CALQUENCE Demonstrated Fewer Incidences of Atrial Fibrillation Versus Ibrutinib in Previously Treated Patients With Chronic Lymphocytic Leukemia and Sustained Patient Benefit at Four Years in the Front-line Setting

ELEVATE-RR head-to-head trial in previously treated patients showed less cardiovascular toxicity and fewer discontinuations due to adverse events for CALQUENCE versus ibrutinib

Long-term follow-up from ELEVATE-TN trial in front-line setting showed CALQUENCE maintained progression-free survival and favorable tolerability at four years

Final results from the head-to-head ELEVATE-RR Phase III trial of AstraZeneca’s CALQUENCE (acalabrutinib) demonstrated non-inferior progression-free survival (PFS) and statistically significantly fewer events of atrial fibrillation versus ibrutinib in adults with previously treated chronic lymphocytic leukemia (CLL), the most common type of leukemia in adults. 1

Separately, updated results at four years of follow-up from the ELEVATE-TN Phase III trial continued to show a strong PFS benefit for CALQUENCE as combination therapy or as monotherapy in previously untreated patients with CLL.

At a median follow-up of 40.9 months, the ELEVATE-RR trial met its primary endpoint of PFS non-inferiority versus ibrutinib with a median PFS of 38.4 months in both arms (based on a hazard ratio [HR] of 1.0, 95% confidence interval [CI] 0.79-1.27). Patients treated with CALQUENCE had a statistically significantly lower incidence of all-grade atrial fibrillation compared with patients treated with ibrutinib (9.4% versus 16.0%), a key secondary endpoint. 2 Atrial fibrillation is an irregular heart rate that can increase the risk of stroke, heart failure and other heart-related complications. 3

John C. Byrd, MD, Distinguished University Professor, The Ohio State University, and lead investigator of the ELEVATE-RR trial, said: “Cardiac adverse events are an important consideration for treating chronic lymphocytic leukemia patients with Bruton’s tyrosine kinase inhibitors because they can produce significant morbidity in some cases and also lead patients to discontinue treatment. These data provide compelling evidence that acalabrutinib is a more tolerable option with reduced cardiovascular toxicity and overall fewer discontinuations due to adverse events, giving clinicians further reassurance when prescribing this medicine that patients can stay on treatment while maintaining ongoing control of their disease.”

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: “Tolerability is a critical factor in treating patients with chronic lymphocytic leukemia who often remain on medicines for many years and experience multiple comorbidities. The totality of the CALQUENCE data at ASCO confirm our confidence in the favorable benefit-risk profile of this medicine, with over 40 months of follow-up in each of these two trials. Together, the results provide strong evidence that CALQUENCE is a preferred option for people living with this chronic and devastating disease.”

The results of both trials were presented during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting on June 7, 2021.

ELEVATE-RR: CALQUENCE versus ibrutinib in relapsed or refractory CLL

ELEVATE-RR (ACE-CL-006) is the first Phase III trial to compare two Bruton’s tyrosine kinase (BTK) inhibitors in patients with previously treated CLL with presence of 17p deletion or presence of 11q deletion. 2 The trial met the non-inferiority endpoint for PFS defined by the trial for CALQUENCE (n=268) versus ibrutinib (n=265) in patients with previously treated CLL with certain high-risk prognostic factors. 2

Patients treated with CALQUENCE had statistically significantly lower incidence of all-grade atrial fibrillation, a key secondary endpoint, compared with patients treated with ibrutinib (9.4% [n=25/266] versus 16.0% [n=42/263]; p=0.02). 2

A lower frequency of adverse events (AEs) was observed with CALQUENCE versus ibrutinib including lower common AEs, Grade 3 or higher AEs, serious AEs, treatment discontinuations due to AEs and overall cardiac events. 2 The safety and tolerability of CALQUENCE in ELEVATE-RR was consistent with the known profile of CALQUENCE .

Adverse events led to treatment discontinuation in 14.7% of patients on CALQUENCE and 21.3% of patients on ibrutinib. AEs of clinical interest for CALQUENCE versus ibrutinib included cardiac events (all grade, 24.1%, and 30.0%, respectively), bleeding events (all grade, 38.0% and 51.3%, respectively), hypertension (all grade, 9.4% and 23.2%, respectively), infections (all grade, 78.2% and 81.4%, respectively), interstitial lung disease/pneumonitis (all grade, 2.6% and 6.5%, respectively) and second primary malignancies excluding non-melanoma skin cancer (all-grade, 9.0% and 7.6%, respectively). 2 Serious AEs (any grade) occurred in 53.8% of patients on CALQUENCE versus 58.6% of patients receiving ibrutinib. 2

Median overall survival (OS) was not reached in either arm, with 63 (23.5%) patients in the CALQUENCE arm and 73 (27.5%) patients in the ibrutinib arm experiencing an event (HR of 0.82, 95% CI 0.59-1.15). 2

ELEVATE-TN: Four-year follow-up for CALQUENCE in previously untreated CLL
ELEVATE-TN (ACE-CL-007) is a randomized, multicenter, open-label Phase III trial evaluating the safety and efficacy of CALQUENCE in combination with obinutuzumab or alone versus chlorambucil in combination with obinutuzumab in previously untreated patients with CLL. 4 The trial met its primary endpoint (IRC-assessed PFS with CALQUENCE plus obinutuzumab versus chlorambucil plus obinutuzumab) at the data cut-off for the interim analysis after a median follow-up of 28.3 months. 5

After a median follow-up of 46.9 months, the ELEVATE-TN Phase III trial showed CALQUENCE plus obinutuzumab reduced the risk of disease progression or death by 90% (HR 0.10, 95% CI 0.07-0.17) and as a monotherapy by 81% (HR 0.19, 95% CI 0.13-0.28) compared with chlorambucil plus obinutuzumab. 4 Estimated PFS rates at 48 months for CALQUENCE plus obinutuzumab or as monotherapy were 87% and 78%, respectively, versus 25% for chlorambucil plus obinutuzumab. 4 PFS findings were consistent across high-risk subgroups. 4 Median PFS was not yet reached for either CALQUENCE arm at four years of follow up. Median OS was not reached in any treatment arm with a trend toward significance in the CALQUENCE plus obinutuzumab group (p=0.0604). 4

CI, confidence interval; NR, not reached; ORR, overall response rate; OS, overall survival

*Investigator-assessed.

The safety profile remained largely unchanged from the interim analysis at 24 months, with similar treatment discontinuation rates across arms (25.1%, 30.7% and 22.6% for CALQUENCE plus obinutuzumab, CALQUENCE monotherapy and chlorambucil plus obinutuzumab, respectively). 4 The most common reasons for treatment discontinuation were AEs (12.8%, 12.34% and 14.7%, respectively) and progressive disease (4.5%, 7.8% and 1.7%, respectively). 4

Selected AEs of interest of any grade in the CALQUENCE combination arm (n=178), CALQUENCE monotherapy arm (n=179) and chlorambucil plus obinutuzumab arm (n=169) included cardiac events (20.8%, 19.0% and 7.7%, respectively), bleeding (47.2%, 41.9% and 11.8%, respectively), hypertension (7.9%, 7.3% and 4.1%, respectively), infections (75.3%, 73.7% and 44.4%, respectively) and second primary malignancies (15.7%, 13.4% and 4.1%, respectively). 4

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

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 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 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.

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), dose 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.

Please see full Prescribing Information , including Patient Information .

CLL
CLL is the most common type of leukemia in adults, with an estimated 114,000 new cases globally in 2017 and 21,250 new cases in the US in 2021, and the number of people living with CLL is expected to grow with improved treatment as patients live longer with the disease. 1,6-9 In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes and these abnormal cells have difficulty fighting infections. As the number of abnormal cells grows there is less room for healthy white blood cells, red blood cells and platelets. This could result in anemia, infection and bleeding. 6 B-cell receptor signaling through BTK is one of the essential growth pathways for CLL.

ELEVATE-RR
ELEVATE-RR (ACE-CL-006) is a randomized, multicenter, open-label Phase III non-inferiority trial of CALQUENCE versus ibrutinib in patients with relapsed or refractory CLL after at least one prior therapy, and at least one of the following prognostic factors: presence of 17p deletion, or presence of 11q deletion. In the trial, 533 patients were randomized (1:1) into two arms. Patients in the first arm received CALQUENCE (100mg orally twice daily) until disease progression or unacceptable toxicity. Patients in the second arm received ibrutinib (420mg orally once daily) until disease progression or unacceptable toxicity. 2

The primary endpoint for the trial was PFS assessed by an independent review committee (non-inferiority; tested after 250 events, HR upper margin of <1.429). 2 Secondary endpoints included incidence of atrial fibrillation, incidence of Grade 3 or higher infections, incidence of Richter’s transformation (a condition in which CLL changes into an aggressive form of lymphoma) and OS. 2,10

ELEVATE-TN
ELEVATE-TN (ACE-CL-007) is a randomized, multicenter, open-label Phase III trial evaluating the safety and efficacy of CALQUENCE alone or in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab in previously untreated patients with CLL. In the trial, 535 patients were randomized (1:1:1) into three arms. Patients in the first arm received chlorambucil in combination with obinutuzumab. Patients in the second arm received CALQUENCE (100mg twice daily until disease progression) in combination with obinutuzumab. Patients in the third arm received CALQUENCE monotherapy (100mg twice daily until disease progression). 4

The primary endpoint was PFS in the CALQUENCE and obinutuzumab arm compared to the chlorambucil and obinutuzumab arm, assessed by an independent review committee (IRC), and a key secondary endpoint was IRC-assessed PFS in the CALQUENCE monotherapy arm compared to the chlorambucil and obinutuzumab arm. Other secondary endpoints included objective response rate, time to next treatment, OS and investigator-assessed PFS. 4 After interim analysis, assessments were by investigator only. 4

Initial results from the ELEVATE-TN Phase III trial were presented in December 2019 at the American Society of Hematology Annual Meeting and Exhibition. 11 The findings, along with previously reported data from the Phase III ASCEND trial in relapsed or refractory CLL, supported the approvals of CALQUENCE by the US FDA and the Australian Therapeutic Goods Administration for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL) and by the European Union and Health Canada for CLL.

CALQUENCE
CALQUENCE (acalabrutinib) is a next-generation, selective inhibitor of BTK. CALQUENCE binds covalently to BTK, thereby inhibiting its activity. 12,13 In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. 12

CALQUENCE is approved for the treatment of CLL and SLL in the US, approved for CLL in the EU and several other countries worldwide, and approved in Japan for relapsed or refractory CLL and SLL. A Phase I trial is currently underway in Japan for the treatment of front-line CLL.

In the US and several other countries, CALQUENCE is also approved for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. The US MCL 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 not currently approved for the treatment of MCL in Europe or Japan.

As part of an extensive clinical development program, AstraZeneca and Acerta Pharma are currently evaluating CALQUENCE in more than 20 company-sponsored clinical trials. CALQUENCE is being evaluated for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenström’s macroglobulinaemia, follicular lymphoma and other hematologic malignancies.

AstraZeneca in hematology
AstraZeneca is pushing the boundaries of science to redefine care in hematology. Applying our deep understanding of blood cancers and leveraging our strength in solid tumor oncology, we are driving the development of novel therapies designed to target underlying drivers of disease across six scientific platforms. By addressing blood cancers with high unmet medical needs, our aim is to deliver innovative medicines and approaches to healthcare services that have a meaningful impact on patients and caregivers, transforming the hematologic cancer care experience.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

AstraZeneca
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References

1. American Cancer Society. What is Chronic Lymphocytic Leukemia. Available online . Accessed June 2021.
2. Byrd JC, Hillmen P, Ghia P, et al. First Results of a Head-to-Head Trial of Acalabrutinib versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia. Oral presentation at: American Society for Clinical Oncology (ASCO) Annual Meeting; June 4-8, 2021; virtual. Abstract ID: 7500.
3. Mayo Clinic. Patient Care & Health Information, Diseases & Conditions - Atrial Fibrillation. Available online . Accessed June 2021.
4. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± Obinutuzumab vs Obinutuzumab + Chlorambucil in Treatment-Naïve Chronic Lymphocytic Leukemia: ELEVATE-TN 4-Year Follow-up [abstract and poster]. Presented at: American Society for Clinical Oncology (ASCO) Annual Meeting; June 4-8, 2021; virtual. Abstract ID: 7509. Accessed June 2021.
5. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE-TN): a randomised, controlled, phase 3 trial. Lancet . 2020;395:1278-1291. doi:10.1182/blood-2019-128404.
6. National Cancer Institute. Chronic Lymphocytic Leukemia Treatment (PDQ ® )–Patient Version. Available online . Accessed June 2021.
7. Global Burden of Disease Cancer Collaboration. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017. JAMA Oncol . 2019;5(12):1749-1768.
8. American Cancer Society. Cancer Facts & Figures 2021. Key Statistics for Chronic Lymphocytic Leukemia. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf . Accessed January 2021.
9. Jain N, et al. Prevalence and Economic Burden of Chronic Lymphocytic Leukemia (CLL) in the Era of Oral Targeted Therapies. Blood . 2015;126:871.5.
10. Leukaemia Foundation. Richter’s Syndrome. Available online . Accessed June 2021.
11. Sharman JP, Egyed M, Jurczak W, 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). Oral presentation at: American Society of Hematology 2019 Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.
12. CALQUENCE (acalabrutinib) [U.S. prescribing information]. Wilmington, DE; AstraZeneca Pharmaceuticals LP; 2019.
13. Wu J, Zhang M & Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016;9(21).

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