New Long-Term Data on CALQUENCE Presented at ASH 2018

New Long-Term Data on CALQUENCE Presented at ASH 2018

26 months median duration of response achieved in relapsed or refractory mantle cell lymphoma at updated two-year analysis

97% overall response rate in treatment-naïve chronic lymphocytic leukemia trial population at three and a half years

AstraZeneca and Acerta Pharma, its hematology research and development center of excellence, have presented new, long-term follow-up results for CALQUENCE^® (acalabrutinib) in patients with relapsed or refractory mantle cell lymphoma (MCL) and updated results of an ongoing clinical trial assessing acalabrutinib monotherapy in treatment-naïve patients with chronic lymphocytic leukemia (CLL) at the 60^th American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, CA.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer, said: “The data from these two clinical trials validate previous findings and add to the growing body of evidence that support the promise of CALQUENCE in multiple blood cancers. We are very encouraged by these results, which reinforce our commitment to advancing innovative treatments for blood cancer patients.”

CALQUENCE follow-up data in MCL confirms efficacy and tolerability

Long-term follow-up data presented from the Phase II ACE-LY-004 trial in relapsed or refractory MCL showed sustained and clinically meaningful responses to CALQUENCE with a median follow-up of more than two years (26 months), confirming its efficacy and safety profile in this patient population. Initial data from this trial served as the basis for the accelerated approval of CALQUENCE for the treatment of adult patients with MCL who have received at least one prior therapy by the US Food and Drug Administration (FDA) in October 2017.

Michael L. Wang, MD, Professor, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, and Principal Investigator of the ACE-LY-004 MCL trial, said: “It’s encouraging to see the sustained duration of response in the updated analysis and the safety profile of acalabrutinib maintained consistently over time in MCL patients. As we gain more and more experience with this therapy, its importance as a treatment option for relapsed or refractory MCL is being more fully realized across the clinical and patient community.”

Summary of key investigator-assessed^a efficacy results from the open-label, single-arm clinical trial of CALQUENCE in 124 adult patients with relapsed or refractory MCL:

^a Response was assessed based on the Lugano classification.
^b Confidence interval (CI).
^c Includes patients without any adequate post-baseline disease assessment.

The median follow-up was 26 months, with 40% of patients remaining on treatment with CALQUENCE at the time of analysis. An exploratory analysis of the trial found that an undetectable minimal residual disease status was achieved in a sub-set of patients.

In this trial, the most frequent adverse events (AEs ? 20%, all grades) were headache (38%), diarrhea (36%), fatigue (28%), cough (22%) and myalgia (21%). These events were primarily Grade 1/2. Grade 3/4 AEs (reported ? 5%) were anemia (11%), neutropenia (11%) and pneumonia (6%). There were 13 patients (10%) with 16 cardiac events including four Grade 3/4 events, each in one patient (acute coronary syndrome, acute myocardial infarction, cardiorespiratory arrest, coronary artery disease). There was no new onset of atrial fibrillation. Bleeding events occurred in 33% of patients, most frequently contusion (13%) and petechiae (9%); and all bleeding events but three (2%, Grade 3) were Grade 1/2 events. Ten patients discontinued treatment due to AEs. In total there were six deaths due to AEs (none of which were considered to be related to CALQUENCE).

New data from ongoing CLL clinical trial demonstrate strong efficacy

Updated results of the Phase I/II ACE-CL-001 trial were presented today in an oral session. In a cohort of treatment-naïve patients with CLL, a long-term safety and efficacy assessment showed high response rates with no new safety signals identified. The median time on trial was 42 months, with 89% of patients remaining on treatment with acalabrutinib at the time of analysis.

John C. Byrd, MD, Distinguished University Professor, The Ohio State University, and Principal Investigator for the ACE-CL-001 CLL clinical trial, said: “A key challenge in the treatment of CLL is ensuring patients have therapies that they can tolerate and benefit from over the long term. The results seen in this patient cohort at 3.5 years of follow-up are encouraging for both durability of response and tolerability of therapy. We look forward to continued data from ongoing studies evaluating acalabrutinib in CLL.”

Summary of key investigator-assessed^a efficacy results from the Phase I/II open-label, single-arm ACE-CL-001 acalabrutinib trial in 99 patients with CLL, evaluating the treatment-naïve cohort:

^a Response was assessed using International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria with modification for lymphocytosis.
^b Only responders with ? partial response were included in this analysis.
^c Not reached (NR).
^d Confidence interval (CI).
^e Based on the Kaplan-Meier estimates.

In this trial, the most common AEs (? 20%, all grades) were diarrhea (49%), headache (44%), upper respiratory tract infection (40%), contusion (39%), arthralgia (33%), weight increased (31%), nausea (30%) and cough (23%). Grade 3/4 AEs (reported ? 5%) were neutropenia (8%), hypertension (7%), diarrhea (5%) and headache (5%). Atrial fibrillation and hypertension (all grades) occurred in 6% and 17% of patients, respectively, with Grade 3 events occurring in 2% and 7% of patients. Bleeding events (all grades) occurred in 64% of patients with contusion being most common (39%). All but three (3% Grade 3) bleeding events were Grade 1/2 events and no patients discontinued due to bleeding. Overall, 11% of patients discontinued treatment, 5% of which were due to AEs, including secondary malignancies (angiosarcoma, glioblastoma multiforme, small cell lung cancer), sepsis (Grade 4) and urinary tract infection (Grade 3). One Grade 5 event (multiorgan failure) in the setting of pneumonia was reported, which was considered unrelated to acalabrutinib.

IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE (acalabrutinib)

Hemorrhage

Serious hemorrhagic events, including fatal events, have occurred in the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy. Grade 3 or higher bleeding events, including gastrointestinal, intracranial, and epistaxis, have been reported in 2% of patients. Overall, bleeding events, including bruising and petechiae of any grade, occurred in approximately 50% of patients with hematological malignancies.

The mechanism for the bleeding events is not well understood.

CALQUENCE may further increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies, and patients should be monitored for signs of bleeding.

Consider the benefit-risk of withholding CALQUENCE for 3 to 7 days pre- and post-surgery, depending upon the type of surgery and the risk of bleeding.

Infection

Serious infections (bacterial, viral, or fungal), including fatal events and opportunistic infections, have occurred in the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy. Grade 3 or higher infections occurred in 18% of these patients. The most frequently reported Grade 3 or 4 infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy (PML) have occurred.

Monitor patients for signs and symptoms of infection and treat as medically appropriate. Consider prophylaxis in patients who are at increased risk for opportunistic infections.

Cytopenias

In the combined safety database of 612 patients with hematologic malignancies, patients treated with CALQUENCE monotherapy experienced Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (11%), and thrombocytopenia (8%), based on laboratory measurements. Monitor complete blood counts monthly during treatment.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinomas, have occurred in 11% of patients with hematologic malignancies treated with CALQUENCE monotherapy in the combined safety database of 612 patients. The most frequent second primary malignancy was skin cancer, reported in 7% of patients. Advise protection from sun exposure.

Atrial Fibrillation and Flutter

In the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy, atrial fibrillation and atrial flutter of any grade occurred in 3% of patients, and Grade 3 in 1% of patients. Monitor for atrial fibrillation and atrial flutter and manage as appropriate.

ADVERSE REACTIONS

The most common adverse reactions (?20%) of any grade were anemia,* thrombocytopenia,* headache (39%), neutropenia,* diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%).

*Treatment-emergent decreases (all grades) of hemoglobin (46%), platelets (44%), and neutrophils (36%) were based on laboratory measurements and adverse reactions.

The most common Grade ? 3 non-hematological adverse reaction (reported in at least 2% of patients) was diarrhea (3.2%).

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 twice daily.

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

There is insufficient clinical data on CALQUENCE use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Advise women of the potential risk to a fetus.

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.

Please see complete Prescribing Information including Patient Information.

NOTES TO EDITORS

About CALQUENCE (acalabrutinib)

CALQUENCE^® (acalabrutinib) is an inhibitor of Bruton tyrosine kinase (BTK). CALQUENCE binds covalently to BTK, thereby inhibiting its activity. In B cells, BTK signaling results in activation of pathways necessary for B cell proliferation, trafficking, chemotaxis, and adhesion.

CALQUENCE was granted accelerated approval by the US Food and Drug Administration (FDA) in October 2017 for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. CALQUENCE is not currently licensed for the treatment of chronic lymphocytic leukemia (CLL).

Acalabrutinib was granted Orphan Drug Designation for the treatment of patients with CLL, MCL and Waldenström macroglobulinemia in 2015, and Breakthrough Therapy Designation in August 2017 by the US FDA for the treatment of patients with MCL who have received at least one prior therapy.

About Mantle Cell Lymphoma (MCL)

MCL is a rare type of B-cell non-Hodgkin lymphoma (NHL). MCL accounts for approximately 3% of new NHL cases in the US, with approximately 3,300 new cases of MCL diagnosed in the US each year. The median age at diagnosis is 68 years, with MCL occurring more than twice as often in men than women. While MCL patients initially respond to treatment, there is a high relapse rate.

About Chronic Lymphocytic Leukemia (CLL)

CLL is the most common type of leukemia in adults and accounts for approximately one in four cases of leukemia. The average age at the time of diagnosis is approximately 70 years of age. 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. B cell receptor signaling through BTK is one of the essential growth pathways for CLL.

About 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 US FDA-approved medicines 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 center of excellence. AstraZeneca partners with like-minded science-led companies to advance the discovery and development of therapies to address unmet need.

In October 2018, AstraZeneca and Innate Pharma announced a global strategic collaboration that included Innate Pharma licensing the US commercial rights of LUMOXITI™ (moxetumomab pasudotox-tdfk), and with support from AstraZeneca, will continue EU development and commercialization, pending regulatory submission and approval.

About 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 at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as a key growth driver focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by our investment in Acerta Pharma in hematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – 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 Acerta Pharma

Acerta Pharma, a member of the AstraZeneca Group, is creating novel therapies intended for the treatment of cancer and autoimmune diseases. AstraZeneca acquired a majority stake interest in Acerta Pharma, which serves as AstraZeneca’s hematology research and development center of excellence. For more information, please visit www.acerta-pharma.com.

About MedImmune

MedImmune is the global biologics research and development arm of AstraZeneca, a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialization of small molecule and biologic prescription medicines. MedImmune is pioneering innovative research and exploring novel pathways across Oncology, Respiratory, Cardiovascular, Renal and Metabolic Diseases, and Infection and Vaccines. The MedImmune headquarters is located in Gaithersburg, MD, one of AstraZeneca’s three global R&D centers, with additional sites in Cambridge, UK and South San Francisco, CA. For more information, please visit www.medimmune.com.

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.

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