On November 27, 2018 AstraZeneca, together with Acerta Pharma, its hematology research and development center of excellence, and MedImmune, its global biologics research and development arm, reported that it will present 27 abstracts, including six oral presentations, at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in San Diego, CA, December 1-4 (Press release, AstraZeneca, NOV 27, 2018, View Source [SID1234531643]).
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New data include presentations on CALQUENCE (acalabrutinib) and LUMOXITI (moxetumomab pasudotox-tdfk), as well as research findings from AstraZeneca’s early pipeline, across a variety of blood cancers.
Dave Fredrickson, Executive Vice President, Head of Oncology Business Unit, said: "In less than a year, we have launched two innovative medicines to treat blood cancers. At this year’s ASH (Free ASH Whitepaper), we will continue our momentum by presenting new results from two important trials of CALQUENCE in mantle cell lymphoma and chronic lymphocytic leukemia, and further showcase our broad pipeline with data from our novel MCL1 and CDK9 inhibitors."
Updated results for acalabrutinib in chronic lymphocytic leukemia (CLL)
An oral presentation will focus on new three-year follow-up efficacy and safety results (median 33 months) from the ongoing Phase I/II ACE-CL-001 clinical trial, assessing acalabrutinib monotherapy in a cohort of treatment-naive patients with CLL (Abstract #692).
These data expand on findings previously reported and highlight the promising overall and durable response rates and safety profile in this patient population. Trial data continue to be collected and analyzed.
New long-term CALQUENCE data in previously-treated mantle cell lymphoma (MCL)
Long-term follow up data (median 26.3 months) being presented for CALQUENCE further confirm results from the registrational Phase II ACE-LY-004 clinical trial in relapsed or refractory MCL (Abstract #2876). Initial analysis of 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.
New data from recently approved LUMOXITI
Results will be presented from trials of LUMOXITI in relapsed or refractory hairy cell leukemia which evaluated whether minimal residual disease eradication, as measured by different quantitative testing approaches, is associated with improved complete response duration (Abstract #1861).
Early pipeline offers new insights into MCL1 inhibition and resistance
New data from AstraZeneca’s early hematology pipeline will be presented, including four oral presentations, on different potential new medicines across multiple blood cancers. The presentations feature new insights into the therapeutic potential of inhibiting the anti-apoptotic protein, myeloid cell leukemia-1 (MCL1) target.
Key pipeline data that will be presented includes preclinical activity of the novel MCL1 inhibitor AZD5991 in multiple myeloma (Abstract #952), findings on the potential to overcome MCL1 resistance in multiple myeloma (Abstract #472), and data on the influence of myeloma patient-derived MCL1 point mutations in MCL1-inhibitor function (Abstract #951). Data will also be presented on MCL1/CDK9 targeting by AZD5991 and the CDK9 inhibitor AZD4573 (Abstract #768).
Key AstraZeneca, Acerta and MedImmune presentations at ASH (Free ASH Whitepaper) 2018:
Lead author Title Presentation details
Acalabrutinib
Wang, M
Long-Term Follow-Up of
Acalabrutinib Monotherapy in
Patients With Relapsed/Refractory
Mantle Cell Lymphoma
Poster session
Sunday, December 2, 6:00-8:00 PM
Location: San Diego Convention
Center, Hall GH
Abstract #2876
Byrd, J
Acalabrutinib in Treatment-Naïve
(TN) Chronic Lymphocytic
Leukemia (CLL): Updated Results
from the Phase 1/2 ACE-CL-001
Study
Oral session
Monday, December 3
Presentation time: 10:45 AM
Location: San Diego Convention
Center, Ballroom 20A
Abstract #692
Kabadi, S
Real World Treatment Patterns,
Adverse Events and Healthcare
Resource Utilization and Costs
Among Chronic Lymphocytic
Leukemia (CLL) Patients in the
United States
Oral session
Monday, December 3
Presentation time: 3:15 PM
Location: San Diego Convention
Center, Room 25B
Abstract #837
Moxetumomab pasudotox
Arons, E
Molecular Remissions with Anti-
CD22 Recombinant Immunotoxin
Moxetumomab Pasudotox are
Associated with Improved
Complete Remission Durations
During Phase I and III Testing
Poster session
Saturday December 1, 6:15-8:15 PM
Location: San Diego Convention
Center, Hall GH
Abstract #1861
Early pipeline
Siu, K
Overcoming MCL1 Resistance in
Multiple Myeloma
Oral session
Sunday, December 2
Presentation time: 5:15 PM
Location: Marriott Marquis San
Diego Marina, Grand Ballroom 7
Abstract #472
Carter, B
MCL-1/CDK9 Targeting by
AZD5991/AZD4573 Overcomes
Intrinsic and Acquired Venetoclax
Resistance in Vitro and in Vivo in PDX
Model of AML Through
Modulation of Cell Death and
Novel Metabolic Functions
Oral session
Monday, December 3
Presentation time: 4:00 PM
Location: Manchester Grand Hyatt
San Diego, Seaport Ballroom F
Abstract #768
Chen, B
Myeloma Patient-Derived MCL1
Point Mutations can Influence
MCL1-Inhibitor Function
Oral session
Monday, December 3
Presentation time: 5:00 PM
Location: San Diego Convention
Center, Ballroom 20D
Abstract #951
Matulis, S
Preclinical Activity of Novel MCL1
Inhibitor AZD5991 in Multiple
Myeloma
Oral session
Monday, December 3
Presentation time: 5:15 PM
Location: San Diego Convention
Center, Ballroom 20D
Abstract #952
CALQUENCE (acalabrutinib) Important Safety Information
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.
INDICATIONS
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.
Please see complete Prescribing Information including Patient Information.
LUMOXITI (moxetumomab pasudotox-tdfk) Important Safety Information, INCLUDING BOXED WARNING
WARNING: CAPILLARY LEAK SYNDROME and HEMOLYTIC UREMIC SYNDROME
Capillary Leak Syndrome (CLS), including life-threatening cases, occurred in patients receiving LUMOXITI. Monitor weight and blood pressure; check labs, including albumin, if CLS is suspected. Delay dosing or discontinue LUMOXITI as recommended
Hemolytic Uremic Syndrome (HUS), including life-threatening cases, occurred in patients receiving LUMOXITI. Monitor hemoglobin, platelet count, serum creatinine, and ensure adequate hydration. Discontinue LUMOXITI in patients with HUS
WARNINGS AND PRECAUTIONS
Capillary leak syndrome (CLS), including life-threatening cases, has been reported among patients treated with LUMOXITI and is characterized by hypoalbuminemia, hypotension, symptoms of fluid overload, and hemoconcentration. In the combined safety database of HCL patients treated with LUMOXITI, CLS occurred in 34% (44/129) of patients, including Grade 2 in 23% (30/129), Grade 3 in 1.6% (2/129), and Grade 4 in 2% (3/129).
Most cases of CLS occurred in the first 8 days (range: 1 to 19) of a treatment cycle, however, cases have also been reported on other days throughout the cycle. The median time to resolution of CLS was 12 days (range: 1 to 53).
Monitor patient weight and blood pressure prior to each LUMOXITI infusion and as clinically indicated during treatment. Assess patients for signs and symptoms of CLS, including weight gain (increase in 5.5 pounds (2.5 kg) or ≥ 5% from Day 1 of current cycle), hypotension, peripheral edema, shortness of breath or cough, and pulmonary edema and/or serosal effusions. In addition, the following changes in laboratory parameters may help identify CLS: hypoalbuminemia, elevated hematocrit, leukocytosis, and thrombocytosis.
CLS may be life-threatening or fatal if treatment is delayed. Counsel patients to seek immediate medical attention should signs or symptoms of CLS occur at any time. Patients who develop CLS should receive appropriate supportive measures, including concomitant oral or intravenous corticosteroids, and hospitalization as clinically indicated. Withhold LUMOXITI for Grade 2 CLS until resolution, and permanently discontinue for Grade ≥ 3 CLS.
Hemolytic Uremic Syndrome (HUS), including life threatening cases, has been reported in patients treated with LUMOXITI and is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and progressive renal failure. In the combined safety database of HCL patients treated with LUMOXITI, HUS occurred in 7% (9/129) of patients, including Grade 3 in 3% (4/129) and Grade 4 in 0.8% (1/129).
Most cases of HUS occurred in the first 9 days (range: 1 to 16) of a treatment cycle, however, cases have also been reported on other days throughout the cycle. The median time to resolution of HUS was 11.5 days (range: 2 to 44). All cases resolved, including those who discontinued LUMOXITI.
Avoid LUMOXITI in patients with prior history of severe thrombotic microangiopathy (TMA) or HUS. Administer prophylactic intravenous fluids before and after LUMOXITI infusions. In Study 1053, patients with a platelet count ≥ 100,000/mm3 received low-dose aspirin on Days 1 through 8 of each 28-day cycle for prophylaxis of thrombosis.
Monitor blood chemistry and complete blood counts prior to each dose and on Day 8 of each treatment cycle. Monitoring mid-cycle is also recommended. Consider the diagnosis of HUS in patients who develop hemolytic anemia, worsening or sudden onset of thrombocytopenia, increase in creatinine levels, elevation of bilirubin and/or LDH, and have evidence of hemolysis based on peripheral blood smear schistocytes.
The events of HUS may be life-threatening if treatment is delayed with increased risk of progressive renal failure requiring dialysis. If HUS is suspected initiate appropriate supportive measures, including fluid repletion, hemodynamic monitoring, and consider hospitalization as clinically indicated. Discontinue LUMOXITI in patients with HUS.
Renal Toxicity has been reported in patients treated with LUMOXITI therapy. In the combined safety database of HCL patients treated with LUMOXITI, 26% (34/129) reported adverse events of renal toxicity, including acute kidney injury (2.3%), renal failure (2.3%), renal impairment (1.6%), serum creatinine increased (17%), and proteinuria (8%). Grade 3 acute kidney injury occurred in 1.6% (2/129) of patients.
Based on laboratory findings, during treatment, serum creatinine increased by two or more grades from baseline in 22% (29/129) of patients, including increases of Grade 3 in 1.6% (2/129) of patients. At the end of treatment, serum creatinine levels remained elevated at 1.5- to 3-times the upper limit of normal in 5% of patients. Patients who experience HUS, those ≥ 65 years of age, or those with baseline renal impairment may be at increased risk for worsening of renal function following treatment with LUMOXITI.
Monitor renal function prior to each infusion of LUMOXITI, and as clinically indicated throughout treatment. Delay LUMOXITI dosing in patients with Grade ≥ 3 elevations in creatinine, or upon worsening from baseline by ≥ 2 grades.
Infusion Related Reactions occurred in patients treated with LUMOXITI, and were defined as the occurrence of any one of the following events on the day of study drug infusion: chills, cough, dizziness, dyspnea, feeling hot, flushing, headache, hypertension, hypotension, infusion related reaction, myalgia, nausea, pyrexia, sinus tachycardia, tachycardia, vomiting, or wheezing. In Study 1053, infusion related reactions occurred in 50% (40/80) of patients, including Grade 3 events in 11% (9/80) of patients. The most frequently reported infusion related events were nausea (15%), pyrexia (14%), chills (14%), vomiting (11%), headache (9%), and infusion related reaction (9%).
Infusion related reactions may occur during any cycle of treatment with LUMOXITI. Premedicate with antihistamines and antipyretics prior to each LUMOXITI dose. If a severe infusion related reaction occurs, interrupt the LUMOXITI infusion and institute appropriate medical management. Administer an oral or intravenous corticosteroid approximately 30 minutes before resuming, or before the next LUMOXITI infusion.
Electrolyte Abnormalities: In the combined safety database of HCL patients treated with LUMOXITI, electrolyte abnormalities occurred in 57% (73/129) of patients with the most common electrolyte abnormality being hypocalcemia occurring in 25% of patients. Grade 3 electrolyte abnormalities occurred in 14% (18/129) of patients and Grade 4 electrolyte abnormalities occurred in 0.8% (1/129) of patients. Electrolyte abnormalities co-occurred in the same treatment cycle with CLS, HUS, fluid retention, or renal toxicity in 37% (48/129) of patients.
Monitor serum electrolytes prior to each dose and on Day 8 of each treatment cycle. Monitoring mid-cycle is also recommended.
ADVERSE REACTIONS
Most common non-laboratory adverse reactions (≥ 20%) of any grade were infusion related reactions (50%), edema peripheral (39%), nausea (35%), fatigue (34%), headache (33%), pyrexia (31%), constipation (23%), anemia (21%), and diarrhea (21%). The most common Grade 3 or 4 adverse reactions (reported in at least ≥ 5% of patients) were hypertension, febrile neutropenia, and HUS.
Most common laboratory abnormalities (≥ 20%) of any grade were creatinine increased, ALT increased, hypoalbuminemia, AST increased, hypocalcemia, hypophosphatemia, hemoglobin decreased, neutrophil count decreased, hyponatremia, blood bilirubin increased, hypokalemia, GGT increased, hypomagnesemia, platelet count decreased, hyperuricemia, and alkaline phosphate increased.
Adverse reactions resulting in permanent discontinuation of LUMOXITI occurred in 15% (12/80) of patients. The most common adverse reaction leading to LUMOXITI discontinuation was HUS (5%). The most common adverse reaction resulting in dose delays, omissions, or interruptions was pyrexia (3.8%).
SPECIFIC POPULATIONS
Pregnancy: There are no available data on LUMOXITI use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Advise pregnant women of the potential risk to a fetus.
Lactation: Advise women not to breastfeed.
Geriatric Use: Exploratory analyses suggest a higher incidence of adverse reactions leading to drug discontinuation (23% versus 7%) and renal toxicity (40% versus 20%) for patients 65 years of age or older as compared to those younger than 65 years.
Please see full Prescribing Information, including Boxed WARNING, Patient Information (Medication Guide), and Instructions for Use
NOTES TO EDITORS
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, and with support from AstraZeneca, will continue EU development and commercialization, pending regulatory submission and approval.