CALQUENCE® Data To Show Improved Progression-Free Survival In Phase III Front-Line Chronic Lymphocytic Leukemia At ASH 2019 Annual Meeting

Robust early-stage pipeline advancements and presentations across multiple scientific platforms demonstrate potential to improve treatment outcomes in blood cancers with high unmet need

WILMINGTON, Del.–(BUSINESS WIRE)–AstraZeneca will present the first data from the Phase III ELEVATE-TN trial assessing CALQUENCE^® (acalabrutinib), a next-generation selective Bruton’s tyrosine kinase (BTK) inhibitor, in patients with previously untreated chronic lymphocytic leukemia (CLL), as well as data from novel-combination trials across multiple blood cancers at the 2019 American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, USA, December 7-10.

The Company will present over 30 abstracts, including seven oral presentations, in CLL, mantle cell lymphoma (MCL), acute myeloid leukemia (AML), diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Key data include:

• The first presentation of data from the pivotal Phase III ELEVATE-TN trial evaluating CALQUENCE in combination with obinutuzumab and CALQUENCE monotherapy versus obinutuzumab combined with chlorambucil chemotherapy in previously untreated CLL
• Long-term efficacy, safety and tolerability data on CALQUENCE in relapsed or refractory CLL from the Phase I/II ACE-CL-001 trial
• First-time data on roxadustat as a potential new treatment for anemia in patients with primary myelodysplastic syndromes (MDS)

Dave Fredrickson, Executive Vice President, Oncology Business Unit said: “AstraZeneca continues to demonstrate its strength in hematology, presenting new research at ASH that spans targeted therapies across eight blood cancers. This year we are especially excited to present the ELEVATE-TN data demonstrating the impressive efficacy and tolerability of CALQUENCE in 1st-line chronic lymphocytic leukemia.”

Key headline data from the CALQUENCE Phase III ELEVATE-TN trial
Efficacy measure		CALQUENCE plus obinutuzumab N = 179		CALQUENCE monotherapy N = 179		Obinutuzumab plus chlorambucil N = 177
Stratified analysis, median follow-up 28 months
Hazard ratio for PFS endpoint (vs. obinutuzumab + chlorambucil), stratified analysis		HR 0.10 (primary endpoint) 95% CI 0.06–0.17, p<0.0001 median not reached		HR 0.20 (secondary endpoint) 95% CI 0.13–0.30, p<0.0001 median not reached		n/a median 22.6 months

Select adverse events (AEs) include infusion reactions, which were less frequent with CALQUENCE plus obinutuzumab (13%) than with obinutuzumab plus chlorambucil (40%). Additionally, AEs led to treatment discontinuation in 12% of patients on CALQUENCE plus obinutuzumab, 9% of patients on CALQUENCE, and 14% of patients on obinutuzumab plus chlorambucil. With >2 y of follow-up, 79% of patients in both the CALQUENCE-containing arms remain on CALQUENCE as monotherapy. Other select AEs (CALQUENCE plus obinutuzumab or CALQUENCE vs chlorambucil plus obinutuzumab) included atrial fibrillation (any grade: 3% or 4% vs. 1%), bleeding (any grade/Grade ≥3: 43%/2% or 39%/2% vs. 12%/0%), and hypertension (Grade ≥3: 3% or 2% vs. 3%).

Full data from the ELEVATE-TN trial will be presented at ASH by the primary investigators. AstraZeneca has submitted CALQUENCE for US regulatory review in 1st-line and relapsed/refractory CLL.

Raising the bar for CLL treatment outcomes with CALQUENCE

In addition to the oral presentation on the ELEVATE-TN results, key presentations include:

• An oral presentation on preliminary data from a Phase II investigator-initiated trial evaluating CALQUENCE combined with obinutuzumab and venetoclax in patients with previously untreated CLL, including high-risk disease status and a trial-in-progress poster detailing an ongoing Phase III trial to evaluate this novel combination in patients with previously untreated CLL without del(17p) or TP53 mutation.
• Long-term (42-month) follow-up results from the Phase I/II ACE-CL-001 trial confirming CALQUENCE initial efficacy from this trial for the treatment of relapsed or refractory CLL and providing additional data on duration of response and long-term tolerability.

Exploring a potential treatment option for a challenging comorbidity in blood cancer

• An oral presentation on first-time data from a global Phase III trial evaluating roxadustat to treat anemia in patients with primary MDS. Considered a type of cancer, MDS is a group of diverse bone marrow disorders in which the bone marrow does not produce enough healthy blood cells. Approximately one in three MDS patients can progress to AML.

Exploring potential new medicines from the pipeline and new treatment strategies for aggressive or treatment-resistant blood cancers

• In AML, an oral presentation and four poster presentations, including results from an IMFINZI^® (durvalumab) and azacitidine combination for the 1st-line treatment of older, chemotherapy-ineligible patients and data from a Phase I/II clinical trial of AZD2811(nanoparticles), as a monotherapy or in combination with azacitidine in previously untreated or relapsed/refractory patients who are not eligible for intensive induction therapy.
• In DLBCL, five abstracts, including a poster presentation detailing the ongoing Phase I PRISM trial of CALQUENCE in four different combinations with potential new medicines targeting STAT3, ATR, CD47 and BRD4.
• In MM, three poster presentations, including results of a Phase I trial of MEDI2228, a BCMA antibody-PBD conjugate and potential new medicine, as a monotherapy and in combinations with bortezomib and DNA damage response medicines and results from an in vitro trial of AZD4785 alone or with proteasome inhibitors targeting mutant KRAS.

Key AstraZeneca presentations at ASH 2019
Lead author		Abstract title		Presentation details
Chronic lymphocytic leukemia
Sharman, J.		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 Saturday 7 December 07:30 ET Orange County Convention Center, Hall D
Lampson, BL.		Preliminary Safety and Efficacy Results from a Phase 2 Study of Acalabrutinib, Venetoclax and Obinutuzumab in Patients with Previously Untreated Chronic Lymphocytic Leukemia (CLL)		Oral Presentation Saturday 7 December 07:45 ET Orange County Convention Center, Hall D
Frei, CR.		Treatment Patterns and Outcomes of 1205 Patients on Novel Agents in the US Veterans Health Administration (VHA) System: Results from the Largest Retrospective EMR and Chart Review Study in the Real-World Setting		Oral Presentation Monday 9 December 15:15 ET Orange County Convention Center, Valencia A (W415A)
Goyal, RK.		Overall Survival, Adverse Events, and Economic Burden in Medicare Patients with Chronic Lymphocytic Leukemia Receiving Cancer-Directed Therapy		Oral Presentation Monday 9 December 15:15 ET Orange County Convention Center, Valencia A (W415A)
Furman, RR.		Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: long-term follow-up of a phase 2 study		Poster Presentation Sunday 8 December 18:00 to 20:00 ET Orange County Convention Center, Hall B
Brown, JR.		A Phase 3 Trial Comparing the Efficacy and Safety of Acalabrutinib in Combination with Venetoclax with or without Obinutuzumab, Compared with Investigator’s Choice of Chemoimmunotherapy in Patients with Previously Untreated Chronic Lymphocytic Leukemia (CLL) without del(17p) or TP53 Mutation		Poster Presentation Monday 9 December 18:00 to 20:00 ET Orange County Convention Center, Hall B
Mantle cell lymphoma
Kabadi, S.		Overall Survival, Adverse Events, and Economic Burden in Medicare Patients with Mantle Cell Lymphoma Receiving Cancer-Directed Therapy		Oral Presentation Saturday 7 December 08:00 ET Orange County Convention Center, W308
Ryan, K.		Characteristics of Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL) Patients Treated with Acalabrutinib in a Real World Setting in the United States		Poster Presentation Sunday 8 December 18:00 to 20:00 ET Orange County Convention Center, Hall B
Acute myeloid leukemia
Zeidan, A.		Efficacy and Safety of Azacitidine (AZA) in Combination with the Anti-PD-L1 Durvalumab (durva) for the Front-line Treatment of Older Patients (pts) with Acute Myeloid Leukemia (AML) Who Are Unfit for Intensive Chemotherapy (IC) and Pts with Higher-Risk Myelodysplastic Syndromes (HR-MDS): Results from a Large, International, Randomized Phase 2 Study		Oral Presentation Monday 9 December 16:30 ET Orange County Convention Center, Chapin Theater (W320)
Donnellan, W.		A Phase I/II study of AZD2811NP as monotherapy or in combination in treatment-naïve or R/R AML/MDS patients not eligible for intensive induction therapy		Poster Presentation Monday 9 December 18:00 to 20:00 ET Orange County Convention Center, Hall B
Diffuse large B-cell lymphoma
Roschewski, M.		A platform protocol for the treatment of relapsed/refractory aggressive Non-Hodgkin’s Lymphoma		Poster Presentation Sunday 8 December 18:00 to 20:00 ET Orange County Convention Center, Hall B
Moskowitz, CH.		Safety and Antitumor Activity Study of Loncastuximab Tesirine and Durvalumab in Diffuse Large B-Cell, Mantle Cell, or Follicular Lymphoma
Multiple myeloma
Xing, L.		Anti-BCMA PBD MEDI2228 combats drug resistance and synergizes with bortezomib and inhibitors to DNA damage response in multiple myeloma: further therapeutic implication		Poster Presentation Saturday 7 December 17:30 to 19:30 ET Orange County Convention Center, Hall B
Sacco, A.		Specific targeting of KRAS using a novel high-affinity KRAS antisense oligonucleotide in myeloma		Poster Presentation Sunday 8 December 18:00 to 20:00 ET Orange County Convention Center, Hall B
Xing, L.		MEDI2228, a novel BCMA antibody-PBD conjugate, sensitizes human multiple myeloma cells to NK cell-mediated cytotoxicity and upregulates CD38 expression in MM cells: further clinical implication		Poster Presentation Sunday 8 December 18:00 to 20:00 ET Orange County Convention Center, Hall B
Primary MDS-induced anemia
Henry, D.		Roxadustat (FG4592; ASP1517; AZD9941) in the Treatment of Anemia in Patients with Lower Risk Myelodysplastic Syndrome (LR-MDS) and Low Red Blood Cell (RBC) Transfusion Burden (LTB)		Oral Presentation Monday 9 December 16:30 to 18:00 ET Orange County Convention Center, W311ABCD

Indication and Usage for CALQUENCE^® (acalabrutinib)

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 trial.

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.

– ENDS –

NOTES TO EDITORS

About ELEVATE-TN

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, a CD20 monoclonal antibody, or CALQUENCE alone vs. chlorambucil, a chemotherapy, 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 or unacceptable toxicity) in combination with obinutuzumab. Patients in the third arm received CALQUENCE monotherapy (100mg twice daily until disease progression or unacceptable toxicity).

The primary endpoint is progression-free survival (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 is IRC-assessed PFS in the CALQUENCE monotherapy arm compared to the chlorambucil and obinutuzumab arm. Other secondary endpoints include objective response rate, time to next treatment and overall survival.

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 arm. AstraZeneca partners with like-minded science-led companies to advance the discovery and development of therapies to address unmet need.

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 one of AstraZeneca’s four Growth Platforms 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 the 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 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 and 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.

US-34759 Last Updated 11/19

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