First results from AMPLIFY trial will reinforce CALQUENCE® as leading second-generation BTK inhibitor in frontline chronic lymphocytic leukemia with fixed-duration regimen
Next generation cell therapy and T-cell engagers will demonstrate promising early results in multiple types of blood cancer
New, long-term data for VOYDEYA™ as add-on to ULTOMIRIS® or SOLIRIS® will show low rate of breakthrough hemolysis events and sustained improvements in quality-of-life measures in PNH with extravascular hemolysis
WILMINGTON, Del.--(BUSINESS WIRE)--AstraZeneca advances its ambition to redefine cancer care with new data across its industry-leading and diverse pipeline in hematology at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition December 7-10, 2024.
A total of 57 abstracts will feature 13 approved and potential new medicines from across AstraZeneca’s portfolio and pipeline in hematology, including from Alexion, its rare disease group, with data in key settings including chronic lymphocytic leukemia (CLL), multiple myeloma (MM), paroxysmal nocturnal hemoglobinuria (PNH) and other hematologic diseases.
Anas Younes, Senior Vice President, Hematology R&D, AstraZeneca, said: “Our data at ASH from the AMPLIFY Phase III trial will demonstrate the efficacy and safety of our leading second-generation BTK inhibitor, CALQUENCE®, as a fixed-duration therapy in first-line CLL. In addition, new results for our novel T-cell engager, AZD0486, will reinforce its promising clinical profile in lymphomas, and data for our novel CAR T cell therapy, AZD0120, will highlight the potential of this therapy to transform treatment in multiple myeloma.”
Christophe Hotermans, Senior Vice President, Head of Global Medical Affairs, Alexion, said: “Our ASH presentations will highlight the transformative impact of our medicines, including new analyses from the ALPHA Phase III trial reaffirming the safety and efficacy of our first-in-class Factor D inhibitor, VOYDEYA™ as add-on to ULTOMIRIS® or SOLIRIS® for the subset of patients with PNH experiencing clinically significant extravascular hemolysis. Further, new insights from our robust pipeline will enhance the understanding of several rare hematologic and cardiovascular conditions, underscoring our commitment to innovation in rare disease.”
CALQUENCE combinations demonstrate significant benefits across CLL and MCL
An oral presentation on interim results from the pivotal AMPLIFY Phase III trial will demonstrate the potential of fixed-duration CALQUENCE in combination with venetoclax, with or without obinutuzumab, in previously untreated adults with CLL compared to standard-of-care chemoimmunotherapy.1 These results will be featured during the ASH Press Briefing on Sunday, December 9.
An updated analysis from the pivotal ECHO Phase III trial will further highlight the use of CALQUENCE in combination with bendamustine and rituximab as a first-line treatment option by demonstrating high and durable undetectable minimal residual disease (MRD) rates in previously untreated patients with mantle cell lymphoma (MCL) as well as showing the benefit of CALQUENCE across all patients including those with high-risk disease characteristics.2 Results from ECHO were first presented as a late-breaking oral presentation at the European Hematology Association (EHA) 2024 Hybrid Congress in June.3
Results will also be shared from the ChangE Phase III trial, evaluating CALQUENCE compared with chlorambucil plus rituximab in first-line CLL in patients in China.4
New data show promise of next generation T-cell engagers and chimeric antigen receptor T-cell (CAR T) therapy
Two oral presentations will share results for the novel CD19xCD3 bispecific T-cell engager AZD0486, reinforcing the potential of this novel medicine as a new treatment option for B-cell malignancies.5-6 Phase I results demonstrate high response rates, with a 96% overall response rate, 85% complete response rate and high rates of undetectable MRD in patients with relapsed/refractory follicular lymphoma (R/R FL) at doses of 2.4 mg and above.5 Additionally, interim Phase I results will show the early potential of AZD0486 in patients with heavily pretreated diffuse large B-cell lymphoma (DLBCL).6 Data will also reinforce the safety profile of AZD0486, with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) events effectively mitigated by the double step-up dosing schedule.7
Early data for AZD0120 (GC012F), a novel BCMAxCD19 dual-targeting autologous CAR T developed using the Gracell FasTCAR rapid manufacturing process, will show potential as a first-line therapy for elderly patients with newly diagnosed transplant ineligible MM.8 Preliminary results from the ongoing investigator-initiated trial of AZD0120 suggest deep responses and an acceptable safety profile, with no ICANS and no ≥Grade 2 CRS events observed in this patient population.8
An oral presentation will share preclinical data demonstrating the anti-tumor activity of AZD5492, a next-generation CD8 selective, CD20-targeting T-cell engager, designed using AstraZeneca’s innovative Target Induced T-cell Activating Nanobody (TITAN) platform. AZD5492 is currently being evaluated in Phase I clinical trials in R/R Non-Hodgkin lymphoma (NHL) and CLL.9
VOYDEYA (danicopan) as add-on to ULTOMIRIS (ravulizumab-cwvz) or SOLIRIS (eculizumab) demonstrates low rate of mild or moderate BTH events and improves quality-of-life measures in patients with PNH and clinically significant EVH
Data will be presented detailing events of breakthrough hemolysis (BTH), a key indicator of intravascular hemolysis and PNH disease control, reported in the ALPHA trial evaluating VOYDEYA as add-on to ULTOMIRIS or SOLIRIS in patients with PNH experiencing clinically significant extravascular hemolysis (EVH) and separately in the PEGASUS Phase III trial evaluating pegcetacoplan in patients with PNH previously treated with SOLIRIS. Data will show that 5/84 patients (6.0%) in the ALPHA trial and 19/80 patients (23.8%) in the PEGASUS trial experienced one or more BTH events. Moreover, most BTH events (6/7 or 85.7%) in the ALPHA trial were either mild or moderate, and all events were resolved without transfusion, dose modification or treatment withdrawal.10
Separately, final long-term patient-reported outcomes from the ALPHA trial will demonstrate VOYDEYA as add-on to ULTOMIRIS or SOLIRIS resulted in sustained improvements in fatigue, quality-of-life and physical function for up to 72 weeks in the subset of patients with PNH who experience clinically significant EVH.11
Advancing understanding of life-threatening rare diseases
A US, retrospective chart review will provide real-world evidence showing hematologic and renal improvements in adults with atypical hemolytic uremic syndrome (aHUS) who switched to ULTOMIRIS after short-term use of SOLIRIS, with early responses and continued improvements through one year of treatment with ULTOMIRIS.12
Additionally, two presentations on amyloid light chain (AL) amyloidosis will highlight unmet medical needs in this progressive, debilitating disease, reinforcing the importance of bringing forward novel therapies to improve cardiovascular outcomes and organ function.13-14
Key presentations during the 66th ASH Annual Meeting and Exposition
Lead Author | Abstract Title | Presentation details (PST) |
CALQUENCE® (acalabrutinib) | ||
Brown, JR et al. | Fixed-Duration Acalabrutinib plus Venetoclax with or without Obinutuzumab versus Chemoimmunotherapy for First-Line Treatment of Chronic Lymphocytic Leukemia: Interim Analysis of the Multicenter, Open-label, Randomized, Phase 3 AMPLIFY Trial | Abstract #1009 |
Qiu, L et al. | Acalabrutinib Versus Chlorambucil Plus Rituximab in Patients with Previously Untreated Chronic Lymphocytic Leukemia: A Randomized, Multicenter, Open Label, Phase 3 Study | Abstract #3251 |
Dreyling, M et al. | High-risk Subgroups and MRD: An Updated Analysis of the Phase 3 ECHO Trial of Acalabrutinib with Bendamustine/Rituximab in Previously Untreated Mantle Cell Lymphoma
| Abstract #1626 |
Simon, F et al. | Efficacy and Safety of Acalabrutinib Treatment in Very Old (≥80y) and/or Frail Patients with Chronic Lymphocytic Leukemia (CLL) – Primary Endpoint Analysis of the Phase II CLL-Frail Trial | Abstract #4618 |
Swaminathan, M et al. | Early Obinutuzumab Significantly Increases Bone Marrow Undetectable MRD (10-4 sensitivity) (uMRD4) Rate when Combined with Acalabrutinib and Venetoclax in a Randomized Phase II Trial for Treatment Naïve CLL | Abstract #1855 |
Jerkeman, M et al. | Acalabrutinib and Rituximab in Elderly Patients with Newly Diagnosed Mantle Cell Lymphoma Including a Matched Population-Based External Comparator- the Nordic Lymphoma Group NLG-MCL8 (ALTAMIRA) Phase II Trial | Abstract #747 |
Christofyllakis, K et al. | Toxicity of R-mini-CHOP with or without Acalabrutinib in Older Adults with Untreated DLBCL – An Interim Analysis of Serious Adverse Events in the ARCHED / GLA 2022-1 Randomized, Open-Label, Phase 3 Trial | Abstract #4498 |
AZD0486 | ||
Gaballa, S et al. | Evaluation of AZD0486, a Novel CD19xCD3 T-Cell Engager, in Relapsed/Refractory Diffuse Large B-cell Lymphoma in an Ongoing First-in-Human Phase 1 Study: High Complete Responses Seen in CAR-T–naive and CAR-T–exposed Patients | Abstract #868 |
Hou, J et al. | Escalating Doses of AZD0486, a Novel CD19xCD3 T-cell Engager, Result in High Complete Remissions with Rapid Clearance of Minimal Residual Disease in Patients with Relapsed/Refractory Follicular Lymphoma | Abstract #341 |
Zhu, X et al. | Exposure-Response analysis and Quantitative Systems Pharmacology modelling for an optimal dose selection of AZD0486 in follicular lymphoma patients | Abstract #2794 |
AZD0120 | ||
Du, J et al. | A phase I study of dual targeting BCMA and CD19 FasTCAR-T cells (GC012F) as first-line therapy for transplant-ineligible newly diagnosed multiple myeloma | Abstract #2072 |
AZD5492 | ||
Lawrence, R et al. | Pre-Clinical Evaluation of AZD5492, a Novel CD8-Guided T Cell Engager, for B-Non-Hodgkin Lymphoma Indications | Abstract #959 |
VOYDEYA™ (danicopan) | ||
Schrezenmeier, H | Breakthrough Hemolysis Events in Patients with Paroxysmal Nocturnal Hemoglobinuria: Data from Danicopan and Pegcetacoplan Trials | Abstract #2694 |
Piatek, C | Danicopan as Add-On Therapy to Ravulizumab or Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Long-Term Patient-Reported Outcomes from the Phase 3 ALPHA Trial | Abstract #2692 |
ULTOMIRIS® (ravulizumab-cwvz) and SOLIRIS® (eculizumab) | ||
Griffiths, E | Real-World Drug Adherence, Persistence, and Healthcare Resource Utilization in Patients with Paroxysmal Nocturnal Hemoglobinuria in the USA: The ADVANTAGE Study | Abstract #5074 |
Chaturvedi, S | Real-World Effectiveness of Ravulizumab Among Adults with Atypical Hemolytic Uremic Syndrome (aHUS) who Switched to Ravulizumab Within 3 Months of Eculizumab Treatment: A Physician Panel-Based Chart Review Study (aHUS IMPACT) | Abstract #2613 |
Iori, AP | REACTION - Real Life Use of Ravulizumab in Italian PatiEnts with PAroxysmal NoCturnal Hemoglobinuria a MulTicenter ObservatIONal Retrospective and Prospective Cohort Study, Final Results | Abstract #2464 |
PNH | ||
Wagner-Ballon, O | High Proportion of PNH Type II Neutrophils, l.e Relative Percentage 3%, Is Associated with Thrombosis in Patients Displaying a PNH Clone >1%: Evidence from Analysis of the 5-Year French Nation-Wide Multicenter Observational Study | Abstract #4080 |
HSCT-TMA | ||
Dandoy, C | Survival Outcomes in Adult and Pediatric Patients Who Experienced Thrombotic Microangiopathy After Hematopoietic Stem Cell Transplant: A Systematic Review and Meta-Analysis | Abstract #7286
|
Amyloidosis | ||
Laires, P | Comparison Of Alternative Mayo Staging Classification Systems Used in Light-Chain Amyloidosis | Abstract #6887 |
Thompson, J | Evaluation of Functional Cardiac Measures and Response to Treatment Initiation in Patients with Systemic Light-Chain (AL) Amyloidosis: Results from a Single Site Retrospective Study | Abstract #4677 |
INDICATIONS 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) tablets
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 jirovecii 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.
Cardiac Arrhythmias
Serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. 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. Grade 3 or higher ventricular arrhythmia events were reported in 0.9% of patients. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (eg, palpitations, dizziness, syncope, dyspnea) and manage as appropriate.
Hepatotoxicity, Including Drug-Induced Liver Injury
Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including CALQUENCE.
Evaluate bilirubin and transaminases at baseline and throughout treatment with CALQUENCE. For patients who develop abnormal liver tests after CALQUENCE, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold CALQUENCE. Upon confirmation of DILI, discontinue CALQUENCE.
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 to 1.5 to 3 times the upper limit of normal (ULN) 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 to 1.5 to 3 times ULN 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 to 1.5 to 3 times ULN occurred in 1.3% of patients who received CALQUENCE.
DRUG INTERACTIONS
Strong CYP3A Inhibitors: Avoid co-administration of CALQUENCE with a strong CYP3A inhibitor. If these inhibitors will be used short-term, interrupt CALQUENCE. After discontinuation of strong CYP3A inhibitor for at least 24 hours, resume previous dosage of CALQUENCE.
Moderate CYP3A Inhibitors: Reduce the dosage of CALQUENCE to 100 mg once daily when co-administered with a moderate CYP3A inhibitor.
Strong CYP3A Inducers: Avoid co-administration of CALQUENCE with a strong CYP3A inducer. If co-administration is unavoidable, increase the dosage of CALQUENCE to 200 mg approximately every 12 hours.
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 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 2 weeks after the last dose.
Avoid use of CALQUENCE in patients with severe hepatic impairment (Child-Pugh class C).
Contacts
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