CLL video library

INDICATIONS AND USAGE

CALQUENCE is indicated in combination with bendamustine and rituximab (BR) for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are ineligible for autologous hematopoietic stem cell transplantation (HSCT) and as monotherapy for the treatment of adult patients with MCL who have received at least one prior therapy.

SELECT SAFETY INFORMATION

Serious adverse events, including fatal events, have occurred with CALQUENCE, including serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity, including drug-induced liver injury. The most common adverse reactions (≥30%) are diarrhea, upper respiratory tract infection, headache, musculoskeletal pain, lower respiratory tract infection, and fatigue. The most common Grade 3 or 4 laboratory abnormalities (≥10%) are absolute neutrophil count decreased, absolute lymphocyte count decreased, platelets decreased, and hemoglobin decreased.

Please see full Important Safety Information at the end of the video. Please see full Prescribing Information, including Patient Information.

Hello, my name is Doctor Tycel Phillips. I'm an associate professor at City of Hope National Medical Center located in Duarte, California. I've been practicing for the last 12 years in the management and treatment of patients with malignant B-cell lymphoproliferative disorders.

In this video, we will be discussing the 3-year median follow-up data from the LY-004 trial of CALQUENCE in patients with relapsed/refractory mantle cell lymphoma. When I look at follow-up study data for patients with relapsed/refractory mantle cell lymphoma, I ask myself, are the safety and efficacy data at long-term follow-up consistent with the initial analysis? Are safety and tolerability data consistent with the established safety profile? What endpoints are most relevant to helping my patients achieve treatment goals?

LY-004 is one of the largest clinical trials in relapsed or refractory mantle cell lymphoma. LY-004 was a Phase 2, open-label, single-arm, multicenter trial of CALQUENCE monotherapy in 124 patients aged 18 or older with mantle cell lymphoma, who had received at least one prior line of therapy.

The primary endpoint was investigator-assessed overall response rate (ORR); secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS). The initial analysis had a median follow-up of 15.2 months. The long-term analysis had a median follow-up of 38.1 months.

Now, let's take a look at the efficacy data.

The response rate of CALQUENCE was consistent in patients with relapsed or refractory mantle cell lymphoma and has continued to show deep responses over time. In the initial analysis at a median follow-up of 15.2 months, CALQUENCE demonstrated an IRC-assessed overall response rate of 80%: complete response rate of 40%, and partial response rate of 40%. In the long-term analysis, with a median follow-up of 38.1 months, CALQUENCE has continued to show deep responses, with 48% of patients having a complete response. Overall response rate was 81% and partial response rate was 34%.

Duration of response was measured in the 101 patients who achieved a complete response or partial response at the 38-month median follow-up. The median duration of response was around 29 months.

The most important aspect of the LY-004 data, which helps as far as making decisions for treatment for patients with relapsed/refractory mantle cell lymphoma, is efficacy and duration of response data. This calls to mind a patient who was recently started on CALQUENCE. Unfortunately, this patient had a very short duration of response to frontline chemoimmunotherapy. The patient was subsequently started on CALQUENCE and was noted to being in a complete response at first interim assessment after 3 months of therapy.

Now, let's take a look at the safety data from the trial.

In the long-term analysis, with a median follow-up of 38.1 months, the safety profile of CALQUENCE was consistent with the initial analysis. The most common treatment-emergent adverse events occurring in greater than or equal to 20% of patients were infections, headache, diarrhea, bleeding events, fatigue, cough, myalgia, and nausea.

CALQUENCE has demonstrated low rates of atrial fibrillation and hypertension in the LY-004 study. At the long-term analysis, with a median follow-up of 38.1 months, atrial fibrillation was 1.6% for all grades and 0% for Grade 3 or higher, and hypertension was 4% for all grades and 1.6% for Grade 3 or higher. At the interim analysis, with a median follow-up of 15.2 months, atrial fibrillation was 0% for all grades or Grade 3 or higher, and hypertension was 2.4% for all grades and 0.8% for Grade 3 or higher.

These data are consistent with what I see in my clinical practice. Safety continues to be an important aspect of any continuous therapy. The long-term data from LY-004 continues to support the safety of CALQUENCE in patients with relapsed/refractory mantle cell lymphoma. The adverse reactions noted are all generally managed with the assistance of the healthcare team.

Few patients discontinued therapy due to adverse reactions. In the initial analysis, dose reductions due to adverse reactions were reported in 1.6% of patients, and 6.5% of patients discontinued therapy due to adverse reactions. Median duration of therapy was 16.6 months, with a range of 0.1 to 26.6 months. At the 38-month median follow-up, dose reductions due to adverse events were reported in 2% of patients, and 11% of patients discontinued therapy due to adverse events.

In LY-004, 8 out of 10 patients with relapsed/refractory mantle cell lymphoma responded to CALQUENCE, with a 29-month duration of response at the 38-month median follow-up. At a median follow-up of 15.2 months, the most common adverse reactions occurring in greater than or equal to 20% of patients with CALQUENCE were anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, and bruising. The safety profile remained consistent over time as demonstrated in the initial analysis and observed with the 38-month data, including low rates of atrial fibrillation and hypertension.

The 3-year follow-up data from the LY-004 study is consistent with what I see in my clinical practice. Thanks for watching. Stay tuned for full Important Safety Information for CALQUENCE.

INDICATIONS AND USAGE

CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor indicated in combination with bendamustine and rituximab (BR) for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are ineligible for autologous hematopoietic stem cell transplantation (HSCT) and as monotherapy for the treatment of adult patients with MCL who have received at least one prior therapy.

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 32% of 1,764 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (19% of all patients, including pneumonia in 9%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 2.7% 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 treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 4.4% of patients, with fatal hemorrhage occurring in 0.2% of 1,764 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 40% of patients. Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 7% of patients taking CALQUENCE without antithrombotic agents and 4% 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 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias

CALQUENCE can cause Grade 3 or 4 cytopenias. Grade 3 or 4 cytopenias included absolute neutrophil count decreased (26%), platelets decreased (10%), hemoglobin decreased (10%), and absolute lymphocyte count decreased (10%) in patients treated with CALQUENCE alone or in combination with obinutuzumab; Grade 4 neutropenia developed in 14% 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 18% of 1,764 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 10% of patients, followed by other solid tumors in 9% (including melanoma, lung cancer, gastrointestinal cancers, and genitourinary cancers) and hematologic malignancies (1%). Monitor patients for the development of second cancers and advise protection from sun exposure.

Cardiac Arrhythmias

Fatal and serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade 3 or 4 atrial fibrillation or flutter was reported in 2.6% of 1,764 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 7% of all patients. Grade 3 or higher ventricular arrhythmia events were reported in 0.6% of patients, including fatal cases in 0.3% of all patients. The risk of arrhythmias may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (For 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

Previously Untreated Mantle Cell Lymphoma

The most common adverse reactions (≥15%) of any grade in patients with previously untreated MCL who received CALQUENCE plus BR were rash (47%), COVID-19 (38%), fatigue (37%), diarrhea (37%), pneumonia (31%), headache (31%), upper respiratory tract infection (30%), pyrexia (29%), cough (27%), vomiting (26%), constipation (25%), hemorrhage (20%), edema (20%), secondary primary malignancy (19%), dizziness (18%), arthralgia (18%), and dyspnea (17%). Grade 4 laboratory abnormalities in >15% of patients treated with CALQUENCE plus BR include lymphocytes decreased (26%), absolute neutrophils decreased (36%), and uric acid increased (17%).

Serious adverse reactions occurred in 69% of patients who received CALQUENCE plus BR. Serious adverse reactions reported in ≥2% of patients were pneumonia (23%; includes COVID-19 pneumonia), COVID-19 (20%; includes COVID-19 pneumonia), second primary malignancy (7%), pyrexia (6%), rash (3.4%), febrile neutropenia (3.4%), atrial fibrillation (3%), sepsis (2.7%), and anemia (2.4%). Fatal adverse reactions that occurred within 30 days of the last study treatment were reported in 12% who received CALQUENCE plus BR including COVID-19 (6%; includes COVID-19 pneumonia), pneumonia (1%), second primary malignancy (0.7%), sepsis (0.3%), and pneumonitis (0.3%).

Adverse reactions led to permanent discontinuation of CALQUENCE in 43%, dosage interruptions in 74%, and dosage reductions in 10% of patients. Adverse reactions that resulted in dosage modification in >10% included infections, cytopenias, rashes, and gastrointestinal toxicity. Adverse reactions which resulted in permanent discontinuation of CALQUENCE in ≥4% of patients included COVID-19 (includes COVID-19 pneumonia) and neutropenia.

Previously Treated Mantle Cell Lymphoma

The most common adverse reactions (≥20%) of any grade in patients with relapsed or refractory MCL exposed to CALQUENCE 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 to 1.5 to 3 times the upper limit of normal (ULN) occurred in 4.8% of patients.

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.

INDICATION AND USAGE

CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

SELECT SAFETY INFORMATION

Serious adverse events, including fatal events, have occurred with CALQUENCE, including serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity, including drug-induced liver injury.

My name is Dr Elizabeth Brem and I am a medical oncologist at UCI Health.

I specialize in the diagnosis and treatment of B-cell malignancies, including chronic lymphocytic leukemia, or CLL. I see adult patients with CLL across various ages and disease states, with the majority of them being 50 years or older.

We know that CLL is a chronic disease that requires a long-term management, and more long-term follow up data can be valuable when making treatment decisions.

When it comes to informing my treatment decisions, factors including long-term follow-up data, a demonstrated safety profile, dosage and administration, and the patient's other medical problems play a crucial role in deciding on an appropriate treatment for my patients.

It's the data, including long-term follow-up data for CALQUENCE, that give me confidence in this treatment. And of course, in terms of its demonstrated safety profile, I have a high opinion of CALQUENCE based on both data from the clinical trials, as well as my personal experience.

My patients on CALQUENCE have done incredibly well and many have been progression-free for several years with some side effects that can be managed. This experience has reinforced my confidence in prescribing CALQUENCE.

Let's first look at the CALQUENCE data in first-line CLL.

ELEVATE-TN was a study of patients with previously untreated CLL for which there was a 90% PFS risk reduction with CALQUENCE plus obinutuzumab vs obinutuzumab plus chlorambucil and an 80% PFS risk reduction with CALQUENCE monotherapy vs obinutuzumab plus chlorambucil at 28.3-month median follow-up.

We also now have long-term follow-up data at 6 years. You can see here an estimated 6-year PFS of 78% in the CALQUENCE plus obinutuzumab arm and 62% in the CALQUENCE monotherapy arm.

Based on my experience, these data are consistent with what I have seen in my own patients on CALQUENCE.

I tend to prescribe BTK inhibitors in my high-risk patients with TP53 mutation or 17p deletion.

ELEVATE-TN included both CALQUENCE with obinutuzumab and CALQUENCE as a monotherapy. Which means that I have the option to use CALQUENCE with or without the monoclonal antibody, depending on my patient's treatment goal.

And as you can see, the rates of select cardiovascular AEs were low with CALQUENCE, both with and without obinutuzumab, which reinforces my confidence in prescribing CALQUENCE.

From the interim analysis for the most common ARs and events of clinical interest shown here, the safety and tolerability results of CALQUENCE at 6-year follow up were consistent.

When the ELEVATE-RR data was released, I genuinely appreciated AstraZeneca's bold decision to evaluate CALQUENCE in a head-to-head trial versus ibrutinib.

ELEVATE-RR is another study that helps in my treatment decision making for patients with relapse or refractory CLL.

ELEVATE-RR was the first Phase 3 study of a highly selective, next-generation BTKi vs ibrutinib and all of the patients enrolled in this study were high-risk patients. As you can see in the figure, the median PFS was 38.4 months for both arms at 41-month median follow-up.

Safety results seen in ELEVATE-RR were consistent with the ASCEND study in patients with relapsed/refractory CLL.

One of the reasons that I choose CALQUENCE for my patients is because of its established cardiovascular safety profile including the low rates of atrial fibrillation, hypertension, and Grade 3 or higher bleeding. This data is especially important to consider when it comes to my patients with cardiovascular comorbidities.

The approval of CALQUENCE was based on two Phase 3 studies: ELEVATE-TN for previously untreated CLL and ASCEND for relapsed/refractory CLL.

I touched on the ELEVATE-TN study earlier, but ASCEND was the first Phase 3 study of a BTKi vs IdR or BR in relapsed/refractory CLL. With a follow-up of nearly 4 years, you can see there is an estimated PFS of 62% in the CALQUENCE arm and 19% in the IdR/BR arm.

Consistent with the other studies, there were also low rates of atrial fibrillation, hypertension, and major hemorrhage. Together, the overall safety profile of CALQUENCE gives me assurance when prescribing CALQUENCE for my patients.

To learn more about CALQUENCE, take a moment to read through the study designs and additional clinical data, including the most common adverse events and events of clinical interest for ELEVATE-TN, ELEVATE-RR, and the ASCEND Phase 3 studies here.

With 6-year median follow-up data and demonstrated safety profile, I know what I can expect with CALQUENCE.

Regarding dosing and administration, for my patients with difficulty swallowing, I use CALQUENCE because of the small tablet size and its straightforward dosing regimen.

In my experience, for the majority of my patients, CALQUENCE is a tolerable treatment, where I can help manage some of their side effects.

Additionally, the MAIC, or matched-adjusted indirect comparison analysis, between CALQUENCE and Zanubrutinib may provide some additional context that may be helpful.

While a MAIC analysis has its limitations, it is an established method for indirectly comparing the relative treatment effect of different therapies.

Despite the limitations of conducting these types of analyses, they do help to see the differences, as the inclusion criteria differed between the studies.

By accounting for population differences between the studies, the MAIC analysis may help make informed decisions with the data currently available.

Scan these QR codes to learn more.

To learn more about CALQUENCE, scan the QR code or visit calquencehcp.com

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 29% of 2,055 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (18% of all patients, including pneumonia in (14%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 8% 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 treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 4.7% of patients, with fatal hemorrhage occurring in 0.1% of 2,055 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 39% of patients. Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 5% of patients taking CALQUENCE without antithrombotic agents and 3.2% 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 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias

CALQUENCE can cause Grade 3 or 4 cytopenias. Grade 3 or 4 cytopenias included absolute neutrophil count decreased (28%), absolute lymphocyte count decreased (10%), hemoglobin decreased (9%), and platelets decreased (9%) in 1,758 patients treated with CALQUENCE alone and in combination with obinutuzumab or venetoclax; Grade 4 neutropenia developed in 14% 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 16% of 2,055 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 9% of patients, followed by other solid tumors in 8% (including melanoma, lung cancer, gastrointestinal cancers, and genitourinary cancers) and hematologic malignancies (1.1%). Fatal second primary malignancies occurred in 0.8% of patients. Monitor patients for the development of second cancers and advise protection from sun exposure.

Cardiac Arrhythmias

Fatal and serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade 3 or 4 atrial fibrillation or flutter was reported in 2.2% of 2,055 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 7% of all patients. Grade 3 or higher ventricular arrhythmia events were reported in 0.5% of patients, including fatal cases in 0.3% of all patients. The risk of arrhythmias 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

Chronic Lymphocytic Leukemia

The most common adverse reactions (≥30%) of any grade in patients with CLL in the ELEVATE-TN and ASCEND studies exposed to CALQUENCE (n=511) 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 in the ELEVATE-TN study exposed to CALQUENCE (n=357), 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% (69/178) of patients in the CALQUENCE plus obinutuzumab arm (n=178) and 32% (57/179) in the CALQUENCE monotherapy arm (n=179), most often due to events of pneumonia (2.8% to 7%).

Adverse reactions led to CALQUENCE dose reduction in 7% and 4% of patients in the CALQUENCE plus obinutuzumab arm and CALQUENCE monotherapy arm, respectively. Adverse reactions led to discontinuation in 11% and 10% of patients, respectively. Increases in creatinine to 1.5 to 3 times 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 in the ASCEND study exposed to CALQUENCE (n=154), 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, 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.

INDICATION AND USAGE

CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

SELECT SAFETY INFORMATION

Serious adverse events, including fatal events, have occurred with CALQUENCE, including serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity, including drug-induced liver injury.

My name is Dr Yair Levy and I serve as the director of hematologic malignancies research at Texas Oncology-Baylor Charles A. Sammons Cancer Center. I specialize in hematology, including lymphoma, myeloma, and leukemia.

I see about 150 CLL patients at any given time. In CLL, there's no such thing as a typical patient. One patient may present symptomatic, while another patient may present with only an elevated white blood cell count.

But there are some things we can expect. CLL is a disease that primarily impacts the elderly. As a result, many patients have comorbidities at the time of CLL diagnosis, and some comorbidities are cardiovascular-related. For example, hypertension is an important comorbidity, and obesity and poor cytogenetics may also contribute to a patient's baseline risk. Additionally, managing hypertension is important, as some CLL treatments are associated with hypertension.

Tolerability today can be different. From my experience, many of my patients who have been treated with a BTKi tolerate their treatment well. So, when it comes time to informing my treatment decisions, safety data, including cardiovascular risk, are important considerations.

The reason I choose CALQUENCE is based on its cardiovascular safety data specifically for its low rates of atrial fibrillation, hypertension, and major bleeding. Let's take a closer look at these.

In ELEVATE-TN, a study of patients with previously untreated chronic lymphocytic leukemia, there were low rates of atrial fibrillation, hypertension, and major bleeding in the group of patients who received CALQUENCE with or without obinutuzumab.

ELEVATE-RR was the first head-to-head trial of CALQUENCE versus ibrutinib. It was a randomized, multicenter, open-label Phase 3 trial of CALQUENCE versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia with the presence of del 17p and/or del 11q.

In this trial, the rates of atrial fibrillation, hypertension, and bleeding events with CALQUENCE remained steady over time.

The overall incidence rate of any grade atrial fibrillation for CALQUENCE was 9% and for ibrutinib was 16% at a median follow-up of 41 months and 9% and 23%, respectively, for hypertension. For any grade bleeding events, CALQUENCE had an overall incidence rate of 38% and ibrutinib had 51%.

To learn more about CALQUENCE, take a moment to read through the study designs and additional safety data, including the most common adverse events and events of clinical interest for ELEVATE-TN, ELEVATE-RR, and the ASCEND Phase 3 studies here.

I'm comfortable with the CALQUENCE safety profile based on my experience. Additional safety results from ELEVATE-TN in 1L CLL showed that the discontinuation rates due to adverse events remained low in the CALQUENCE + obinutuzumab arm, with longer treatment exposure. This was also shown to be the case in ELEVATE-TN for both CALQUENCE monotherapy and combination therapy.

For ELEVATE-RR, at the 41-month median follow-up, discontinuation due to adverse events was 15% for patients taking CALQUENCE, while in ASCEND, at the 46.5-month follow-up, it was 23%.

The cardiovascular safety profile is an important consideration. Based on the cardiovascular safety data and profile, which include low rates of atrial fibrillation, hypertension, and major bleeding, I choose CALQUENCE.

I also like to take into consideration additional analyses to help make informed decisions. While there's no head-to-head studies between CALQUENCE and zanubrutinib the matching-adjusted indirect comparisons, or MAIC, are helpful resources. Scan these QR codes to learn more.

To learn more about CALQUENCE, scan the QR code or visit calquencehcp.com.

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 29% of 2,055 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (18% of all patients, including pneumonia in 14%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 8% 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 treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 4.7% of patients, with fatal hemorrhage occurring in 0.1% of 2,055 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 39% of patients. Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 5% of patients taking CALQUENCE without antithrombotic agents and 3.2% 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 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias

CALQUENCE can cause Grade 3 or 4 cytopenias. Grade 3 or 4 cytopenias included absolute neutrophil count decreased (28%), absolute lymphocyte count decreased (10%), hemoglobin decreased (9%), and platelets decreased (9%) in 1,758 patients treated with CALQUENCE alone and in combination with obinutuzumab or venetoclax; Grade 4 neutropenia developed in 14% 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 16% of 2,055 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 9% of patients, followed by other solid tumors in 8% (including melanoma, lung cancer, gastrointestinal cancers, and genitourinary cancers) and hematologic malignancies (1.1%). Fatal second primary malignancies occurred in 0.8% of patients. Monitor patients for the development of second cancers and advise protection from sun exposure.

Cardiac Arrhythmias

Fatal and serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade 3 or 4 atrial fibrillation or flutter was reported in 2.2% of 2,055 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 7% of all patients. Grade 3 or higher ventricular arrhythmia events were reported in 0.5% of patients, including fatal cases in 0.3% of all patients. The risk of arrhythmias 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

Chronic Lymphocytic Leukemia

The most common adverse reactions (≥30%) of any grade in patients with CLL in the ELEVATE-TN and ASCEND studies exposed to CALQUENCE (n=511) 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 in the ELEVATE-TN study exposed to CALQUENCE (n=357), 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% (69/178) of patients in the CALQUENCE plus obinutuzumab arm (n=178) and 32% (57/179) in the CALQUENCE monotherapy arm (n=179), most often due to events of pneumonia (2.8% to 7%).

Adverse reactions led to CALQUENCE dose reduction in 7% and 4% of patients in the CALQUENCE plus obinutuzumab arm and CALQUENCE monotherapy arm, respectively. Adverse reactions led to discontinuation in 11% and 10% of patients, respectively. Increases in creatinine to 1.5 to 3 times 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 in the ASCEND study exposed to CALQUENCE (n=154), 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, 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.

INDICATION AND USAGE

CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

SELECT SAFETY INFORMATION

Serious adverse events, including fatal events, have occurred with CALQUENCE, including serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity, including drug-induced liver injury. The most common adverse reactions (≥30%) are upper respiratory tract infection, diarrhea, headache, and musculoskeletal pain. The most common Grade 3 or 4 laboratory abnormalities (≥10%) are absolute neutrophil count decreased, uric acid increased, absolute lymphocyte count decreased, and platelets decreased.

Please see full Important Safety Information at the end of the video.

Please see full Prescribing Information, including Patient Information.

Hi. I'm Dr. Susan O'Brien. I'm a professor of medicine at the University of California at Irvine Chao Family Comprehensive Cancer Center in Orange, California. And I'm going to talk to you today about the six-year follow-up of the ELEVATE-TN trial.

As you can see, 535 adult patients with previously untreated CLL were randomized into three arms: CALQUENCE plus obinutuzumab, CALQUENCE monotherapy, or obinutuzumab plus chlorambucil. We will take a look at baseline characteristics in a moment.

The primary endpoint at the interim analysis was PFS for CALQUENCE and obinutuzumab versus obinutuzumab and chlorambucil, which was assessed by an Independent Review Committee, or IRC. Select secondary endpoints included IRC-assessed PFS of CALQUENCE monotherapy versus obinutuzumab and chlorambucil, and IRC-assessed overall response rate, overall survival, and safety.

At six-year median follow-up, investigator-assessed PFS, overall response rate, and overall survival were reported. The interim analysis had a median 28.3-month follow-up, with a range of 0 to 40.8 months. The long-term analysis had a median follow-up of 74.5 months, with a range of 0 to 89 months.

The table shows that baseline demographic and disease characteristics were similar, and generally well balanced between treatment arms. The study included a wide range of patient types, many with high-risk genomic features.

The interim analysis at 28.3 months median follow-up showed an unprecedented progression-free survival benefit with CALQUENCE plus or minus obinutuzumab versus chlorambucil-obinutuzumab as a first-line treatment for CLL. There was a 90% PFS risk reduction with CALQUENCE plus obinutuzumab compared to chlorambucil and obinutuzumab, and an 80% PFS risk reduction with CALQUENCE monotherapy.

In the long-term analysis of ELEVATE-TN over approximately six years, there was an 86% risk reduction in disease progression or death with CALQUENCE plus obinutuzumab. Please note that the timing of long-term follow-up was not prespecified and the analysis was descriptive in nature.

What we see in the graph on screen is the estimated percentage of patients who were alive and progression-free in each arm. At 72 months, these percentages were 78% with CALQUENCE and obinutuzumab, 62% with CALQUENCE monotherapy, and 17% with chlorambucil and obinutuzumab. The median PFS was not reached for patients treated with CALQUENCE, with or without obinutuzumab, and was 27.8 months with chlorambucil and obinutuzumab.

The ELEVATE-TN data provides me with reassurance regarding selecting CALQUENCE as a first-line treatment option for my appropriate patients. I've observed similar results with CALQUENCE treatment in first-line CLL in my practice, so the data helps reinforce this treatment approach for me.

Next, I'd like to discuss the overall survival results. Overall survival was a select secondary endpoint in the ELEVATE-TN study. The estimated 72-month overall survival rates were 84% with CALQUENCE and obinutuzumab, 76% with CALQUENCE monotherapy, and 75% with chlorambucil and obinutuzumab.

Of note, a total of 79 patients, or 45%, after progressing on chlorambucil and obinutuzumab, crossed over to the CALQUENCE monotherapy arm. I'd also like to point out that at 74.5-month median follow-up, the overall survival data were immature. Hence, the hazard ratio is not stable and can continue to change as more events occur. Median overall survival was not reached in any treatment arm of the ELEVATE-TN trial at 74.5-month median follow-up.

At 28.3-month median follow-up, CALQUENCE and obinutuzumab had superior overall response rate versus chlorambucil plus obinutuzumab. The difference was not statistically significant for CALQUENCE monotherapy versus chlorambucil plus obinutuzumab.

Now, let's move on to the overall response rate findings at the 74.5-month median follow-up. The CALQUENCE plus obinutuzumab overall response rate was 96%, and there was a combined complete response with incomplete hematologic recovery equal to 37%. The overall response rate for CALQUENCE monotherapy was 90%, and the combined complete response with incomplete hematologic recovery was 19%.

The obinutuzumab and chlorambucil arm had an overall response rate of 83%, and a combined complete response with incomplete hematologic recovery of 14%. Please note that the timing of long-term follow-up was not prespecified, and the analysis was descriptive in nature.

Before we review the safety data of ELEVATE-TN, I'd like to briefly share PFS observations in specific subgroups. At 28.3-month median follow-up, CALQUENCE plus or minus obinutuzumab delivered consistent PFS results across high-risk subgroups.

The results of investigator-assessed PFS in patients with deletion 17p and/or TP53 mutations, typically considered high-risk genomic profiles, are shown in the graph you see here. CALQUENCE with or without obinutuzumab delivered consistent PFS results, regardless of 17p deletion or TP53 mutational status. These are important results, since approximately 4 to 9% of previously untreated CLL patients present with deletion 17p, and 5 to 12% present with TP53 mutation.

Another important CLL feature that has historically affected prognosis is IGHV gene mutation status; and unmutated status has generally predicted a more aggressive clinical course. Up to 60% of previously untreated CLL patients can present with unmutated IGHV status.

The PFS rates of first-line CLL patients treated with CALQUENCE based on IGHV status are shown in the graph you see here.

CALQUENCE with or without obinutuzumab delivered consistent PFS results, regardless of IGHV mutational status.

Let's spend time reviewing the long-term safety data from ELEVATE-TN. Safety and tolerability results in the 6-year median follow-up were consistent with the established profile of CALQUENCE. At 74.5-month follow-up, any grade infections at 83%, bleeding at 53%, and second primary malignancies at 20%, were reported in patients in the CALQUENCE plus obinutuzumab arm.

Any grade infections at 80%, bleeding at 45%, and second primary malignancies at 20%, were also reported in patients in the CALQUENCE monotherapy arm. There were low rates of atrial fibrillation, hypertension, and major bleeding. At median 74.5-month follow-up,, rate of any grade atrial fibrillation was 7%, hypertension was 11%, and major bleeding was 9% in the CALQUENCE plus obinutuzumab arm. Rate of any grade atrial fibrillation was 9%, hypertension was 11%, and major bleeding was 6% in the CALQUENCE monotherapy arm.

I like using CALQUENCE in my patients because it has a very low rate of hypertension. And I've generally not encountered much problems with patients needing, let's say, an increase in their anti-hypertensives, or new anti-hypertensives. Certainly, atrial fibrillation can occur. I would say it's infrequent, but it does occur. And if I'm going to manage that, I'm going to manage that with a cardiologist.

As you can see in the table, at 6-year median follow-up, the most common adverse events, of any grade and grade 3 or greater, were consistent with the established profile of CALQUENCE, apart from COVID-19 observed during the pandemic. The most common adverse events, seen in at least 30%, of any grade in the CALQUENCE plus obinutuzumab arm, were diarrhea, headache, arthralgia, neutropenia, and fatigue. In the CALQUENCE monotherapy arm, the most common adverse events were diarrhea and headache. The most common adverse events of any grade, meaning those observed in 30% or more of patients, were diarrhea, headache, arthralgia, neutropenia, and fatigue.

In terms of managing the adverse events, for diarrhea I generally use loperamide.

The oldest patient that I have ever treated with CALQUENCE was a 90-year-old gentleman. And when we sat down and discussed it, I talked about the side effects, and in particular, I mentioned headache, because it's not infrequent, and I wanted him to know what he could do if he got a headache. And so, I told him he could use aspirin, or acetaminophen, or even caffeine seems to work quite well. And that the duration, if it occurred, would be pretty short.

So, the data from the ELEVATE-TN trial, including the 6 years of median follow-up, really reflect what I've seen in my practice.

At the interim analysis, with a median follow-up of 28.3 months, treatment discontinuation rates due to adverse events were 10% for CALQUENCE monotherapy and 11% for CALQUENCE plus obinutuzumab. In the long-term analysis, with a median follow-up of 74.5 months, treatment discontinuation rates due to adverse events were 18% for CALQUENCE monotherapy and 21% for CALQUENCE plus obinutuzumab.

Treatment was ongoing in 54% of patients in the CALQUENCE plus obinutuzumab arm and 47% of patients in the CALQUENCE monotherapy arm at the time of the data cutoff of March 3rd, 2023.

In my view, these low discontinuation rates are encouraging. Tolerability is important for treatment, and I am able to help support my patients with monitoring and management of adverse events.

In summary, at 74.5-month median follow-up, the hazard ratio was 0.14, with a 95% confidence interval of 0.1 to 0.2 for CALQUENCE and obinutuzumab versus chlorambucil and obinutuzumab.

Estimated 6-year PFS rate with CALQUENCE and obinutuzumab was 78%, and the estimated PFS rate at this time period with CALQUENCE monotherapy was 62%.

The estimated 72-month overall survival rates were 84% with CALQUENCE and obinutuzumab and 76% with CALQUENCE monotherapy.

Safety and tolerability, aside from COVID-19 that was observed during the pandemic, were consistent with the established safety profile, and the incidence rates of cardiovascular adverse events, including atrial fibrillation, hypertension, and major bleeding, were low with CALQUENCE with and without obinutuzumab. Seeing the ELEVATE-TN, including 6-year median follow-up data, has been helpful to inform CLL treatment decisions in my clinical practice because this data adds to the growing body of evidence supporting the use of CALQUENCE as a first-line treatment option.

The data from ELEVATE-TN, including the six years of median follow-up, do reflect what I have seen in my practice, which is that patients can stay on the drug.

The ELEVATE-TN trial showed that both CALQUENCE arms were better than chlorambucil and obinutuzumab. So, you can choose whether to use CALQUENCE as a monotherapy, or in combination with obinutuzumab.

I think an important component of the ELEVATE-TN study that gives me a lot of confidence in the results is the 6-year follow-up. That's a pretty long follow-up in a front-line CLL population, and the data look really excellent.

Thanks for watching and stay tuned for the Important Safety Information for CALQUENCE.

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 29% of 2,055 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (18% of all patients, including pneumonia in 14%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 8% 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 treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 4.7% of patients, with fatal hemorrhage occurring in 0.1% of 2,055 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 39% of patients. Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 5% of patients taking CALQUENCE without antithrombotic agents and 3.2% 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 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias

CALQUENCE can cause Grade 3 or 4 cytopenias. Grade 3 or 4 cytopenias included absolute neutrophil count decreased (28%), absolute lymphocyte count decreased (10%), hemoglobin decreased (9%), and platelets decreased (9%) in 1,758 patients treated with CALQUENCE alone and in combination with obinutuzumab or venetoclax; Grade 4 neutropenia developed in 14% 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 16% of 2,055 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 9% of patients, followed by other solid tumors in 8% (including melanoma, lung cancer, gastrointestinal cancers, and genitourinary cancers) and hematologic malignancies (1.1%). Fatal second primary malignancies occurred in 0.8% of patients. Monitor patients for the development of second cancers and advise protection from sun exposure.

Cardiac Arrhythmias

Fatal and serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade 3 or 4 atrial fibrillation or flutter was reported in 2.2% of 2,055 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 7% of all patients. Grade 3 or higher ventricular arrhythmia events were reported in 0.5% of patients, including fatal cases in 0.3% of all patients. The risk of arrhythmias 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

Chronic Lymphocytic Leukemia

The most common adverse reactions (≥30%) of any grade in patients with CLL in the ELEVATE-TN and ASCEND studies exposed to CALQUENCE (n=511) 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 in the ELEVATE-TN study exposed to CALQUENCE (n=357), 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% (69/178) of patients in the CALQUENCE plus obinutuzumab arm (n=178) and 32% (57/179) in the CALQUENCE monotherapy arm (n=179), most often due to events of pneumonia (2.8% to 7%).

Adverse reactions led to CALQUENCE dose reduction in 7% and 4% of patients in the CALQUENCE plus obinutuzumab arm and CALQUENCE monotherapy arm, respectively. Adverse reactions led to discontinuation in 11% and 10% of patients, respectively. Increases in creatinine to 1.5 to 3 times 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 in the ASCEND study exposed to CALQUENCE (n=154), 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, 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.

INDICATION AND USAGE

CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

SELECT SAFETY INFORMATION

Serious adverse events, including fatal events, have occurred with CALQUENCE, including serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity, including drug-induced liver injury. The most common adverse reactions (≥30%) are upper respiratory tract infection, diarrhea, headache, and musculoskeletal pain. The most common Grade 3 or 4 laboratory abnormalities (≥10%) are absolute neutrophil count decreased, uric acid increased, absolute lymphocyte count decreased, and platelets decreased.

Please see full Important Safety Information at the end of the video.

Please see full Prescribing Information, including Patient Information.

Hello. My name is Alan Skarbnik. I'm the Director of the Lymphoma and Chronic Lymphocytic Leukemia Program and the Immune Effector Cell Therapeutics Program at Novant Health Cancer Institute in Charlotte, North Carolina.

Two clinical trials studied CALQUENCE in patients with relapsed/refractory CLL. The ASCEND trial compared CALQUENCE versus either idelalisib and rituximab or bendamustine and rituximab, and ELEVATE-RR, which compared CALQUENCE versus ibrutinib.

ALPINE, zanubrutinib versus ibrutinib, is another independent trial in relapsed/refractory CLL.

Currently, there are no head-to-head clinical data available to make a direct comparison between CALQUENCE and zanubrutinib. Cross-trial comparisons are confounded by differences in patient population, follow-up, and analysis protocols. And the impact of the trial differences is unknown, which may make direct comparisons of the results unreliable.

A descriptive analysis called a matching-adjusted indirect comparison was performed between two Phase 3 trials to better understand the profiles of CALQUENCE and zanubrutinib relative to each other. This analysis does not imply superior efficacy or safety of one drug over the other and is provided for informational purposes only.

Before looking further at the MAIC analysis, let's review the ASCEND and ALPINE trials. ASCEND was a Phase 3, open label, randomized, multicentered trial in 310 patients with relapsed/refractory CLL, evaluating CALQUENCE versus the investigator's choice of idelalisib-rituximab or bendamustine-rituximab.

The primary endpoint at the interim analysis, median follow-up of 16.1 months, was Independent Review Committee–assessed progression-free survival or PFS. After the interim analysis, PFS was investigator-assessed only.

Select secondary endpoints were overall response rate, overall survival, and safety. The four-year analysis had a median follow-up of 46.5 months.

ALPINE was a Phase 3, open-label, randomized, multicentered trial in 652 patients with relapsed/refractory CLL, comparing Zanubrutinib versus ibrutinib. The primary endpoint was investigator-assessed overall response rate. Key secondary endpoints were investigator-assessed PFS and incidents of atrial fibrillation or flutter. The final analysis had a median follow-up of 29.6 months.

The estimated percentage of patients who were alive and progression-free at 42 months was 62% for CALQUENCE and 19% for idelalisib-rituximab or bendamustine-rituximab.

At median 46.5-month follow-up, median PFS was not reached with CALQUENCE versus 16.8 months for idelalisib-rituximab or bendamustine-rituximab. The median 46.5-month follow-up data from ASCEND have not been reviewed by the FDA and are not included in the prescribing information for CALQUENCE.

In ASCEND, safety results of the 46.5-month median follow-up were consistent with the interim analysis results.

At 46.5-month median follow-up, in patients treated with CALQUENCE, common adverse events and events of clinical interest included: infections, 68% any grade, 29% grade three or higher; hemorrhage, 31% any grade, 2.6% grade three or higher, including major hemorrhage, 3.2% any grade, 2.6% grade three or higher; atrial fibrillation, 8% any grade, 1.3% grade three or higher; hypertension, 8% any grade, 4.5% grade three or higher;

Second primary malignancies, excluding non-melanoma skin carcinoma, 7% any grade, 6% grade three or higher and tumor lysis syndrome, 0.6% any grade, 0.6% grade three or higher. The median duration of CALQUENCE exposure was 44.2 months, ranging from 1.1 to 54.2 months. And treatment discontinuations due to adverse events occurred in 23% of CALQUENCE-treated patients.

MAIC is a type of indirect treatment comparison that can provide an alternative way to look at data from two independent clinical trials. MAIC is accepted by major health economics and outcomes research organizations, including the National Institute for Health and Care Excellence, NICE.

ASCEND (CALQUENCE versus idelalisib-rituximab or bendamustine-rituximab) and ALPINE (Zanubrutinib versus ibrutinib) patient populations were similar enough to compare in an unanchored, indirect treatment comparison. The studies also provided an appropriate sample size for analysis after match adjusting.

In this analysis, the matching-adjusted indirect comparison involved weighting individual patient characteristics of the CALQUENCE arm of the ASCEND trial to match the mean baseline characteristics of the zanubrutinib arm of the ALPINE trial. Variables included in the matching-adjusted indirect comparison were age, region of enrollment, sex, bulky disease, IGHV, deletion 17p, deletion 11q, TP53 mutations without deletion 17p, Rai stage, ECOG performance status, prior chemoimmunotherapy, and number of prior lines of therapy. The weighted analysis included 149 patients from the CALQUENCE arm of ASCEND and 327 patients from the zanubrutinib arm of ALPINE.

Complex karyotype and beta-2 microglobulin were not included in the matching because of the high proportion of missing data for complex karyotype in ALPINE, and the lack of prognostic or predictive effect of beta-2 microglobulin on investigator-assessed PFS.

The matching of patient characteristics across studies have only limited impact on baseline and outcome data, given the similarity and characteristics across studies. The MAIC results were therefore consistent with an unweighted comparison.

Matching-adjusted indirect comparison of estimated progression-free survival at 12 months was, CALQUENCE weighted, 91%, zanubrutinib 92%. Matching-adjusted indirect comparison of estimated progression-free survival at 24 months was, CALQUENCE weighted, 76%, and zanubrutinib 78%.

The prematching hazard ratio for CALQUENCE and zanubrutinib was 0.94. The post-matching hazard ratio for CALQUENCE and zanubrutinib was 0.9.

For the safety analysis, 148 patients were evaluated using the same weighing as the efficacy analysis. The data cutoff was applied to the CALQUENCE data set, resulting in a 28.4 months median duration of treatment exposure that was comparable to that of the zanubrutinib data set of ALPINE.

According to the matching-adjusted indirect comparison of adverse events, the occurrence of atrial fibrillation or flutter was all grade, 6% with CALQUENCE, and 5% with zanubrutinib; grade three or higher, 1.4% with CALQUENCE, and 2.5% with zanubrutinib.

The incidence of hemorrhage was, any grade, 28% with CALQUENCE and 42% with zanubrutinib; grade three or higher, 2% with CALQUENCE, and 3.4% with zanubrutinib.

The incidence of hypertension was, any grade, 5% with CALQUENCE and 24% with zanubrutinib; grade three or higher, 4.1% with CALQUENCE and 15% with zanubrutinib.

The incidence of serious adverse events was, any grade, 31% with CALQUENCE and 42% with zanubrutinib; grade three or higher, not applicable.

Adverse events leading to treatment discontinuation occurred in 18% of patients on CALQUENCE and 16% of patients on zanubrutinib. Adverse events leading to dose reduction occurred in 4.1% of patients on CALQUENCE and 12.3% of patients on zanubrutinib. Please note, the comparison of safety results across data sets may be subject to confounding, if variables predictive of safety outcomes were imbalanced across arms. Any event, new or worsening of an existing event, after the data cutoff, were not included.

In the absence of a head-to-head trial comparing those two agents, MAIC is an established methodology to compare across trials, while trying to minimize bias, and informing us on what could be an appropriate decision for our patients. Thanks for watching.

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 29% of 2,055 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (18% of all patients, including pneumonia in 14%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 8% 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 treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 4.7% of patients, with fatal hemorrhage occurring in 0.1% of 2,055 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 39% of patients. Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 5% of patients taking CALQUENCE without antithrombotic agents and 3.2% 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 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias

CALQUENCE can cause Grade 3 or 4 cytopenias. Grade 3 or 4 cytopenias included absolute neutrophil count decreased (28%), absolute lymphocyte count decreased (10%), hemoglobin decreased (9%), and platelets decreased (9%) in 1,758 patients treated with CALQUENCE alone and in combination with obinutuzumab or venetoclax; Grade 4 neutropenia developed in 14% 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 16% of 2,055 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 9% of patients, followed by other solid tumors in 8% (including melanoma, lung cancer, gastrointestinal cancers, and genitourinary cancers) and hematologic malignancies (1.1%). Fatal second primary malignancies occurred in 0.8% of patients. Monitor patients for the development of second cancers and advise protection from sun exposure.

Cardiac Arrhythmias

Fatal and serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade 3 or 4 atrial fibrillation or flutter was reported in 2.2% of 2,055 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 7% of all patients. Grade 3 or higher ventricular arrhythmia events were reported in 0.5% of patients, including fatal cases in 0.3% of all patients. The risk of arrhythmias 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

Chronic Lymphocytic Leukemia

The most common adverse reactions (≥30%) of any grade in patients with CLL in the ELEVATE-TN and ASCEND studies exposed to CALQUENCE (n=511) 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 in the ELEVATE-TN study exposed to CALQUENCE (n=357), 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% (69/178) of patients in the CALQUENCE plus obinutuzumab arm (n=178) and 32% (57/179) in the CALQUENCE monotherapy arm (n=179), most often due to events of pneumonia (2.8% to 7%).

Adverse reactions led to CALQUENCE dose reduction in 7% and 4% of patients in the CALQUENCE plus obinutuzumab arm and CALQUENCE monotherapy arm, respectively. Adverse reactions led to discontinuation in 11% and 10% of patients, respectively. Increases in creatinine to 1.5 to 3 times 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 in the ASCEND study exposed to CALQUENCE (n=154), 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, 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.

INDICATION AND USAGE

CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

SELECT SAFETY INFORMATION

Serious adverse events, including fatal events, have occurred with CALQUENCE, including serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity, including drug-induced liver injury. The most common adverse reactions (≥30%) are diarrhea, upper respiratory tract infection, headache, musculoskeletal pain, lower respiratory tract infection, and fatigue. The most common Grade 3 or 4 laboratory abnormalities (≥10%) are absolute neutrophil count decreased, absolute lymphocyte count decreased, platelets decreased, and hemoglobin decreased.

Please see full Important Safety Information at the end of the video.

Please see full Prescribing Information, including Patient Information.

Hello, I'm Dr. Shuo Ma. I'm Associate Professor of Medicine in Hematology/Oncology at the Feinberg School of Medicine of Northwestern University and the Robert H. Lurie Comprehensive Cancer Center.

BTK inhibitors have become a common treatment choice for CLL patients in our practice since they came to the market.

CALQUENCE is a next-generation selective BTK inhibitor approved for patients with CLL.

The ELEVATE-RR study is a very important trial because this is a head-to-head comparison of two BTK inhibitors in CLL treatment. I'm excited to review with you today the Phase III head-to-head trial comparing the safety and efficacy of CALQUENCE versus ibrutinib in patients with previously treated CLL.

FDA approval of CALQUENCE for adult patients with CLL or SLL was based on the results of two Phase 3 trials, including the ASCEND trial in patients with relapsed or refractory CLL.

In the ASCEND trial, which included 310 patients, CALQUENCE monotherapy in 155 patients reduced the risk of disease progression or death by 73%, versus rituximab plus investigator's choice of either idelalisib or bendamustine in 155 patients, after a median follow-up time of 22 months.

The median progression-free survival was not reached with CALQUENCE, versus 16.8 months with idelalisib plus rituximab or bendamustine plus rituximab.

In the final analysis, the most common adverse reactions occurred in at least 20% of any grade in patients receiving CALQUENCE, which included 154 patients, were headache, neutropenia, diarrhea, upper respiratory tract infection.

The median duration of exposure was 21.9 months. Safety and tolerability results in the final analysis were consistent with those of the interim analysis, with a median follow-up time of 16.1 months.

In the interim analysis, atrial fibrillation of any grade was reported in 5% of patients receiving CALQUENCE, and Grade 3 or higher atrial fibrillation in 1.3% of the patients.

Infections of any grade was reported in 56% of patients, and Grade 3 or higher infections in 15% of patients. The median duration of exposure was 15.7 months.

ELEVATE-RR was a randomized, multicenter, open-label Phase 3 trial. A total of 533 adult patients with previously treated CLL were randomized into two arms. The CALQUENCE arm included 268 patients and the ibrutinib arm included 265 patients.

Patients included in the study had either 17p deletion or 11q deletion CLL, and were stratified by the presence of 17p deletion, ECOG performance status, and the number of prior therapies.

The primary endpoint was non-inferiority of progression-free survival assessed by independent review committee after approximately 250 events.

The secondary endpoints included incidence of any grade atrial fibrillation, incidence of Grade 3 or higher infections, incidence of Richter's transformation, and the overall survival.

As you can see here on this table, the baseline demographic and disease characteristics were generally well balanced between the two treatment arms.

Here is the Kaplan-Meier curve for the IRC-assessed progression-free survival with CALQUENCE shown in orange and ibrutinib shown in grey line. A median follow-up time of 41 months with a range of 0 to 59.1 months, the hazard ratio was 1.00, with a 95% confidence interval of 0.79 to 1.27.

The median progression-free survival was 38.4 months for both arms.

Secondary endpoints for atrial fibrillation, infection and Richter transformation are shown here with breakdowns for a Grade 1 and 2, or a Grade 3 and higher for atrial fibrillation or flutter and infections. Of the 266 patients receiving CALQUENCE, 9% of patients experienced any grade atrial fibrillation or flutter; 4.9% of these events were Grade 3 or higher. Of the 263 patients receiving ibrutinib, 16% of patients experienced any grade atrial fibrillation or flutter; 3.8% of these events were grade three or higher. Rates of new onset AFib or flutter of any grade in patients without prior history of AFib or flutter were 6% among CALQUENCE-treated patients and 15% among ibrutinib-treated patients. Discontinuation rate among patients who experienced AFib or flutter events were 0% for CALQUENCE-treated patients and 17% for ibrutinib-treated patients. Incidence of Richter transformation were 3.8% in CALQUENCE-treated patients and 4.9% in ibrutinib-treated patients. Rates of any grade infection occurred in 78% of CALQUENCE-treated patients and 81% of ibrutinib-treated patients. Rates of Grade 3 or higher infections occurred in 31% of CALQUENCE treated patients and 30% of ibrutinib-treated patients.

The table here shows the adverse events of clinical interest which were identified by the clinical investigators up front. This included any grade bleeding events occurred in 38% of patients on CALQUENCE and 51% of patients on ibrutinib. Grade 3 or higher bleeding events occurred in 3.8% of patients receiving CALQUENCE and 4.6% of patients receiving ibrutinib. Any grade hypertension occurred in 9% of patients on CALQUENCE and 23% of patients on ibrutinib. Grade 3 or higher hypertension occurred in 4.1% of patients receiving CALQUENCE and 9% of patients receiving ibrutinib.

In patients treated with CALQUENCE, the most common AEs of any grade of at least 20% were infections, bleeding, diarrhea, headache, cough, upper respiratory tract infection, neutropenia, pyrexia, anemia and fatigue. In patients treated with ibrutinib, the most common adverse events of any grade of at least 20% were infections, bleeding, diarrhea, upper respiratory tract infection, neutropenia, arthralgia, hypertension, cough and headache.

Discontinuations due to AEs occurred in 15% of patients on CALQUENCE and 22% of patients on ibrutinib. The median duration of exposure were 38.3 months for CALQUENCE and 35.5 months for ibrutinib.

From what I hear from my patients, most of the patients do tolerate CALQUENCE very well. Some of them may experience some early adverse events, such as headache or mild GI side effects, but those typically tend to improve after several weeks, consistent with what I've seen from the data.

ELEVATE-RR was one of the first Phase 3 studies of a next-generation BTK inhibitor against ibrutinib in relapsed/refractory CLL. The primary endpoint was progression-free survival. The secondary endpoints of any grade atrial fibrillation was 9% of patients for CALQUENCE and 16% of patients for ibrutinib. Grade 3 or higher atrial fibrillation was 4.9% and 3.8%, respectively. Discontinuations due to AEs were 15% of patients for CALQUENCE and 22% of patients for ibrutinib. Safety and tolerability with CALQUENCE were consistent with what was seen in the ASCEND trial in patients with relapsed and refractory CLL. The ELEVATE-RR study confirmed my impression that CALQUENCE is an effective and tolerable treatment for patients with relapsed and refractory CLL. So this data does help with my treatment decision-making, especially for patient who has significant cardiac risk.

Thank you for spending the time watching this video today.

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 32% of 1,764 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (19% of all patients, including pneumonia in 9%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 2.7% 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 treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 4.4% of patients, with fatal hemorrhage occurring in 0.2% of 1,764 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 40% of patients. Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 7% of patients taking CALQUENCE without antithrombotic agents and 4% 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 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias

CALQUENCE can cause Grade 3 or 4 cytopenias. Grade 3 or 4 cytopenias included absolute neutrophil count decreased (26%), platelets decreased (10%), hemoglobin decreased (10%), and absolute lymphocyte count decreased (10%) in patients treated with CALQUENCE alone or in combination with obinutuzumab; Grade 4 neutropenia developed in 14% 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 18% of 1,764 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 10% of patients, followed by other solid tumors in 9% (including melanoma, lung cancer, gastrointestinal cancers, and genitourinary cancers) and hematologic malignancies (1%). Monitor patients for the development of second cancers and advise protection from sun exposure.

Cardiac Arrhythmias

Fatal and serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade 3 or 4 atrial fibrillation or flutter was reported in 2.6% of 1,764 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 7% of all patients. Grade 3 or higher ventricular arrhythmia events were reported in 0.6% of patients, including fatal cases in 0.3% of all patients. The risk of arrhythmias 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 exposed to CALQUENCE 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 (2.8% to 7%). 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.

You are encouraged to report negative side effects of AstraZeneca prescription drugs by calling 1-800-236-9933. If you prefer to report these to the FDA, call 1-800-FDA-1088.

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INDICATION AND USAGE

CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

SELECT SAFETY INFORMATION

Serious adverse events, including fatal events, have occurred with CALQUENCE, including serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity, including drug-induced liver injury.

The most common adverse reactions (≥30%) are upper respiratory tract infection, diarrhea, headache, and musculoskeletal pain. The most common Grade 3 or 4 laboratory abnormalities (≥10%) are absolute neutrophil count decreased, uric acid increased, absolute lymphocyte count decreased, and platelets decreased.

Please see full Important Safety Information at the end of the video.

Please see full Prescribing Information, including Patient Information.

Hi. I'm Tajuana Bradley, an oncology nurse practitioner in Atlanta, Georgia, where I practice with Georgia Cancer Specialists, an affiliate of Northside Hospital Cancer Institute.

So we know that adherence to treatment is critical, and probably one of the most important aspects of achieving therapeutic goals for our patients. Upfront it's important for us to look for non-adherence, because it's gonna be one of those things that could potentially impact the outcome of treatment for patients, for instance, decreasing their relapse free time and their overall survival.

When considering barriers to adherence, we need to consider five dimensions. And they include therapy-related factors, condition related factors, social-economic factors, health system or healthcare team factors, and patient-related factors.

Adherence strategies that address these reasons for non-adherence may be effective. And I think it's important for us to really set expectations upfront, so we can help these patients stay on therapy.

I think it's really important, before the prescription is even written, to talk to patients and being proactive about side effects and adverse reactions, and what they could potentially experience. Not only with them, but also their care team. I think having open dialogue and setting the stage and setting expectations will help patients in terms of being able to stay on therapy.

And in our institution, we have weekly calls by our nurses to follow up with the patients to find out how they're tolerating therapy, to discuss any adverse reactions that they could potentially be experiencing, as well as utilizing our specialty pharmacists, where they also will call the patients and counsel them on medication adherence, as well as assessing for any kind of adverse reactions.

In ELEVATE-TN, there were a total of 535 adult patients with previously untreated CLL, who were randomized into three arms. In the first arm, you had CALQUENCE plus obinutuzumab. The second arm, CALQUENCE monotherapy. Third arm, obinutuzumab plus chlorambucil. Baseline demographic and disease characteristics were similar between treatment arms.

In the ELEVATE-TN Trial, most adverse reactions for CALQUENCE regimens in patients with previously untreated CLL were mostly grades 1 or 2.

The most common adverse reactions greater than or equal to 30 percent were anemia, neutropenia, thrombocytopenia, headache, upper respiratory tract infection, and diarrhea.

The median duration of exposure to CALQUENCE in the CALQUENCE plus obinutuzumab, and CALQUENCE monotherapy arms, was 27.7 months.

Note, statistical comparisons between treatment arms, with respect to ARs, were not conducted.

In the ASCEND Trial, most adverse reactions for CALQUENCE monotherapy were mostly grades 1 or 2. The median duration of exposure varied by treatment. For the CALQUENCE arm, it was 15.7 months. Idelalisib it was 11.5 months. 83 percent of the patients completed six cycles of BR.

The most common adverse reactions in patients with relapsed refractory CLL treated with CALQUENCE included infection, neutropenia, anemia, and thrombocytopenia. The AR profile for CALQUENCE is consistent with its established profile.

Headache and diarrhea are two common adverse reactions and were mostly grades 1 or 2. Vascular disorders, i.e. hemorrhage, are a known adverse reaction to CALQUENCE. These were primarily grade 1 or 2. Note, patients in the ASCEND Trial were permitted to take anti-thrombotic agents other than warfarin or equivalent vitamin K antagonists.

Serious adverse events, including fatal events, have occurred with CALQUENCE, including serious and opportunistic infections, hemorrhage, cytopenias, secondary primary malignancies, and atrial fibrillation and flutter.

So, we know that many of our therapies will have some adverse reactions, right? But what I've seen with CALQUENCE is that it's a tolerable therapy for our patients. And the majority of my patients, in my experience, aside from the week or two that they have a headache, they are doing exceptionally well.

In addition to proactively communicating with your patients and initiating adverse reaction management, advisory of potential drug-drug interactions may help your patients stay on therapy.

CALQUENCE interacts with CYP3A inducers or inhibitors. So it's really recommended to do a medication reconciliation prior to prescribing, and on each visit.

For many of our therapies that we give our patients, particularly in CLL, this is a chronic condition. And they're going to be on treatment for quite a while. When trying to encourage patients to stay on therapy, I find it really impactful when I can show patients their labs from visit to visit. They get really excited when they're seeing that, you know, drop in those counts, and things are getting better. And it's really nice to be able to show them how they're responding, now that they are on therapy with CALQUENCE.

Important points to keep in mind when managing patients taking CALQUENCE; being proactive, having open communication, adverse reaction management may help improve adherence. Communication of symptoms to care team is essential for aiding in adherence and improving potential outcomes. Most common adverse reactions with CALQUENCE were grades 1 or 2. Management strategies exist to mitigate severity of adverse reactions that patients treated with CALQUENCE may experience.

Thanks for watching.

AstraZeneca's CALQUENCE tablet formulation received FDA approval in August 2022. The tablet formulation of CALQUENCE differs from the capsule version in that CALQUENCE tablets can be taken by people who also take acid-reducing agents such as PPIs, antacids, or H2-receptor antagonists without any restrictions or dose modifications. The same efficacy and safety can be expected with the tablet formulation since CALQUENCE 100-mg tablets have been proven to be bioequivalent to 100-mg CALQUENCE capsules. CALQUENCE 100-mg tablets also follow the same straightforward dosing schedule as CALQUENCE capsules. As with CALQUENCE 100-mg capsules, patients take one 100-mg tablet twice daily, approximately every 12 hours. For more information on the CALQUENCE tablet formulation, please contact your AstraZeneca sales representative.

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 29% of 2,055 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (18% of all patients, including pneumonia in 14%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 8% 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 treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 4.7% of patients, with fatal hemorrhage occurring in 0.1% of 2,055 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 39% of patients.

Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 5% of patients taking CALQUENCE without antithrombotic agents and 3.2% 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 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias

CALQUENCE can cause Grade 3 or 4 cytopenias. Grade 3 or 4 cytopenias included absolute neutrophil count decreased (28%), absolute lymphocyte count decreased (10%), hemoglobin decreased (9%), and platelets decreased (9%) in 1,758 patients treated with CALQUENCE alone and in combination with obinutuzumab or venetoclax; Grade 4 neutropenia developed in 14% 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 16% of 2,055 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 9% of patients, followed by other solid tumors in 8% (including melanoma, lung cancer, gastrointestinal cancers, and genitourinary cancers) and hematologic malignancies (1.1%). Fatal second primary malignancies occurred in 0.8% of patients. Monitor patients for the development of second cancers and advise protection from sun exposure.

Cardiac Arrhythmias

Fatal and serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade 3 or 4 atrial fibrillation or flutter was reported in 2.2% of 2,055 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 7% of all patients. Grade 3 or higher ventricular arrhythmia events were reported in 0.5% of patients, including fatal cases in 0.3% of all patients. The risk of arrhythmias may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (For 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

Chronic Lymphocytic Leukemia

The most common adverse reactions (≥30%) of any grade in patients with CLL in the ELEVATE-TN and ASCEND studies exposed to CALQUENCE (n=511) 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 in the ELEVATE-TN study exposed to CALQUENCE (n=357), 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% (69/178) of patients in the CALQUENCE plus obinutuzumab arm (n=178) and 32% (57/179) in the CALQUENCE monotherapy arm (n=179), most aften due to events of pneumonia (2.8% to 7%).

Adverse reactions led to CALQUENCE dose reduction in 7% and 4% of patients in the CALQUENCE plus obinutuzumab arm and CALQUENCE monotherapy arm, respectively. Adverse reactions led to discontinuation in 11% and 10% of patients, respectively. Increases in creatinine to 1.5 to 3 times 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 in the ASCEND study exposed to CALQUENCE (n=154), 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, 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.

INDICATION AND USAGE

CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

SELECT SAFETY INFORMATION

Serious adverse events, including fatal events, have occurred with CALQUENCE, including serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity, including drug-induced liver injury. The most common adverse reactions (≥30%) are upper respiratory tract infection, diarrhea, headache, and musculoskeletal pain. The most common Grade 3 or 4 laboratory abnormalities (≥10%) are absolute neutrophil count decreased, uric acid increased, absolute lymphocyte count decreased, and platelets decreased.

Please see full Important Safety Information at the end of the video.

Please see full Prescribing Information, including Patient Information.

Hello. I'm Dr. Edward Pearson, a hematologist at Texas Oncology in Dallas, Texas.

Bruton's tyrosine kinase plays a key role in B cell receptor signaling.

CALQUENCE is a small molecule inhibitor of BTK, which binds irreversibly to BTK, thereby inhibiting its activity. In non-clinical studies, CALQUENCE inhibited BTKmediated activation of downstream signaling proteins CD86 and CD69, and inhibited malignant B cell proliferation and survival.

CALQUENCE is a selective next generation Bruton's tyrosine kinase inhibitor.

Biochemical models were used to measure inhibition activity of ibrutinib and CALQUENCE. The kinome plot visually shows which kinases are inhibited with larger circles representing stronger inhibition. Bruton's tyrosine kinase is shown in green. And the off-target kinases are shown in red.

The relationship between this data on enzyme inhibition and clinical outcome has not been established. For CALQUENCE, the only kinase with more than 99 percent inhibition at one micromolar concentration was BTK.

The kinome plot visually illustrates the relationship between various tyrosine kinases. I find it a very compelling illustration of CALQUENCE's ability to target BTK with few off-target effects. In the era of targeted therapies, having an agent be as specific to its target as possible is very important to me. I'm certainly concerned with off-target activities. One of the most concerning things in medicine is not knowing what you don't know.

To review, the key attributes of CALQUENCE from a mechanism of action perspective, CALQUENCE selectively targets Bruton's tyrosine kinase.

CALQUENCE is a more potent inhibitor of Bruton's tyrosine kinase than of any other kinase. And CALQUENCE inhibits few off-target kinases, such as TEC, EGFR, and ITK.

Thanks for watching.

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 29% of 2,055 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (18% of all patients, including pneumonia in 14%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 8% 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 treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 4.7% of patients, with fatal hemorrhage occurring in 0.1% of 2,055 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 39% of patients. Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 5% of patients taking CALQUENCE without antithrombotic agents and 3.2% 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 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias

CALQUENCE can cause Grade 3 or 4 cytopenias. Grade 3 or 4 cytopenias included absolute neutrophil count decreased (28%), absolute lymphocyte count decreased (10%), hemoglobin decreased (9%), and platelets decreased (9%) in 1,758 patients treated with CALQUENCE alone and in combination with obinutuzumab or venetoclax; Grade 4 neutropenia developed in 14% 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 16% of 2,055 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 9% of patients, followed by other solid tumors in 8% (including melanoma, lung cancer, gastrointestinal cancers, and genitourinary cancers) and hematologic malignancies (1.1%). Fatal second primary malignancies occurred in 0.8% of patients. Monitor patients for the development of second cancers and advise protection from sun exposure.

Cardiac Arrhythmias

Fatal and serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade 3 or 4 atrial fibrillation or flutter was reported in 2.2% of 2,055 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 7% of all patients. Grade 3 or higher ventricular arrhythmia events were reported in 0.5% of patients, including fatal cases in 0.3% of all patients. The risk of arrhythmias 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

Chronic Lymphocytic Leukemia

The most common adverse reactions (≥30%) of any grade in patients with CLL in the ELEVATE-TN and ASCEND studies exposed to CALQUENCE (n=511) 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 in the ELEVATE-TN study exposed to CALQUENCE (n=357), 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% (69/178) of patients in the CALQUENCE plus obinutuzumab arm (n=178) and 32% (57/179) in the CALQUENCE monotherapy arm (n=179), most often due to events of pneumonia (2.8% to 7%).

Adverse reactions led to CALQUENCE dose reduction in 7% and 4% of patients in the CALQUENCE plus obinutuzumab arm and CALQUENCE monotherapy arm, respectively. Adverse reactions led to discontinuation in 11% and 10% of patients, respectively. Increases in creatinine to 1.5 to 3 times 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 in the ASCEND study exposed to CALQUENCE (n=154), 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, 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.

INDICATIONS AND USAGE

CALQUENCE is indicated in combination with bendamustine and rituximab (BR) for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are ineligible for autologous hematopoietic stem cell transplantation (HSCT) and as monotherapy for the treatment of adult patients with MCL who have received at least one prior therapy.

SELECT SAFETY INFORMATION

Serious adverse events, including fatal events, have occurred with CALQUENCE, including serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity, including drug-induced liver injury. The most common adverse reactions (≥30%) are upper respiratory tract infection, diarrhea, headache, and musculoskeletal pain. The most common Grade 3 or 4 laboratory abnormalities (≥10%) are absolute neutrophil count decreased, uric acid increased, absolute lymphocyte count decreased, and platelets decreased.

Please see full Important Safety Information at the end of the video. Please see full Prescribing Information, including Patient Information.

Hello, my name is Doctor Tycel Phillips. I'm an associate professor at City of Hope National Medical Center located in Duarte, California. I've been practicing for the last 12 years in the management and treatment of patients with malignant B-cell lymphoproliferative disorders.

In this video, we will be discussing the 3-year median follow-up data from the LY-004 trial of CALQUENCE in patients with relapsed/refractory mantle cell lymphoma. When I look at follow-up study data for patients with relapsed/refractory mantle cell lymphoma, I ask myself, are the safety and efficacy data at long-term follow-up consistent with the initial analysis? Are safety and tolerability data consistent with the established safety profile? What endpoints are most relevant to helping my patients achieve treatment goals?

LY-004 is one of the largest clinical trials in relapsed or refractory mantle cell lymphoma. LY-004 was a Phase 2, open-label, single-arm, multicenter trial of CALQUENCE monotherapy in 124 patients aged 18 or older with mantle cell lymphoma, who had received at least one prior line of therapy.

The primary endpoint was investigator-assessed overall response rate (ORR); secondary endpoints included duration of response (DoR).

The initial analysis had a median follow-up of 15.2 months. The long-term analysis had a median follow-up of 38.1 months.

Now, let's take a look at the efficacy data.

The response rate of CALQUENCE was consistent in patients with relapsed or refractory mantle cell lymphoma and has continued to show deep responses over time. In the initial analysis at a median follow-up of 15.2 months, CALQUENCE demonstrated an IRC-assessed overall response rate of 80%: complete response rate of 40%, and partial response rate of 40%. In the long-term analysis, with a median follow-up of 38.1 months, CALQUENCE has continued to show deep responses, with 48% of patients having a complete response. Overall response rate was 81% and partial response rate was 34%.

Duration of response was measured in the 101 patients who achieved a complete response or partial response at the 38-month median follow-up. The median duration of response was around 29 months.

The most important aspect of the LY-004 data, which helps as far as making decisions for treatment for patients with relapsed/refractory mantle cell lymphoma, is efficacy and duration of response data. This calls to mind a patient who was recently started on CALQUENCE. Unfortunately, this patient had a very short duration of response to frontline chemoimmunotherapy. The patient was subsequently started on CALQUENCE and was noted to being in a complete response at first interim assessment after 3 months of therapy. Now, let's take a look at the safety data from the trial.

In the long-term analysis, with a median follow-up of 38.1 months, the safety profile of CALQUENCE was consistent with the initial analysis. The most common treatment-emergent adverse events occurring in greater than or equal to 20% of patients were infections, headache, diarrhea, bleeding events, fatigue, cough, myalgia, and nausea.

CALQUENCE has demonstrated low rates of atrial fibrillation and hypertension in the LY-004 study. At the long-term analysis, with a median follow-up of 38.1 months, atrial fibrillation was 1.6% for all grades and 0% for Grade 3 or higher, and hypertension was 4% for all grades and 1.6% for Grade 3 or higher. At the interim analysis, with a median follow-up of 15.2 months, atrial fibrillation was 0% for all grades or Grade 3 or higher, and hypertension was 2.4% for all grades and 0.8% for Grade 3 or higher.

These data are consistent with what I see in my clinical practice. Safety continues to be an important aspect of any continuous therapy. The long-term data from LY-004 continues to support the safety of CALQUENCE in patients with relapsed/refractory mantle cell lymphoma. The adverse reactions noted are all generally managed with the assistance of the healthcare team.

Few patients discontinued therapy due to adverse reactions. In the initial analysis, dose reductions due to adverse reactions were reported in 1.6% of patients, and 6.5% of patients discontinued therapy due to adverse reactions. Median duration of therapy was 16.6 months, with a range of 0.1 to 26.6 months. At the 38-month median follow-up, dose reductions due to adverse events were reported in 2% of patients, and 11% of patients discontinued therapy due to adverse events.

In LY-004, 8 out of 10 patients with relapsed/refractory mantle cell lymphoma responded to CALQUENCE, with a 29-month duration of response at the 38-month median follow-up. At a median follow-up of 15.2 months, the most common adverse reactions occurring in greater than or equal to 20% of patients with CALQUENCE were anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, and bruising. The safety profile remained consistent over time as demonstrated in the initial analysis and observed with the 38-month data, including low rates of atrial fibrillation and hypertension.

The 3-year follow-up data from the LY-004 study is consistent with what I see in my clinical practice. Thanks for watching. Stay tuned for full Important Safety Information for CALQUENCE.

INDICATIONS AND USAGE

CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor indicated in combination with bendamustine and rituximab (BR) for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are ineligible for autologous hematopoietic stem cell transplantation (HSCT) and as monotherapy for the treatment of adult patients with MCL who have received at least one prior therapy.

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 29% of 2,055 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (18% of all patients, including pneumonia in 14%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 8% 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 treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 4.7% of patients, with fatal hemorrhage occurring in 0.1% of 2,055 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 39% of patients. Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 5% of patients taking CALQUENCE without antithrombotic agents and 3.2% 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 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias

CALQUENCE can cause Grade 3 or 4 cytopenias. Grade 3 or 4 cytopenias included absolute neutrophil count decreased (28%), absolute lymphocyte count decreased (10%), hemoglobin decreased (9%), and platelets decreased (9%) in 1,758 patients treated with CALQUENCE alone and in combination with obinutuzumab or venetoclax; Grade 4 neutropenia developed in 14% 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 16% of 2,055 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 9% of patients, followed by other solid tumors in 8% (including melanoma, lung cancer, gastrointestinal cancers, and genitourinary cancers) and hematologic malignancies (1.1%). Fatal second primary malignancies occurred in 0.8% of patients. Monitor patients for the development of second cancers and advise protection from sun exposure.

Cardiac Arrhythmias

Fatal and serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade 3 or 4 atrial fibrillation or flutter was reported in 2.2% of 2,055 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 7% of all patients. Grade 3 or higher ventricular arrhythmia events were reported in 0.5% of patients, including fatal cases in 0.3% of all patients. The risk of arrhythmias 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

Previously Untreated Mantle Cell Lymphoma

The most common adverse reactions (≥15%) of any grade in patients with previously untreated MCL in the ECHO study who received CALQUENCE plus BR (n=297) were rash (47%), COVID-19 (38%), fatigue (37%), diarrhea (37%), pneumonia (31%), headache (31%), upper respiratory tract infection (30%), pyrexia (29%), cough (27%), vomiting (26%), constipation (25%), hemorrhage (20%), edema (20%), secondary primary malignancy (19%), dizziness (18%), arthralgia (18%), and dyspnea (17%). Grade 4 laboratory abnormalities in >15% of patients treated with CALQUENCE plus BR include absolute lymphocyte count decreased (26%), absolute neutrophil count decreased (36%), and uric acid increased (17%).

Serious adverse reactions occurred in 69% of patients who received CALQUENCE plus BR. Serious adverse reactions reported in ≥2% of patients were pneumonia (23%; includes COVID-19 pneumonia), COVID-19 (20%; includes COVID-19 pneumonia), second primary malignancy (7%), pyrexia (6%), rash (3.4%), febrile neutropenia (3.4%), atrial fibrillation (3%), sepsis (2.7%), and anemia (2.4%). Fatal adverse reactions that occurred within 30 days of the last study treatment were reported in 12% who received CALQUENCE plus BR including COVID-19 (6%; includes COVID-19 pneumonia), pneumonia (1%), second primary malignancy (0.7%), sepsis (0.3%), and pneumonitis (0.3%).

Adverse reactions led to permanent discontinuation of CALQUENCE in 43%, dosage interruptions in 74%, and dosage reductions in 10% of patients. Adverse reactions that resulted in dosage modification in >10% included infections, cytopenias, rashes, and gastrointestinal toxicity. Adverse reactions which resulted in permanent discontinuation of CALQUENCE in ≥4% of patients included COVID-19 (includes COVID-19 pneumonia) and neutropenia.

Previously Treated Mantle Cell Lymphoma

The most common adverse reactions (≥20%) of any grade in patients with relapsed or refractory MCL in the LY-004 study exposed to CALQUENCE (n=124) 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 to 1.5 to 3 times the upper limit of normal (ULN) occurred in 4.8% of patients.

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.

INDICATION AND USAGE

CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

SELECT SAFETY INFORMATION

Serious adverse events, including fatal events, have occurred with CALQUENCE, including serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity, including drug-induced liver injury. The most common adverse reactions (≥30%) are upper respiratory tract infection, diarrhea, headache, and musculoskeletal pain. The most common Grade 3 or 4 laboratory abnormalities (≥10%) are absolute neutrophil count decreased, uric acid increased, absolute lymphocyte count decreased, and platelets decreased.

Please see full Important Safety Information at the end of the video.

Please see full Prescribing Information, including Patient Information.

Hello. I'm Dr. Edward Pearson, a hematologist at Texas Oncology in Dallas, Texas.

Bruton's tyrosine kinase plays a key role in B cell receptor signaling.

CALQUENCE is a small molecule inhibitor of BTK, which binds irreversibly to BTK, thereby inhibiting its activity. In non-clinical studies, CALQUENCE inhibited BTKmediated activation of downstream signaling proteins CD86 and CD69, and inhibited malignant B cell proliferation and survival.

CALQUENCE is a selective next generation Bruton's tyrosine kinase inhibitor.

Biochemical models were used to measure inhibition activity of ibrutinib and CALQUENCE. The kinome plot visually shows which kinases are inhibited with larger circles representing stronger inhibition. Bruton's tyrosine kinase is shown in green. And the off-target kinases are shown in red.

The relationship between this data on enzyme inhibition and clinical outcome has not been established. For CALQUENCE, the only kinase with more than 99 percent inhibition at one micromolar concentration was BTK.

The kinome plot visually illustrates the relationship between various tyrosine kinases. I find it a very compelling illustration of CALQUENCE's ability to target BTK with few off-target effects. In the era of targeted therapies, having an agent be as specific to its target as possible is very important to me. I'm certainly concerned with off-target activities. One of the most concerning things in medicine is not knowing what you don't know.

To review, the key attributes of CALQUENCE from a mechanism of action perspective, CALQUENCE selectively targets Bruton's tyrosine kinase.

CALQUENCE is a more potent inhibitor of Bruton's tyrosine kinase than of any other kinase. And CALQUENCE inhibits few off-target kinases, such as TEC, EGFR, and ITK.

Thanks for watching.

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 29% of 2,055 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (18% of all patients, including pneumonia in 14%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 8% 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 treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 4.7% of patients, with fatal hemorrhage occurring in 0.1% of 2,055 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 39% of patients. Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 5% of patients taking CALQUENCE without antithrombotic agents and 3.2% 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 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias

CALQUENCE can cause Grade 3 or 4 cytopenias. Grade 3 or 4 cytopenias included absolute neutrophil count decreased (28%), absolute lymphocyte count decreased (10%), hemoglobin decreased (9%), and platelets decreased (9%) in 1,758 patients treated with CALQUENCE alone and in combination with obinutuzumab or venetoclax; Grade 4 neutropenia developed in 14% 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 16% of 2,055 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 9% of patients, followed by other solid tumors in 8% (including melanoma, lung cancer, gastrointestinal cancers, and genitourinary cancers) and hematologic malignancies (1.1%). Fatal second primary malignancies occurred in 0.8% of patients. Monitor patients for the development of second cancers and advise protection from sun exposure.

Cardiac Arrhythmias

Fatal and serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade 3 or 4 atrial fibrillation or flutter was reported in 2.2% of 2,055 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 7% of all patients. Grade 3 or higher ventricular arrhythmia events were reported in 0.5% of patients, including fatal cases in 0.3% of all patients. The risk of arrhythmias 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

Chronic Lymphocytic Leukemia

The most common adverse reactions (≥30%) of any grade in patients with CLL in the ELEVATE-TN and ASCEND studies exposed to CALQUENCE (n=511) 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 in the ELEVATE-TN study exposed to CALQUENCE (n=357), 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% (69/178) of patients in the CALQUENCE plus obinutuzumab arm (n=178) and 32% (57/179) in the CALQUENCE monotherapy arm (n=179), most often due to events of pneumonia (2.8% to 7%).

Adverse reactions led to CALQUENCE dose reduction in 7% and 4% of patients in the CALQUENCE plus obinutuzumab arm and CALQUENCE monotherapy arm, respectively. Adverse reactions led to discontinuation in 11% and 10% of patients, respectively. Increases in creatinine to 1.5 to 3 times 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 in the ASCEND study exposed to CALQUENCE (n=154), 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, 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.

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