Fixed-duration CALQUENCE plus venetoclax demonstrated superior PFS vs. standard of care in previously untreated CLL, with 77% of patients progression free at three years in AMPLIFY Phase III trial
CALQUENCE plus venetoclax with obinutuzumab reduced the risk of disease progression or death by 58% versus standard of care in this setting
CALQUENCE plus venetoclax poised to become first all-oral fixed-duration regimen of a second-generation BTK inhibitor plus venetoclax in 1st-line CLL
These results will be presented at the
At a median follow up of 41 months, results showed CALQUENCEplus venetoclax reduced the risk of disease progression or death by 35% compared to standard-of-care chemoimmunotherapy (hazard ratio [HR] 0.65; 95% confidence interval [CI] 0.49-0.87; p=0.0038). CALQUENCEplus venetoclax with obinutuzumab demonstrated a 58% reduction in the risk of disease progression or death compared to standard-of-care chemoimmunotherapy (HR 0.42; 95% CI 0.30-0.59; p<0.0001). Median PFS was not reached for either experimental arm versus median PFS of 47.6 months for chemoimmunotherapy.
Interim overall survival (OS) data demonstrated a favorable trend which was nominally statistically significant for CALQUENCE plus venetoclax (HR 0.33; 95% CI 0.18-0.56; p<0.0001), however the OS data were immature at the time of this analysis and the trial will continue to assess OS as a key secondary endpoint.
Both investigational arms demonstrated durable responses, with estimated 36-month PFS rates of 76.5% for CALQUENCEplus venetoclax and 83.1% with the addition of obinutuzumab compared to 66.5% for chemoimmunotherapy. Patients also demonstrated a robust response in both investigational arms with an overall response rate (ORR) of 92.8% for CALQUENCEplus venetoclax and 92.7% with the addition of obinutuzumab, compared to 75.2% for chemoimmunotherapy.
Summary of Results: AMPLIFY
|
CALQUENCEplus venetoclax |
CALQUENCEplus venetoclax and obinutuzumab |
Control arm |
Patient population (n) |
291 |
286 |
290 |
Median PFS (months) |
NR |
NR |
47.6 |
PFS HR vs. control (95% CI) |
0.65 p=0.0038 |
0.42 p<0.0001 |
Reference |
36-month PFS rate |
76.5% |
83.1% |
66.5% |
ORR (95% CI) |
92.8% (89.4-95.4) p<0.0001 |
92.7% (89.2-95.3) p<0.0001 |
75.2% (70.0-79.9) |
OS HR vs. control (95% CI) |
0.33 (0.18-0.56) p<0.0001 |
0.76 (0.49-1.18) p=0.2224 |
Reference |
NR=Not reached |
|||
Control arm = Investigator’s choice of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab |
The safety and tolerability of CALQUENCEwas consistent with its known safety profile, and no new safety signals were identified. Grade 3 or higher adverse events (AEs) occurred in 53.6% of patients treated with CALQUENCEplus venetoclax, 69.4% of patients treated with CALQUENCEplus venetoclax with obinutuzumab and 60.6% for patients treated with standard-of-care chemoimmunotherapy. The most common Grade 3 or higher AE was neutropenia across all arms, seen in 26.8%, 35.2% and 32.4% of patients respectively. There were over twice as many COVID-19 related deaths in the CALQUENCEplus venetoclax with obinutuzumab arm compared with the CALQUENCEplus venetoclax arm.
Notably, low rates of tumor lysis syndrome (TLS) were observed in both CALQUENCEarms with events of any grade seen in 0.3% of patients treated with CALQUENCEplus venetoclax and 0.4% with the addition of obinutuzumab, compared to 3.1% for patients treated with chemoimmunotherapy. No cases of clinical TLS were observed across CALQUENCEtreatment arms.
CALQUENCEhas been used to treat more than 85,000 patients worldwide1 and is approved for the treatment of CLL and small lymphocytic lymphoma (SLL) in the US and
INDICATION AND USAGE
CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor 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 (≥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 the upper limit of normal (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). No dosage adjustment of CALQUENCE is recommended in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.
Please see full Prescribing Information , including Patient Information .
Notes
Chronic Lymphocytic Leukemia (CLL)
CLL is the most prevalent type of leukemia in adults, with over 100,000 new cases globally in 2019.2 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.3 In CLL, there is an accumulation of abnormal lymphocytes within the blood, bone marrow and lymph nodes. As the number of abnormal cells increases, there is less room within the marrow for the production of normal white blood cells, red blood cells and platelets.4 This could result in infection, anemia and bleeding. B-cell receptor signaling through BTK is one of the essential growth pathways for CLL.
AMPLIFY
AMPLIFY is a randomized, global, multi-center, open-label Phase III trial evaluating the efficacy and safety of CALQUENCEin combination with venetoclax with and without obinutuzumab compared to investigator's choice of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) in adult patients with previously untreated CLL without del(17p) or TP53 mutation.5 Patients were randomized 1:1:1 to receive either CALQUENCEplus venetoclax, CALQUENCEplus venetoclax with obinutuzumab for a fixed duration or standard-of-care chemoimmunotherapy.5 Both the CALQUENCEcontaining arms were administered for a fixed duration of 14 cycles (each 28 days), and the standard-of-care chemoimmunotherapy was for 6 cycles.5
The primary endpoint is PFS in the CALQUENCEand venetoclax arm as assessed by an Independent Review Committee and PFS in the CALQUENCEplus venetoclax with obinutuzumab is a key secondary endpoint. Other key secondary endpoints include OS and undetectable measurable residual disease.5 The trial includes 27 countries across
The AMPLIFY trial enrolled patients from 2019 to 2021, continuing through the COVID-19 pandemic.5 Patients with blood cancer remain at a disproportionately high risk of severe outcomes from COVID-19, including hospitalization and death compared to the general population.6
CALQUENCE®
CALQUENCE(acalabrutinib) is a second-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK).CALQUENCEbinds covalently to BTK, thereby inhibiting its activity.7 In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion.
CALQUENCEis also approved in the US,
As part of an extensive clinical development program, CALQUENCE is currently being evaluated as a single treatment and in combination with standard-of-care chemoimmunotherapy for patients with multiple B-cell blood cancers, including CLL, MCL and diffuse large B-cell lymphoma.
In addition to our marketed products, we are spearheading the development of novel therapies designed to target underlying drivers of disease across multiple scientific platforms. Our acquisitions of Alexion, with expertise in rare, non-malignant blood disorders, and
The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that
References
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Data on File, REF-236261.
AstraZeneca Pharmaceuticals LP . - Yao Y, et al. The global burden and attributable risk factors of chronic lymphocytic leukemia in 204 countries and territories from 1990 to 2019: analysis based on the global burden of disease study 2019. Biomed Eng Online. 2022;1:4.
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American Cancer Society . Signs and Symptoms of Chronic Lymphocytic Leukemia. AccessedNovember 2024 . Available at: https://www.cancer.org/cancer/types/chronic-lymphocytic-leukemia/detection-diagnosis-staging/signs-symptoms.html. -
National Cancer Institute . Chronic lymphocytic leukemia treatment (PDQ®)–Patient version. AccessedNovember 2024 . Available at: https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq. -
ClinicalTrials.gov. Study of Acalabrutinib (ACP-196) in Combination With Venetoclax (ABT-199), With and Without Obinutuzumab (GA101) Versus Chemoimmunotherapy for Previously Untreated CLL (AMPLIFY). Accessed
November 2024 . Available at: https://clinicaltrials.gov/study/NCT03836261. -
Dube S, et al. Continued Increased Risk of COVID-19 Hospitalization and Death in Immunocompromised Individuals Despite Receipt of ≥4 Vaccine Doses: Updated 2023 Results from INFORM, a Retrospective Health Database Study in
England . Poster P0409 at ECCMID 2024. - Wu J, et al. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016;9(21).
US-96571 Last Updated 12/24
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