CALQUENCE® (acalabrutinib) Receives US FDA Approval for New Indication

The US Food and Drug Administration (FDA) has approved CALQUENCE^® (acalabrutinib) capsules for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).[i] CALQUENCE for CLL was granted Breakthrough Therapy Designation by the FDA, and the approval was granted under the FDA’s Real Time Oncology Review (RTOR) and newly established Project Orbis programs.

As you may know, CLL is one of the most common types of leukemia in adults, with an estimated 20,720 new cases in the US annually and prevalence that is expected to grow with improved treatment as patients live longer with the disease. [ii],[iii] This is one of the reasons why we are committed to working collaboratively with health authorities to accelerate the delivery of breakthrough therapies to patients, including those living with CLL.

The approval is based on positive results from the interim analyses of two Phase III clinical trials, ELEVATE-TN (ACE-CL-007) in patients with previously untreated CLL and ASCEND (ACE-CL-309) in patients with relapsed or refractory CLL. Together, the trials showed that acalabrutinib in combination with obinutuzumab and as a monotherapy significantly reduced the relative risk of disease progression or death versus the comparator arms in both front-line and relapsed CLL, with safety and tolerability that was consistent with the Bruton’s tyrosine kinase (BTK) inhibitor’s established profile.¹

In the ELEVATE-TN trial of 535 patients with previously untreated CLL, acalabrutinib in combination with obinutuzumab and acalabrutinib monotherapy significantly reduced the relative risk of disease progression or death by 90% (HR, 0.10; 95% CI, 0.06-0.17; p<0.0001) and 80% (HR, 0.20; 95% CI, 0.13-0.30; p<0.0001) respectively, at a median follow-up of 28 months.¹

We will be presenting detailed results from the pivotal Phase III ELEVATE-TN trial, among additional scientific presentations from our broad pipeline of novel hematology treatments, at the upcoming 2019 American Society of Hematology (ASH) Annual Meeting & Exposition on Saturday, December 7. An invitation to attend a briefing webinar on the FDA approval as well as ASH presentations will be forthcoming after the Congress.

Summary of key results from the ELEVATE-TN trial, as determined by Independent Review Committee (IRC):

• ELEVATE-TN is a randomized, multicenter, open-label, Phase III trial evaluating the safety and efficacy of acalabrutinib in combination with obinutuzumab and acalabrutinib monotherapy vs. chlorambucil plus obinutuzumab  in 535 patients with previously untreated CLL.¹
• At a median follow-up of 28 months, results showed a statistically significant and clinically meaningful improvement in independent review committee (IRC)-assessed progression-free survival (PFS) for patients in the acalabrutinib combined with obinutuzumab arm and acalabrutinib monotherapy arm compared to the chlorambucil plus obinutuzumab arm, reducing the relative risk of disease progression or death by 90% (HR, 0.10; 95% CI, 0.06-0.17; p<0.0001) and 80% (HR, 0.20; 95% CI, 0.13-0.30; p<0.0001) respectively.¹
• In the acalabrutinib plus obinutuzumab arm, the most common adverse reactions (ARs) (≥15%) of any grade included infection (69%), neutropenia (53%), anemia (52%), thrombocytopenia (51%),  headache (40%), diarrhea (39%), musculoskeletal pain (37%), fatigue (34%), bruising (31%), rash (26%), arthralgia (22%), dizziness (20%), nausea (20%), and hemorrhage (20%).¹
• In the acalabrutinib monotherapy arm, the most common ARs (≥15%) of any grade included infection (65%), anemia (53%), headache (39%), diarrhea (35%), musculoskeletal pain (32%), thrombocytopenia (32%), rash (25%), neutropenia (23%), fatigue (23%), nausea (22%), bruising (21%), hemorrhage (20%), lymphocytosis (16%), and arthralgia (16%).¹
• In the chlorambucil plus obinutuzumab arm, the most common ARs (≥15%) of any grade included neutropenia (78%), thrombocytopenia (61%), anemia (54%), infection (46%), nausea (31%), fatigue (24%), diarrhea (21%), and musculoskeletal pain (16%).¹

Results from the pivotal Phase III ASCEND trial in 310 patients with relapsed or refractory CLL were reported earlier this year at the European Hematology Association (EHA) Annual Congress.

Questions or requests for more information may arise as news of this approval begins to travel among patients, healthcare professionals, and the general public. View the full press release here issued by AstraZeneca announcing the FDA approval for your reference.

Please see below for complete Important Safety Information, including Patient Information about CALQUENCE.

You may report side effects related to AstraZeneca products by clicking here.

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.

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 (≥ 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), dosage 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. See details here.

CALQUENCE is a registered trademark of the AstraZeneca group of companies.

©2019 AstraZeneca. All rights reserved. US-31477 Last Updated 11/19

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