AstraZeneca Demonstrates Strength in Hematology With Robust Data at ASH 2020

Presentations support CALQUENCE efficacy and tolerability with long-term follow-up in mantle cell lymphoma and pooled safety data in chronic lymphocytic leukemia

Emerging pipeline shows promise in novel targets and mechanisms to treat resistant and aggressive blood cancers

AstraZeneca will present new research aimed at addressing key unmet needs facing patients with blood cancers at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, held virtually from 5 to 8 December 2020.

The Company will present 27 abstracts spanning five medicines and potential new medicines and eight different hematology conditions that demonstrate the Company’s commitment to advancing hematology research and treatments for patients living with hematologic malignancies.

Key data presentations include:

• A pooled analysis of data from four trials – ELEVATE TN, ASCEND, ACE-CL-001 and 15-H-0016 – expanding on the cardiovascular safety profile of CALQUENCE (acalabrutinib) monotherapy treatment for patients with chronic lymphocytic leukemia (CLL)
• Extended follow-up data from the pivotal Phase II ACE-LY-004 trial that support long-term treatment with CALQUENCE in adult patients with relapsed or refractory mantle cell lymphoma (MCL)
• Data on CALQUENCE in combination with venetoclax and either obinutuzumab or rituximab in patients with CLL, showing a safety profile consistent with previous trials with high complete responses and undetectable minimal residual disease rates after a median follow-up of 26.9 months, with minimal to no drug-drug interactions in the Phase Ib ACE-CL-003 trial
• First-in-human data from the potential new medicine B-cell maturation antigen (BCMA)-targeted antibody drug conjugate, MEDI2228, presenting data on safety and efficacy at all dose levels in relapsed or refractory multiple myeloma
• Data showing pre-clinical evidence of overcoming resistance in relapsed or refractory MCL from the dual BCL2/XL inhibitor, AZD4320, which blocks the anti-apoptotic effect of BCL2 and BCLXL
• Phase I data from the anti-inducible co-stimulator anti-ICOS monoclonal antibody, MEDI-570, demonstrating promising early clinical activity in poor-risk refractory and heavily pretreated patients with angioimmunoblastic T-cell lymphoma
• Multiple studies on roxadustat, the first in a new class of medicines evaluating its clinical effectiveness and safety profile in both the dialysis dependent and non-dialysis dependent anemia of CKD patient populations
• Data on roxadustat assessing efficacy in anemia secondary to lower-risk myelodysplastic syndrome (MDS) regardless of baseline factors. In approximately one in three patients MDS leads to acute myeloid leukemia 1

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: “Our data at ASH this year continue to support CALQUENCE as a well-tolerated treatment with impressive efficacy and safety across multiple blood cancers, reinforcing physicians’ confidence in treating patients with CALQUENCE over the long term. Data at the meeting will also explore CALQUENCE combinations with commonly used therapies, showing potential across a variety of regimens in chronic lymphocytic leukemia to best suit the unique needs of each patient.”

José Baselga, Executive Vice President, Oncology R&D, said: “As we rapidly expand our presence in hematology, we are focused on identifying novel targets and mechanisms of action that can address the most urgent unmet needs across various hematological malignancies. Our early portfolio at this year’s ASH clearly demonstrates our commitment to following the science in combating treatment-resistant and rare blood cancers.”

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 .

CALQUENCE
CALQUENCE (acalabrutinib) is a next-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK). CALQUENCE binds covalently to BTK, thereby inhibiting its activity. 2,3 In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. 2

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 developed for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenström macroglobulinemia, follicular lymphoma, and other hematologic malignancies.

Roxadustat
Roxadustat is a first in a new class of investigational medications that has the potential to promote erythropoiesis through increased endogenous production of erythropoietin; improved iron absorption, transport and mobilization; and downregulation of hepcidin, which helps to overcome the negative impact of inflammation on hemoglobin synthesis and red blood cell production. The roxadustat NDA for the treatment of anemia in CKD in both NDD and DD is under review by the US Food and Drug Administration with a decision expected in Q4 2020. Roxadustat is also in clinical development for anemia associated with myelodysplastic syndromes (MDS) and for chemotherapy-induced anemia (CIA).

AstraZeneca and FibroGen Inc. (FibroGen) are collaborating on the development and commercialization of roxadustat for the potential treatment of anemia in the US, China and other markets in the Americas and in Australia/New Zealand, as well as Southeast Asia. Astellas and FibroGen are collaborating on the development and commercialization of roxadustat for the potential treatment of anemia in territories including Japan, Europe, the Commonwealth of Independent States, the Middle East and South Africa.

AstraZeneca in hematology
Leveraging its strength in oncology, AstraZeneca has established hematology as one of four key oncology disease areas of focus. The Company’s hematology franchise includes two medicines approved by the US Food and Drug Administration and a robust global development program for a broad portfolio of potential blood cancer treatments. Acerta Pharma serves as AstraZeneca’s hematology research and development arm. AstraZeneca partners with like-minded science-led companies to advance the discovery and development of therapies to address unmet need.

AstraZeneca in oncology
AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients' lives and the Company's future. With seven new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

By harnessing the power of six scientific platforms - Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response, Antibody Drug Conjugates, Epigenetics, and Cell Therapies - and by championing the development of personalized combinations, AstraZeneca has the vision to redefine cancer treatment 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, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. 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. American Cancer Society. What Are Myelodysplastic Syndromes? Available online. Accessed October 2020.
2. CALQUENCE (acalabrutinib) [prescribing information]. Wilmington, DE; AstraZeneca Pharmaceuticals LP; 2019.
3. 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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