Median PFS was not reached with CALQUENCE ± obinutuzumab vs 27.8 months with GClb5
TIME TO ATRIAL FIBRILLATION/FLUTTER
CALQUENCE: ADVANCING THE SCIENCE OF TREATING CLL
CALQUENCE has been studied in 3 novel head-to-head Phase 3 CLL trials2-4
BR=bendamustine + rituximab; BTKi=Bruton tyrosine kinase inhibitor; CLL=chronic lymphocytic leukemia; IdR=idelalisib + rituximab; R/R=relapsed/refractory; SLL=small lymphocytic lymphoma; TN=treatment naïve.
ELEVATE-TN: A PHASE 3, OPEN-LABEL, RANDOMIZED, MULTICENTER TRIAL IN PATIENTS WITH PREVIOUSLY UNTREATED CLL1,2
Median PFS was not reached with CALQUENCE ± obinutuzumab vs 27.8 months with GClb5
LONG-TERM ANALYSIS: INVESTIGATOR-ASSESSED PROGRESSION-FREE SURVIVAL‡5
CALQUENCE: Proven efficacy as both a combination therapy and monotherapy5
At the Initial Analysis
At a median follow-up of 28.3 months (range: 0.0-40.8 months), CALQUENCE + obinutuzumab demonstrated a 90% risk reduction in disease progression or death vs GClb (HR=0.10* [95% CI: 0.06-0.17], P<0.0001).‡ CALQUENCE monotherapy demonstrated an 80% reduction in disease progression or death vs GClb (HR=0.20*; [95% CI: 0.13-0.30]; P<0.0001).‡1,2
At a median follow-up at 46.9 months, common AEs (≥25%, any grade) included diarrhea, headache, neutropenia, fatigue, arthralgia, cough, upper respiratory tract infection, and nausea.5
In the interim analysis at median 28.3-month follow-up, common adverse reactions (≥15%) of any grade in patients with previously untreated CLL included infection, neutropenia, anemia, thrombocytopenia, headache, diarrhea, musculoskeletal pain, fatigue, bruising, lymphocytosis, dizziness, nausea, arthralgia, rash, and hemorrhage. Non-hematologic laboratory abnormalities (≥15%, any grade) new or worsening from baseline with CALQUENCE included increases in uric acid, ALT, AST, and bilirubin. In the CALQUENCE + obinutuzumab and CALQUENCE monotherapy arms, 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.1 Serious adverse reactions were reported in 39% of patients in the CALQUENCE + obinutuzumab arm and 32% in the CALQUENCE monotherapy arm, most often due to events of pneumonia (7% and 2.8%, respectively).1,2
535 patients were randomized 1:1:1 to receive either CALQUENCE + obinutuzumab (n=179), CALQUENCE monotherapy (n=179), or GClb (n=177). The primary endpoint was PFS by IRC for CALQUENCE + obinutuzumab vs GClb. Secondary endpoints included PFS for CALQUENCE monotherapy vs GClb, ORR, OS and safety.
*Based on an unstratified Cox proportional-hazards model. Both HRs are compared with the GClb arm.5 †Based on an unstratified log-rank test.5
‡Based on a stratified log-rank test, with an alpha level of 0.012 derived from alpha spending function by the O’Brien-Fleming method.1
§Estimated PFS at 48 months.5
AEs=adverse events; CI=confidence interval; GClb=obinutuzumab + chlorambucil; HR=hazard ratio; ORR=overall response rate; OS=overall survival; PFS=progression-free survival.
ASCEND: A PHASE 3, OPEN-LABEL, RANDOMIZED, MULTICENTER TRIAL IN PATIENTS WITH RELAPSED/REFRACTORY CLL1,3
73% risk reduction in disease progression or death with CALQUENCE vs IdR or BR (HR=0.27* [95% CI: 0.18-0.40], P<0.0001†) at median follow-up of ≈22 months‡6
At median 22 months, median PFS was not reached with CALQUENCE vs 16.8 months (95% CI: 14.1-22.4) with IdR or BR.‡§6
At the Interim Analysis
After a median follow-up of 16.1 monthsll1,3
CALQUENCE is the first and only BTKi monotherapy to demonstrate superior PFS against standard-of-care combinations, including novel agents, in relapsed/refractory CLL1
At the interim analysis, common adverse reactions (≥15%) of any grade in patients with relapsed/refractory CLL included infection, neutropenia, anemia, thrombocytopenia, lymphocytosis, headache, diarrhea, hemorrhage, fatigue, and musculoskeletal pain. Non-hematologic laboratory abnormalities (≥10%, any grade) new or worsening from baseline with CALQUENCE included increases in uric acid, ALT, AST, and bilirubin.1
Safety and tolerability results in the final analysis were consistent with those of the interim analysis.6
10% and 16% of patients, respectively, discontinued CALQUENCE due to adverse reactions at median 16.1-month and 22-month follow-ups.1,6
310 patients were randomized 1:1 to receive either CALQUENCE (n=155) or investigator's choice of idelalisib + rituximab (IdR) or bendamustine + rituximab (BR; n=155). Primary endpoint was IRC-assessed PFS for CALQUENCE vs IdR or BR.
*Based on a stratified Cox proportional-hazards model.1,6
†Based on a stratified log-rank test, stratified by randomization stratification factors as recorded in an interactive voice/web response system.6
‡Median follow-up at the final analysis was approximately 22 months (range: 0.5- 29.1 months).7
§Per 2008 IWCLL criteria.1,6
llThe initial analysis had a median follow-up of 16.1 months (range: 0.03-22.4 months).3
ALT=alanine aminotransferase; AST=aspartate aminotransferase; IRC=Independent Review Committee; IWCLL=International Workshop on CLL.
IN A POOLED ANALYSIS OF CARDIOVASCULAR EVENTS IN CALQUENCE MONOTHERAPY TRIALS IN 762 PATIENTS WITH CLL, RATES OF ATRIAL FIBRILLATION WERE LOW WITH CALQUENCE MONOTHERAPY8
At a median follow-up of 25.9 months, 17% (n=129/762) of patients overall reported cardiac ARs of any grade and 9% (n=67/762) reported hypertension of any grade8,9
ATRIAL FIBRILLATION RATES WITH CALQUENCE8
0.9% (7/762) of patients discontinued treatment due to cardiac ARs after a median follow-up of 25.9 months.8
Data were pooled from 4 clinical trials in patients with CLL* who had received at least 1 dose of CALQUENCE monotherapy, including two pivotal Phase 3 trials (ELEVATE-TN and ASCEND), one Phase 2 trial (15-H-0016), and one Phase 1/2 trial (ACE-CL-001).8
Low rates of atrial fibrillation/flutter and hypertension across CLL studies, including 2 pivotal trials3,4,10
Atrial fibrillation and hypertension rates in two Phase 3 pivotal trials with CALQUENCE monotherapy2,3,8
*n=352 previously untreated; 410 relapsed/refractory.8
†At median 28.3-month follow-up.
‡At median 16.1-month follow-up.
ELEVATE-RR: THE FIRST PHASE 3 STUDY OF A NEXT-GENERATION BTKi VS IBRUTINIB IN R/R CLL
A randomized, multicenter, open-label trial (N=533) in previously treated patients with CLL4
Patients received CALQUENCE 100 mg approximately every 12 hours until disease progression or unacceptable toxicity.4
Patients received ibrutinib 420 mg orally once daily until disease progression or unacceptable toxicity.4
*Derivation of the non-inferiority margin (upper CI limit <1.429) was based on the results of one ibrutinib study. Therefore, it may be difficult to verify the constancy assumption of the historical control.4
ECOG PS=Eastern Cooperative Oncology Group performance status.
PATIENT DEMOGRAPHICS AND DISEASE CHARACTERISTICS WERE GENERALLY WELL BALANCED BETWEEN ARMS4
SELECT DEMOGRAPHICS AND BASELINE CHARACTERISTICS IN ELEVATE-RR4
IRC-ASSESSED PROGRESSION-FREE SURVIVAL
At median follow-up of 41 months, median PFS was 38.4 months (95% CI: 33.0-38.6) with CALQUENCE, and 38.4 months (95% CI: 33.0-41.6) with ibrutinib*4
*Range: 0.0-59.1 months.4
†At the time of analysis, the number of events in each arm was 143 (53%) for CALQUENCE and 136 (51%) for ibrutinib.4
MEDIAN OVERALL SURVIVAL RATE WAS NOT REACHED IN EITHER ARM
At 36 months, an estimated 81% of patients taking CALQUENCE and 76% of patients taking ibrutinib were alive
With a median follow-up of 41 months, median overall survival was not reached in either arm, with 27.5% in the CALQUENCE arm and 25.7% in the ibrutinib arm experiencing an event. Approximately 25% of events have occurred at a median follow-up of 41 months.
ORR was 81% with CALQUENCE†.
CALQUENCE: CR/CRi: 1.9%, 0; PR/nPR: 78.4%, 0.7%
ibrutinib: CR/CRi: 3.0%, 0; PR/nPR: 72.8%, 1.1%
*Overall survival data were immature.
†ORR was an exploratory endpoint.
CALQUENCE HAD SIGNIFICANTLY LOWER RATES OF ATRIAL FIBRILLATION/FLUTTER*
PRIMARY SAFETY ENDPOINT: ALL-GRADE ATRIAL FIBRILLATION/FLUTTER
A pooled analysis of 762 patients with CLL showed consistently low rates of atrial fibrillation/flutter.
NO PATIENTS DISCONTINUED CALQUENCE DUE TO ATRIAL FIBRILLATION/FLUTTER
Significantly lower rates of afib/flutter with CALQUENCE despite higher risk factors in these patients
Among patients with atrial fibrillation, 25% more patients taking CALQUENCE had previous history of atrial fibrillation than patients taking ibrutinib, and 15% more patients taking CALQUENCE had other cardiac risk factors (hypertension, diabetes, MI/ischemia, or cardiac disease) than patients taking ibrutinib.
EVENTS OF CLINICAL INTEREST4
Rates of atrial fibrillation/flutter were 6% (15/243) for CALQUENCE and 15% (37/249) for ibrutinib in patients without history of atrial fibrillation/flutter.4
Median duration of exposure was 38.3 months (range: 0.3-55.9 months) in the CALQUENCE arm and 35.5 months (range: 0.2-57.7 months) in the ibrutinib arm.4
*Defined as preferred terms atrial fibrillation and atrial flutter.4
†Defined as preferred terms torsade de pointes, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, and ventricular tachycardia.4
‡Defined as any hemorrhagic event that was serious, Grade ≥3 in severity, or a central nervous system hemorrhage (any severity grade).4
§Included events with the preferred terms of hypertension, blood pressure increased, and blood pressure systolic increased.4
||Most common Grade ≥3 infections were pneumonia (acalabrutinib, 10.5%; ibrutinib, 8.7%), sepsis (1.5% vs 2.7%), and urinary tract infection (1.1% vs 2.3%).4
As part of the hierarchical testing, statistical analysis of secondary endpoints (atrial fibrillation, Grade ≥3 infections, and Richter’s transformation) could not be validated following interpretation of the primary endpoint.
SAFETY AND TOLERABILITY OF CALQUENCE AND IBRUTINIB
MOST COMMON AEs (ALL GRADES, ≥15% IN EITHER ARM)4
Median duration of exposure: 38.3 months (range: 0.3-55.9 months) in CALQUENCE arm; 35.5 months (range: 0.2-57.7 months) in ibrutinib arm.4
Among most common AEs above, Grade 5 events were reported in 5 (1.9%) patients with CALQUENCE (pyrexia, n=1; pneumonia, n=4) and 4 (1.5%) patients with ibrutinib (upper respiratory tract infection, n=1; pneumonia, n=3).4
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), 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.
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.
CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
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References: 1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019. 2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial [published correction appears in Lancet. 2020;395(10238):1694]. Lancet. 2020;395(10232):1278-1291. 3. Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861. 4. Byrd JC, Hillmen P, Ghia P, et al. First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. Presentation presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 4-8, 2021. 5. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: ELEVATE-TN 4-year follow-up. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 4-8, 2021. 6. Ghia P, Pluta A, Wach M, et al. Acalabrutinib vs idelalisib plus rituximab or bendamustine plus rituximab in relapsed/refractory chronic lymphocytic leukemia: ASCEND final results. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; May 29-31, 2020. 7. Data on File, REF-110039. AstraZeneca Pharmaceuticals LP. 8. Brown JR, Byrd JC, Ghia P, et al. Pooled analysis of cardiovascular events from clinical trials evaluating acalabrutinib monotherapy in patients with chronic lymphocytic leukemia (CLL). Poster presented at: American Society of Hematology (ASH) 62nd Annual Meeting; December 5-8, 2020. Abstract 3146. 9. Brown JR, Byrd JC, Ghia P, et al. Pooled analysis of cardiovascular events from clinical trials evaluating acalabrutinib monotherapy in patients with chronic lymphocytic leukemia (CLL). Abstract presented at: American Society of Hematology (ASH) 62nd Annual Meeting; December 5-8, 2020. Abstract 3146. 10. Data on File, REF-64711. AstraZeneca Pharmaceuticals LP.