CALQUENCE reduced the risk of disease progression or death by 71% vs. standard of care combinations at three years in the ASCEND Phase III trial

ELEVATE-RR head-to-head trial data also presented at ASH showed patients on ibrutinib experienced a 37% higher burden of adverse events of any grade while on treatment vs. patients on CALQUENCE

Updated results from the ASCEND Phase III trial showed AstraZeneca’s CALQUENCE^® (acalabrutinib) maintained a statistically significant progression-free survival (PFS) benefit at three years compared to investigator’s choice of rituximab combined with either idelalisib (IdR) or bendamustine (BR) in adults with relapsed or refractory chronic lymphocytic leukemia (CLL), the most common type of leukemia in adults.^1,2

These data, presented at the 63^rd American Society of Hematology (ASH) Annual Meeting & Exposition, demonstrated CALQUENCE reduced the risk of disease progression or death by 71% versus IdR/BR as assessed by investigators at three years (based on a hazard ratio [HR] of 0.29; 95% confidence interval [CI]: 0.21-0.41; p<0.0001). Similar clinical benefits were observed in an exploratory analysis comparing each regimen with CALQUENCE. Safety and tolerability of CALQUENCE were consistent with earlier findings, with no new safety signals identified.¹

Additional safety analyses from the ELEVATE-RR Phase III trial were also presented at ASH to further characterize adverse events (AEs) related to treatment with Bruton’s tyrosine kinase (BTK) inhibitors CALQUENCE and ibrutinib. Overall, patients on ibrutinib experienced a 37% higher burden of AEs of any grade versus patients on CALQUENCE.³

For any grade atrial fibrillation/flutter, a key secondary endpoint in the ELEVATE-RR Phase III trial, median time to onset was longer for CALQUENCE versus ibrutinib (28.8 versus 16.0 months), and cumulative incidence was lower at all timepoints from six months through two years.³

Additionally, the ELEVATE-RR Phase III trial showed incidence of all-grade atrial fibrillation/flutter was lower for CALQUENCE across subgroups of age, prior line of therapy and among patients without prior history of heart complications.³ Atrial fibrillation is an irregular heart rate that can increase the risk of stroke, heart failure and other heart-related complications.⁴

John F. Seymour, MBBS PhD, Peter MacCallum Centre and the Royal Melbourne Hospital, and a lead investigator on the ELEVATE-RR trial, said: “Patients with relapsed or refractory chronic lymphocytic leukemia face limited options to successfully manage their disease, as they are often older and dealing with significant comorbidities. The risk of cardiac adverse events is an important consideration, especially for treatment with Bruton’s tyrosine kinase inhibitors because they can produce significant morbidity in some cases and also lead patients to discontinue treatment. The ELEVATE-RR data provide compelling evidence that acalabrutinib is a more tolerable option with reduced cardiovascular toxicity, giving clinicians further reassurance when prescribing this medicine that fewer patients will need to cease treatment due to adverse events, thus maintaining ongoing control of their disease, even in this complex setting.”

Anas Younes, Senior Vice President, Haematology R&D, AstraZeneca, said: “These impressive new long-term data support CALQUENCE as the preferred therapy for the most common type of leukemia in adults, with favorable safety compared to the current standards of care. The totality of the ASCEND and ELEVATE-RR data, in addition to data introducing a new tablet formulation for patients who need alternative methods of taking CALQUENCE, continues to reinforce the positive experience that this medicine can deliver for patients with chronic lymphocytic leukemia.”

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.

Notes

ASCEND: Three-year follow-up data for CALQUENCE in relapsed or refractory CLL (abstract #393)

ASCEND is a global, randomized, multicenter, open-label, Phase III trial that evaluated the efficacy and safety of CALQUENCE (100mg twice-daily until disease progression or unacceptable toxicity) versus investigator’s choice of IdR or BR in patients with relapsed or refractory CLL.^1,5 ASCEND is the first randomized trial to directly compare a BTK inhibitor as monotherapy with standard chemoimmunotherapy or idelalisib and rituximab combinations.

Summary of ASCEND results¹

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

*Investigator-assessed

AEs led to treatment discontinuation in 21% of patients on CALQUENCE, 65% of patients on IdR and 17% of patients on BR. Events of clinical interest for CALQUENCE versus comparators included atrial fibrillation/flutter (all grade, 6% and 3%, respectively), hypertension (all grade, 7% and 4%), major hemorrhage (all grade, 3% in both arms), infections (Grade ≥3, 25% and 27%, respectively) and second primary malignancies excluding non-melanoma skin cancer (all grade, 7% and 3%, respectively). Serious AEs (any-grade) occurred in 38% of patients treated with CALQUENCE, 63% of IdR patients and 26% of BR patients.¹

ELEVATE-RR: Additional safety analyses of CALQUENCE versus ibrutinib in relapsed or refractory CLL (abstract #3721)

Results from the ELEVATE-RR Phase III trial were first presented on 7 June 2021 at the American Society of Clinical Oncology (ASCO) Annual Meeting and published in the Journal of Clinical Oncology on 26 July 2021.

Additional safety data were used to characterize BTK inhibitor-related AEs, using measures of frequency, duration and drug exposure (versus incidence alone) to measure AE burden. Median treatment exposures were 38.3 months in the CALQUENCE arm and 35.5 months in the ibrutinib arm.³

For any-grade hypertension, median time to onset was similar for CALQUENCE and ibrutinib (8.1 months versus 7.0), but cumulative incidence was lower for CALQUENCE at 6 months (5% versus 12%), 12 months (6% versus 16%), 18 months (8% versus 20%) and 24 months (8% versus 23%). Hypertension also occurred less frequently with CALQUENCE versus ibrutinib in subgroups of age, prior line of therapy and among patients without prior history.³

Among cardiovascular AEs of clinical interest, incidences of any-grade atrial fibrillation/flutter, hypertension and bleeding were statistically higher with ibrutinib versus CALQUENCE, with higher exposure-adjusted incidence (2.0-, 2.8-, and 1.6-fold, respectively) and exposure-adjusted time with event (2.8-, 3.7-, and 1.8-fold).³

CLL

CLL is the most common type of leukemia in adults, with an estimated 114,000 new cases globally in 2017, and the number of people living with CLL is expected to grow with improved treatment as patients live longer with the disease.^2,6-8

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.

ASCEND

ASCEND (ACE-CL-309) is a global, randomized, multicenter, open-label Phase III trial evaluating the efficacy of CALQUENCE in patients with relapsed or refractory CLL.^5,9

In the trial, 310 patients were randomized (1:1) into two treatment arms. Patients in the first arm received CALQUENCE monotherapy (100mg twice-daily until disease progression or unacceptable toxicity). Patients in the second arm received physician’s choice of either rituximab, a CD20 monoclonal antibody, in combination with idelalisib, a PI3-kinase inhibitor, or rituximab in combination with bendamustine, a chemotherapy.⁹

The primary endpoint at the interim analysis was PFS assessed by an Independent Review Committee (IRC), and key secondary endpoints included investigator-assessed PFS, IRC- and investigator-assessed overall response rate and duration of response, as well as overall survival, patient-reported outcomes and time to next treatment.

ASCEND is the first randomized Phase III trial to directly compare a BTK inhibitor as monotherapy to these combinations in relapsed or refractory CLL.^5,9

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.^10,11

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).¹¹

The primary endpoint for the trial was IRC-assessed PFS (non-inferiority; tested after 250 events, upper margin of 95% CI for HR<1.429). 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 lymphoma¹²) and OS.¹¹

ELEVATE-RR is the first randomized Phase III trial to directly compare two BTK inhibitors as monotherapy in relapsed or refractory CLL.

CALQUENCE

CALQUENCE (acalabrutinib) is a next-generation, selective inhibitor of BTK. CALQUENCE binds covalently to BTK, thereby inhibiting its activity.^13,14 In B cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion.¹³

CALQUENCE is approved for the treatment of CLL and small lymphocytic lymphoma (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 macroglobulinemia, 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.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

References

1. Jurczak W, Pluta A, Wach M, et al. Three-Year Follow-Up of the ASCEND Trial: Acalabrutinib vs Rituximab Plus Idelalisib or Bendamustine in Relapsed/Refractory Chronic Lymphocytic Leukemia [abstract]. Presented at: American Society of Hematology (ASH) Annual Meeting and Exposition; December 11-14, 2021; Atlanta, Georgia. Abs 393.

2. American Cancer Society. What is Chronic Lymphocytic Leukemia. Available online. Accessed December 2021.

3. Seymour JF, Byrd J, Hillmen P, et al. Characterization of Bruton Tyrosine Kinase Inhibitor (BTKi)-Related Adverse Events in a Head-to-Head Trial of Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia (CLL) [abstract and poster]. Presented at: ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, Georgia. Abs 3721.

4. Mayo Clinic. Patient Care & Health Information, Diseases & Conditions - Atrial Fibrillation. Available online. Accessed December 2021.

5. AstraZeneca. A Study of Acalabrutinib vs Investigator's Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in R/R CLL. ClinicalTrials.gov website. Available online. Accessed December 2021.

6. National Cancer Institute. Chronic Lymphocytic Leukemia Treatment (PDQ^®)–Patient Version. Available online. Accessed December 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. Jain N, Chen T, Ayer T, et al. Prevalence and Economic Burden of Chronic Lymphocytic Leukemia (CLL) in the Era of Oral Targeted Therapies. Blood. 2015; 126:871.

9. Ghia P, Pluta A, Wach M, et al. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia [published online ahead of print, 2020 May 27]. J Clin Oncol. 2020;38(25):2849-2861.

10. AstraZeneca. Study of Acalabrutinib (ACP-196) Versus Ibrutinib in Previously Treated Subjects With High Risk CLL. Clinicaltrials.gov website. Available online. Accessed December 2021.

11. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. J Clin Oncol. 2021;39(31):3441-3452.

12. Leukaemia Foundation. Richter’s Syndrome. Available online. Accessed December 2021.

13. CALQUENCE^® (acalabrutinib) [prescribing information]. Wilmington, DE; AstraZeneca Pharmaceuticals LP; 2019.

14. Wu J, Zhang M, Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016;9(21).

US-60413 Last Updated 12/21

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