CALQUENCE Plus Obinutuzumab Demonstrated Sustained Survival Benefit in 1st-line Chronic Lymphocytic Leukemia with 90% of Patients Surviving Five Years in ELEVATE-TN Trial

CALQUENCE also maintained efficacy and a sustained safety profile at four years for previously treated patients in ASCEND trial

Updated results from the ELEVATE-TN Phase III trial showed AstraZeneca’s CALQUENCE^® (acalabrutinib) maintained a statistically significant progression-free survival (PFS) benefit versus chlorambucil plus obinutuzumab and a safety and tolerability profile consistent with the known profile for CALQUENCE at a median follow up of approximately five years in combination and as a monotherapy in chronic lymphocytic leukemia (CLL).¹

Results also showed longer overall survival (OS) for CALQUENCE combined with obinutuzumab compared with chlorambucil combined with obinutuzumab in previously untreated adults with CLL.¹ CLL is the most prevalent type of leukemia in adults, with over 100,000 patients diagnosed globally in 2019.²

At a median follow-up of 58.2 months, CALQUENCE plus obinutuzumab reduced the risk of disease progression or death by 89% (based on a hazard ratio [HR] of 0.11, 95% confidence interval [CI] 0.07-0.16) and as a monotherapy by 79% (based on a HR of 0.21, 95% CI 0.15-0.30), compared with chlorambucil plus obinutuzumab.¹ OS data are immature, and medians were not yet reached in any treatment arm.¹ The relative risk for death was 45% lower in the CALQUENCE plus obinutuzumab arm (based on a HR of 0.55, 95% CI 0.30-0.99).¹ An estimated 90% of patients treated with the CALQUENCE combination were alive at five years versus 84% for CALQUENCE alone and 82% for chlorambucil plus obinutuzumab.¹

Separately, follow-up data from the ASCEND Phase III trial showed CALQUENCE demonstrated a sustained PFS benefit at four years based on investigator assessment compared with investigator’s choice of rituximab combined with either idelalisib (IdR) or bendamustine (BR) in adults with relapsed or refractory CLL.³ At 42 months, an estimated 62% of patients treated with CALQUENCE were alive and had not progressed in comparison with 19% of patients treated with IdR/BR.³ The median follow-up was 46.5 months for CALQUENCE and 45.3 months for IdR/BR.³

The safety and tolerability of CALQUENCE in the ELEVATE-TN and ASCEND trials were consistent with earlier findings, with no new safety signals identified.^1,3

Jeff P. Sharman, MD, Director of Research at Willamette Valley Cancer Institute, Medical Director of Hematology Research for the US Oncology Network, and a lead investigator of the ELEVATE-TN trial, said: “These data from ELEVATE-TN with nearly five years of follow-up support what I have seen in clinical practice and provide clinicians further reassurance when prescribing this therapy. Patients with chronic lymphocytic leukemia often remain on therapy for many years, so long-term efficacy and tolerability are critical factors that physicians consider when deciding on a treatment plan. These data show that acalabrutinib combined with obinutuzumab helped previously untreated patients live longer compared with chlorambucil plus obinutuzumab and was generally well-tolerated.”

Anas Younes, Senior Vice President, Haematology R&D, AstraZeneca, said: “We are committed to bringing efficacious and safe treatments to patients with hematological diseases. With chronic lymphocytic leukemia, these two factors are particularly important due to the chronic nature of the disease and the likelihood of patients having comorbidities. The totality of our longer-term data at ASCO show CALQUENCE’s efficacy benefits and sustained safety profile in key treatment settings, providing more options for patients and their physicians.”

The results were presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting on June 4, 2022.

Treatment is ongoing in 65% of patients on CALQUENCE plus obinutuzumab and 60% of patients on CALQUENCE monotherapy.¹ The most common reasons for treatment discontinuation were adverse events (AEs) (17%, 16% and 14% for CALQUENCE plus obinutuzumab, CALQUENCE monotherapy and chlorambucil plus obinutuzumab, respectively) and progressive disease (6%, 10% and 2%, respectively).¹

Median treatment exposures were 58.1 months and 5.5 months, respectively, for CALQUENCE and obinutuzumab in the CALQUENCE combination arm; 58.0 months for CALQUENCE in the monotherapy arm; and 5.5 months and 5.6 months, respectively, for chlorambucil and obinutuzumab in the chlorambucil plus obinutuzumab arm.¹ Selected AEs of interest of any grade in the CALQUENCE combination arm, CALQUENCE monotherapy arm and chlorambucil plus obinutuzumab arm included bleeding (49.4%, 43.6% and 11.8%, respectively), hypertension (9.6%, 8.9% and 3.6%, respectively) and atrial fibrillation (6.2%, 7.3% and 0.6%, respectively).¹ Common AEs (any grade, greater than or equal to 30% of patients) observed with CALQUENCE with or without obinutuzumab included diarrhea, headache, arthralgia and neutropenia.¹

Median treatment exposures were 44.2 months for CALQUENCE; 11.5 months and 5.5 months, respectively, for idelalisib and rituximab in the IdR arm; and 5.6 months and 5.5 months, respectively, for bendamustine and rituximab in the BR arm.³ AEs led to treatment discontinuation in 23% of patients in the CALQUENCE arm, 67% of patients in the IdR arm and 17% of patients in the BR arm.³ Events of clinical interest for CALQUENCE versus comparators included atrial fibrillation/flutter (all grade, 8% and 3%, respectively), hypertension (all grade, 8% and 5%, respectively), major hemorrhage (all grade, 3% in both arms) and infections (greater than or equal to Grade 3, 29% in both arms).³ Common AEs (any grade, greater than or equal to 15% of patients; or Grade 3 or higher, greater than or equal to 5% of patients) observed with CALQUENCE included neutropenia, headache, diarrhea and upper respiratory tract infection.³

INDICATION 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) 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.

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.

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.

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 1.5 to 3 times the upper limit of normal 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 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.

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 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.

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 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.

Please see full Prescribing Information, including Patient Information.

Notes

CLL

CLL is the most prevalent type of leukemia in adults, with over 100,000 new cases globally in 2019 and an estimated 20,160 new cases in the US in 2022.^2,4 Although some people with CLL may not experience any symptoms at diagnosis, others may experience symptoms, such as weakness, fatigue, weight loss, chills, fever, night sweats, swollen lymph nodes and abdominal pain.⁵

In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes and these abnormal cells have difficulty fighting infections.⁶ As the number of abnormal cells grows, there is less room for healthy white blood cells, red blood cells and platelets.⁶ This could result in anemia, infection and bleeding.⁶ B-cell receptor signaling through Bruton’s tyrosine kinase (BTK) is one of the essential growth pathways for CLL.⁶

ELEVATE-TN

ELEVATE-TN (ACE-CL-007) is a randomized, multicenter, open-label Phase III trial evaluating the safety and efficacy of CALQUENCE alone or in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab in previously untreated patients with CLL. In the trial, 535 patients were randomized (1:1:1) into three arms.⁷ Patients in the first arm received chlorambucil in combination with obinutuzumab.⁷ Patients in the second arm received CALQUENCE (100mg twice daily until disease progression) in combination with obinutuzumab.⁷ Patients in the third arm received CALQUENCE monotherapy (100mg twice daily until disease progression).⁷

The primary endpoint was 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 was IRC-assessed PFS in the CALQUENCE monotherapy arm compared to the chlorambucil and obinutuzumab arm.⁷ Other secondary endpoints included overall response rate, time to next treatment, OS and investigator assessed PFS.⁷ After interim analysis, assessments were by investigator only.^7,8

Initial results from the ELEVATE-TN Phase III trial were presented in December 2019 at the American Society of Hematology Annual Meeting and Exhibition.⁹ The trial met its primary endpoint (IRC-assessed PFS with CALQUENCE plus obinutuzumab versus chlorambucil plus obinutuzumab) at the data cut-off for the interim analysis after a median follow-up of 28.3 months.⁸ The findings, along with previously reported data from the Phase III ASCEND trial in relapsed or refractory CLL, supported the approvals of CALQUENCE by the US FDA and the Australian Therapeutic Goods Administration for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL) and by the European Medicines Agency (EMA) and Health Canada for CLL.

ASCEND

ASCEND (ACE-CL-309) is a global, randomized, multicenter, open-label Phase III trial evaluating the efficacy of CALQUENCE in patients with relapsed or refractory CLL.¹⁰

In the trial, 310 patients were randomized (1:1) into two treatment arms.¹⁰ Patients in the first arm received CALQUENCE monotherapy (100mg twice-daily until disease progression or unacceptable toxicity).¹⁰ Patients in the second arm received physician’s choice of either rituximab, a CD20 monoclonal antibody, in combination with idelalisib, a PI3-kinase inhibitor, or rituximab in combination with bendamustine, a chemotherapy.¹⁰

The primary endpoint at the interim analysis was PFS assessed by an IRC, and key secondary endpoints included investigator-assessed PFS, IRC- and investigator-assessed overall response rate, and duration of response, as well as overall survival, patient-reported outcomes and time to next treatment.^10,11

ASCEND is the first randomized Phase III trial to directly compare a BTK inhibitor as monotherapy to these combinations in relapsed or refractory CLL.¹¹

CALQUENCE

CALQUENCE (acalabrutinib) is a next-generation, selective inhibitor of BTK. CALQUENCE binds covalently to BTK, thereby inhibiting its activity.^12,13 In B cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion.¹³

CALQUENCE is approved for the treatment of CLL and SLL in the US, approved for CLL in the EU and many other countries worldwide and approved in Japan for relapsed or refractory CLL and SLL. A Phase I trial is currently underway in Japan for the treatment of front-line CLL.

In the US and several other countries, CALQUENCE is also approved for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. The US MCL 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 not currently approved for the treatment of MCL in Europe or Japan.

As part of an extensive clinical development program, AstraZeneca and Acerta Pharma are currently evaluating CALQUENCE in more than 20 company-sponsored clinical trials. CALQUENCE is being evaluated for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenström’s macroglobulinemia, marginal zone lymphoma and other hematologic malignancies.

AstraZeneca in hematology

AstraZeneca is pushing the boundaries of science to redefine care in hematology. We have expanded our commitment to patients with hematologic conditions, not only in oncology but also in rare diseases with the acquisition of Alexion, allowing us to reach more patients with the greatest unmet needs. By applying our deep understanding of blood cancers, leveraging our strength in solid tumor oncology and delivering on Alexion’s pioneering legacy in complement science to provide transformative medicines for rare diseases, we are pursuing the end-to-end development of novel therapies designed to target underlying drivers of disease.

By targeting hematological conditions with high unmet medical needs, we aim to deliver innovative medicines and approaches to improve patient outcomes. Our goal is to transform the lives of patients living with malignant, rare and other related hematologic diseases, shaped by insights from patients, caregivers and physicians to have the most meaningful impact.

AstraZeneca in oncology

AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care 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 in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, 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-64404 Last Updated 6/22

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