PATIENTS WITH RELAPSED/REFRACTORY CLL1,5

Multicenter Trial in Patients with R/R CLL Multicenter Trial in Patients with R/R CLL

Patients were randomized 1:1 to receive CALQUENCE 100 mg approximately every 12 hours until disease progression or unacceptable toxicity

OR

Investigator's choice of:

  • Idelalisib 150 mg orally approximately every 12 hours until disease progression or unacceptable toxicity in combination with 8 infusions of rituximab (375 mg/m2 intravenously on Day 1 of Cycle 1, followed by 500 mg/m2 every 2 weeks for 4 doses and then every 4 weeks for 3 doses), with a 28-day cycle length, or
  • Bendamustine 70 mg/m2 intravenously (Days 1 and 2 of each 28-day cycle) in combination with rituximab (375 mg/m2 intravenously on Day 1 of Cycle 1, then 500 mg/m2 on Day 1 of subsequent cycles), for up to 6 cycles1

Key inclusion criteria1,5:

  • Age ≥18 years
  • Received ≥1 prior systemic therapy for CLL
  • Estimated CrCL ≥30 mL/min

Key exclusion criteria1,5:

  • Significant cardiovascular disease within 6 months of screening
  • Required or was receiving anticoagulation with warfarin or equivalent vitamin K antagonists within 7 days of first dose of study drug
    • Novel antithrombotic treatments were allowed

PATIENT CHARACTERISTICS WERE GENERALLY WELL BALANCED ACROSS BOTH ARMS OF THE CLINICAL TRIAL

SELECT DEMOGRAPHICS AND BASELINE CHARACTERISTICS IN ASCEND2

Patient characteristics ASCEND study Patient characteristics ASCEND study
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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.

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 (≥ 30%) of any grade in patients with CLL were anemia,* neutropenia,* thrombocytopenia,* headache, upper respiratory tract infection, and diarrhea.

*Treatment-emergent decreases (all grades) of hemoglobin, platelets, and neutrophils were based on laboratory measurements and adverse reactions.

In patients with previously untreated CLL exposed to CALQUENCE, fatal adverse reactions that occurred in the absence of disease progression and with onset within 30 days of the last study treatment were reported in 2% for each treatment arm, most often from infection. Serious adverse reactions were reported in 39% of patients in the CALQUENCE plus obinutuzumab arm and 32% in the CALQUENCE monotherapy arm, most often due to events of pneumonia (7% and 2.8%, respectively).

Adverse reactions led to CALQUENCE dose reduction in 7% and 4% of patients in the CALQUENCE plus obinutuzumab arm (N=178) and CALQUENCE monotherapy arm (N=179), respectively. Adverse events led to discontinuation in 11% and 10% of patients, respectively. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 3.9% and 2.8% of patients in the CALQUENCE combination arm and monotherapy arm, respectively.

In patients with relapsed/refractory CLL exposed to CALQUENCE, serious adverse reactions occurred in 29% of patients. Serious adverse reactions in > 5% of patients who received CALQUENCE included lower respiratory tract infection (6%). Fatal adverse reactions within 30 days of the last dose of CALQUENCE occurred in 2.6% of patients, including from second primary malignancies and infection.

Adverse reactions led to CALQUENCE dose reduction in 3.9% of patients (N=154), dosage interruptions in 34% of patients, most often due to respiratory tract infections followed by neutropenia, and discontinuation in 10% of patients, most frequently due to second primary malignancies followed by infection. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 1.3% of patients who received CALQUENCE.

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 indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

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. Data on File, REF-64711. AstraZeneca Pharmaceuticals LP. 3. Elevate CLL TN: study of obinutuzumab + chlorambucil, acalabrutinib (ACP-196) + obinutuzumab, and acalabrutinib in subjects with previously untreated CLL. ClinicalTrials.gov identifier: NCT02475681. https://clinicaltrials.gov/ct2/show/NCT02475681. Updated October 14, 2019. Accessed November 14, 2019. 4. Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients (pts) with treatment-naive chronic lymphocytic leukemia (CLL). Abstract for American Society of Hematology Annual Meeting; December 7-10, 2019; Orlando, FL. 5. A study of acalabrutinib vs investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab in R/R CLL. ClinicalTrials.gov identifier: NCT02970318. https://clinicaltrials.gov/ct2/show/NCT02970318. Updated August 16, 2019. Accessed November 14, 2019. 6. Ghia P, Pluta A, Watch M, et al. ASCEND phase 3 study of acalabrutinib vs investigator's choice of rituximab plus idelalisib (IDR) or bendamustine (BR) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: 24th European Hematology Society Congress; June 13-16, 2019; Amsterdam, the Netherlands.

References: 1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019. 2. Data on File, REF-64711. AstraZeneca Pharmaceuticals LP.

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

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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.