Nearly every three minutes, one person in the United States (US) is diagnosed with a blood cancer.1 The medical and scientific communities have made great strides in the understanding and treatment of blood cancers in recent years; however, critical unmet needs remain for this diverse and complex family of diseases.2-12 Here, the heads of AstraZeneca’s US hematology commercial and medical affairs teams discuss the evolving hematology landscape and AstraZeneca’s efforts to achieve their vision of pushing the boundaries of science to redefine care in hematology.
How is AstraZeneca addressing unmet patient needs in hematology?
Erik Schrader, US head of the hematology franchise, sales and marketing: The patients we serve are at the center of all that we do. Each year, we see blood cancers account for approximately 10 percent of the estimated 1.9 million new cancer cases diagnosed in the US.13 While we have recognized important advancements for many people diagnosed with these diseases, significant gaps remain. At AstraZeneca, we are ensuring progress in the care of patients with hematologic malignancies, targeting those blood cancers with remaining high unmet need and focusing on making meaningful improvements in patient outcomes.
The tremendous progress over the past decade in the field of hematology is due not only to breakthrough approaches to care, but also to improving upon existing novel treatments and exploring combinations within those medicines.14-17 As their utilization moves into earlier lines of therapy, transformative approaches, such as cellular therapy, have demonstrated the ability to alter outcomes in patients whose disease has relapsed multiple times or failed to respond to standard therapies.18-20
With over 40 years of heritage and strength in oncology at AstraZeneca, we feel we are well-positioned to help transform patient care. CALQUENCE® (acalabrutinib) serves as our lead asset in AstraZeneca’s hematology franchise, but we have a breadth of pipeline assets across early and later stages of development.21 These assets encompass a range of therapeutic modalities in multiple hematological malignancies with high unmet medical needs, ranging from early clinical stage of development to commercialization.21
What is unique about AstraZeneca’s approach to drug development in hematology?
Alan Yong, US medical affairs franchise head, hematology: We’re pushing the boundaries of science within our hematology division. Our approach to scientific discovery includes identifying and treating patients earlier in their disease and matching patients to the appropriate medicines or combinations of medicines.21 While AstraZeneca has identified six hematologic malignancies as core areas of focus, our approach to drug development in hematology has been spearheaded by treatment advances in the most common blood cancer, chronic lymphocytic leukemia (CLL).22-24
The approval of targeted treatments began transforming the CLL treatment landscape in 2014, providing more effective treatment options for patients with genetic aberrations that were long considered harder to treat.25,26 These novel agents targeting new mechanisms of action have enabled effective and differentiated targeting of cancer cells compared to traditional chemotherapies.3,27-37 Such advancements have in turn opened the possibility of prolonging progression-free survival in patients and the exploration of chemotherapy-free treatments.3,27,38
Another consideration with this patient population is that people are potentially on treatment for years.39 Tolerability is particularly important as patients diagnosed with CLL tend to be older and may have other comorbidities, so in addition to living free from disease progression, an effective option that is also tolerable becomes important.2,40-46
We took all these elements into consideration when developing CALQUENCE, a next-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK).22,47,48 The drug has enhanced selectivity for the BTK receptor in pre-clinical experiments, which means that it may provide effective inhibition of the target kinase with minimal off-target effects on other kinases; however, direct correlation to clinical relevance has not been established.48,49 Researchers have hypothesized that improved selectivity may translate to reduced incidence of certain adverse events compared to other standards of care.48
Tell us more about the development program for CALQUENCE. What’s next for the molecule?
Yong: We recognize that different patients have different needs.50 That is why we’re pursuing a patient-focused development approach with CALQUENCE, looking not only at the significant efficacy and safety of CALQUENCE as a monotherapy and in combination, but also its use in fixed dose regimens that will give healthcare providers and their patients more options to receive the benefit of CALQUENCE.21
Data from the CALQUENCE development program through the ASCEND, ELEVATE-TN and ELEVATE-RR Phase III studies in both relapsed or refractory and frontline settings have now shown that CALQUENCE is effective as a monotherapy and in combination settings with the anti-CD20 monoclonal antibody, obinutuzumab.51-54 From a biological standpoint, it demonstrates that it is an effective agent, both on its own and in combination with an anti-CD20 monoclonal antibody, including across subgroups examined in clinical trials.51-54 The Phase III studies are also relatively mature and have long-term median follow-up of over 40 months in frontline and relapsed settings with ELEVATE-TN and ELEVATE-RR, respectively.51,53,54 All these meaningful and significant long-term data indicate that CALQUENCE is considered to be an effective treatment in CLL, with an established, consistent safety and tolerability profile.51-54 Additionally, it can be further studied as a foundational treatment in “doublet” or “triplet” combinations with other non-chemotherapy agents, in order to progress current treatment standards in this disease.55
We’re now building on what we learned to push forward development programs in frontline CLL, such as the ACE-CL-311 trial, which evaluates CALQUENCE in combinations with venetoclax and/or obinutuzumab, and another large prospective clinical trial evaluating finite combinations of novel therapies.55 These important studies will help define the treatment paradigm of the future.
Looking ahead, what can we expect from AstraZeneca in hematology?
Schrader: Our work with CALQUENCE in CLL will be the cornerstone of our future in hematology as we aim to continually address patients unmet needs across hematologic malignancies. Our goal is to help patients, so we have made significant investments in the hematology pipeline and in our staff expertise. Our robust development program includes more than 20 company-sponsored trials across multiple B-cell blood cancers.21 We will continue to build upon what we learned with CALQUENCE and take bold approaches to provide physicians and their patients with the information they need to choose the best treatment for their needs – across lines of therapy, alone or in combination, and across the broad spectrum of blood cancers.
For more information, visit www.calquence.com.
INDICATION AND USAGE
CALQUENCE is 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.
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.
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.
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.
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.
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.
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21 AstraZeneca Pharmaceuticals LP. Clinical trials appendix Q2 2021 results update. July 29, 2021. https://www.astrazeneca.com/content/dam/az/PDF/2021/h1-2021/H1_2021_results_presentation.pdf. Accessed September 2021.
22 CALQUENCE® (acalabrutinib) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.
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55 AstraZeneca. Study of acalabrutinib (ACP-196) in combination with venetoclax (ABT-199), with and without obinutuzumab (GA101) versus chemoimmunotherapy for previously untreated CLL. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT03836261. Accessed September 2021.
CALQUENCE is a registered trademark of the AstraZeneca group of companies.
©2021 AstraZeneca. All rights reserved. US-55915 Last Updated 9/21