IMBRUVICA® (ibrutinib) Plus VENCLEXTA®/VENCLYXTO® (venetoclax) Combination Shows High Rates of Disease-Free Survival One Year Post-Treatment in Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL)

NORTH CHICAGO, Ill., Dec. 5, 2020 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced new data from the Phase 2 CAPTIVATE (PCYC-1142) clinical trial evaluating IMBRUVICA^® (ibrutinib) in combination with VENCLEXTA^®/VENCLYXTO^® (venetoclax) in previously untreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) during an oral presentation session at the virtual 2020 American Society of Hematology (ASH) Annual Meeting (Abstract #123). The one-year disease-free survival (DFS) rate in patients randomized to placebo or ibrutinib after completing the combination regimen provides data to support a fixed-duration treatment that can offer CLL/SLL patients remission and time off treatment.

"These results show the ibrutinib plus venetoclax combination providing continued disease-free survival for CLL patients once treatment is complete," said Dr. William Wierda, M.D., Professor, Department of Leukemia, University of Texas MD Anderson Cancer Center and principal study investigator. "It will be really exciting for patients to have a potential option in the future that can put them into remission and time off treatment."

These findings build on the previously reported results showing that this first-line combination regimen for CLL resulted in high rates of undetectable minimal residual disease (uMRD) in both peripheral blood (PB) (75% of patients) and in bone marrow (BM) (72% of patients). Undetectable MRD is defined as little to no cancer cells found after treatment. In the Confirmed uMRD group, one-year DFS rate was not significantly different for patients randomized to placebo (95.3%; 95% CI 82.7-98.8) versus ibrutinib (100%; 95% CI 100-100) (P=0.1475).

During the overall study period across all-treated patients (with median treatment duration of 29 months), most common grade 3/4 adverse events (≥5% of patients) were neutropenia (36%), hypertension (10%), thrombocytopenia (5%), and diarrhea (5%). The safety profile of the combination was consistent with known adverse events for ibrutinib and venetoclax individually and no new safety signals emerged.

"IMBRUVICA and VENCLEXTA/VENCLYXTO, individually, have truly transformed the way CLL and some other blood cancers are treated. Today, CLL can be treated without chemotherapy in the form of an oral pill, which is a remarkable advancement, compared to standards of care over the last decade," said Mohamed Zaki, M.D., Ph.D., vice president and global head of oncology development, AbbVie. "The results from this study will add to the evidence required for the development of this combination regimen as a potential new treatment option for CLL."

CLL is one of the two most common forms of leukemia in adults and is a type of cancer that can develop from cells in the bone marrow that later mature into certain white blood cells (called lymphocytes).¹ While these cancer cells start in the bone marrow, they then later spread into the blood. The prevalence of CLL is approximately 115,000 patients in the U.S. with approximately 20,000 newly diagnosed patients every year.^2,3 CLL is predominately a disease of the elderly, with a median age at diagnosis ranging from 65-70 years.⁴

According to the Leukemia & Lymphoma Society, MRD refers to the small number of cancer cells that remain in the body after treatment.⁵ The number of remaining cells may be so small that they do not cause any physical signs or symptoms and often cannot even be detected through traditional methods, this is known as undetectable MRD (uMRD). Doctors use MRD/uMRD to measure the effectiveness of treatment and to predict which patients are at risk of relapse.

There are additional ongoing company-sponsored trials exploring the potential of ibrutinib and venetoclax in combination for CLL treatment, including the Phase 3 GLOW study. Results from the ongoing GLOW study, assessing the ibrutinib plus venetoclax combination in comparison to chlorambucil plus obinutuzumab for first-line treatment of patients with CLL or SLL (NCT03462719), will be presented at an upcoming congress.

About CAPTIVATE
The CAPTIVATE study MRD cohort evaluated 164 patients between the ages of 18 and 70 years old with previously untreated CLL/SLL. Patients received 3 cycles of ibrutinib lead-in followed by 12 cycles of ibrutinib + venetoclax (Ibr 420 mg/day PO; Ven ramp-up to 400 mg/day PO). Patients with confirmed uMRD (defined as uMRD serially over ≥3 cycles, and in both PB and BM) after 12 cycles of ibrutinib + venetoclax were randomized 1:1 to receive double-blind treatment with placebo or ibrutinib. Patients who did not meet the definition of confirmed uMRD were randomized 1:1 to receive open-label treatment with ibrutinib or continued ibrutinib + venetoclax. Primary endpoint was 1-year DFS rate in the confirmed uMRD patients randomized to placebo vs ibrutinib; DFS was defined as survival without progression or MRD relapse (which was defined as an MRD level of 10^-2). Key secondary endpoints were rates of uMRD (<10^-4 by 8-color flow cytometry), response per iwCLL, adverse events (AEs), as well as progression-free survival (PFS). The safety profile of the combination was consistent with known adverse events for ibrutinib and venetoclax individually and no new safety signals emerged.

The depth of response achieved with this regimen is reflected in the 30-month progression-free survival (PFS) rate of ~95% across all treated patients, including the subset receiving placebo after the fixed duration treatment.

About Ibrutinib (IMBRUVICA^®) 
IMBRUVICA (ibrutinib) is a once-daily, first-in-class BTK inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics, LLC, an AbbVie Company, and Janssen Biotech, Inc. (Janssen). The BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiply and spread.^6,7 By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.⁸

Since its launch in 2013, IMBRUVICA has received 11 FDA approvals across six disease areas: chronic lymphocytic leukemia (CLL) with or without 17p deletion (del17p); small lymphocytic lymphoma (SLL) with or without del17p; Waldenström macroglobulinemia; previously-treated patients with mantle cell lymphoma (MCL)*; previously-treated patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy* – and previously-treated patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.⁹

IMBRUVICA is now approved in 101 countries and has been used to treat more than 200,000 patients worldwide across its approved indications. IMBRUVICA is the only FDA-approved medicine in WM and cGVHD. IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases. IMBRUVICA was one of the first medicines to receive FDA approval via the Breakthrough Therapy Designation pathway.

As of early 2019, the National Comprehensive Cancer Network^® (NCCN^®), a not-for-profit alliance of 28 leading cancer centers devoted to patient care, research, and education, recommends ibrutinib (IMBRUVICA) as a preferred regimen for the initial treatment of CLL/SLL and has Category 1 treatment status for treatment-naïve patients without deletion 17p. In February 2020, the NCCN Guidelines^® were updated to elevate IMBRUVICA with or without rituximab from other recommended regimens to a preferred regimen for the treatment of relapsed/refractory MCL. In September 2020, the NCCN guidelines were updated to elevate IMBRUVICA with or without rituximab as the only Category 1 preferred regimen for treatment-naïve WM patients.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA is the most comprehensively studied BTK inhibitor, with more than 150 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. For more information, visit www.IMBRUVICA.com.

*Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Side Effect Information
Before taking IMBRUVICA^®, tell your healthcare provider about all of your medical conditions, including if you:

• have had recent surgery or plan to have surgery. Your healthcare provider may stop IMBRUVICA^® for any planned medical, surgical, or dental procedure.
• have bleeding problems.
• have or had heart rhythm problems, smoke, or have a medical condition that increases your risk of heart disease, such as high blood pressure, high cholesterol, or diabetes.
• have an infection.
• have liver problems.
• are pregnant or plan to become pregnant. IMBRUVICA^® can harm your unborn baby. If you are able to become pregnant, your healthcare provider will do a pregnancy test before starting treatment with IMBRUVICA^®. Tell your healthcare provider if you are pregnant or think you may be pregnant during treatment with IMBRUVICA^®.
• Females who are able to become pregnant should use effective birth control (contraception) during treatment with IMBRUVICA^® and for 1 month after the last dose.
• Males with female partners who are able to become pregnant should use effective birth control, such as condoms, during treatment with IMBRUVICA^® and for 1 month after the last dose.
• are breastfeeding or plan to breastfeed. Do not breastfeed during treatment with IMBRUVICA^® and for 1 week after the last dose.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking IMBRUVICA^® with certain other medicines may affect how IMBRUVICA^® works and can cause side effects.

How should I take IMBRUVICA^®?

• Take IMBRUVICA^® exactly as your healthcare provider tells you to take it.
• Take IMBRUVICA^® 1 time a day.
• Swallow IMBRUVICA^® capsules or tablets whole with a glass of water.
• Do not open, break or chew IMBRUVICA^® capsules.
• Do not cut, crush or chew IMBRUVICA^® tablets.
• Take IMBRUVICA^® at about the same time each day.
• If you miss a dose of IMBRUVICA^® take it as soon as you remember on the same day. Take your next dose of IMBRUVICA^® at your regular time on the next day. Do not take extra doses of IMBRUVICA^® to make up for a missed dose.
• If you take too much IMBRUVICA^® call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid while taking IMBRUVICA^®?

• You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in marmalades) during treatment with IMBRUVICA^®. These products may increase the amount of IMBRUVICA^® in your blood.

What are the possible side effects of IMBRUVICA^®?

IMBRUVICA^® may cause serious side effects, including:

• Bleeding problems (hemorrhage) are common during treatment with IMBRUVICA^®, and can also be serious and may lead to death. Your risk of bleeding may increase if you are also taking a blood thinner medicine. Tell your healthcare provider if you have any signs of bleeding, including: blood in your stools or black stools (looks like tar), pink or brown urine, unexpected bleeding, or bleeding that is severe or that you cannot control, vomit blood or vomit looks like coffee grounds, cough up blood or blood clots, increased bruising, dizziness, weakness, confusion, change in your speech, or a headache that lasts a long time or severe headache. 
• Infections can happen during treatment with IMBRUVICA^®.  These infections can be serious and may lead to death. Tell your healthcare provider right away if you have fever, chills, weakness, confusion, or other signs or symptoms of an infection during treatment with IMBRUVICA^®.
• Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are common with IMBRUVICA^®, but can also be severe.  Your healthcare provider should do monthly blood tests to check your blood counts.
• Heart rhythm problems (ventricular arrhythmias, atrial fibrillation and atrial flutter). Serious heart rhythm problems and death have happened in people treated with IMBRUVICA^®, especially in people who have an increased risk for heart disease, have an infection, or who have had heart rhythm problems in the past. Tell your healthcare provider if you get any symptoms of heart rhythm problems, such as feeling as if your heart is beating fast and irregular, lightheadedness, dizziness, shortness of breath, chest discomfort, or you faint.  If you develop any of these symptoms, your healthcare provider may do a test to check your heart (ECG) and may change your IMBRUVICA^® dose.
• High blood pressure (hypertension). New or worsening high blood pressure has happened in people treated with IMBRUVICA^®. Your healthcare provider may start you on blood pressure medicine or change current medicines to treat your blood pressure.
• Second primary cancers. New cancers have happened during treatment with IMBRUVICA^®, including cancers of the skin or other organs.
• Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS.

The most common side effects of IMBRUVICA^® in adults with B-cell malignancies (MCL, CLL/SLL, WM and MZL) include:

• diarrhea
• tiredness
• muscle and bone pain
• rash
• bruising

The most common side effects of IMBRUVICA^® in adults with cGVHD include:

• tiredness
• bruising
• diarrhea
• mouth sores (stomatitis)
• muscle spasms
• nausea
• pneumonia

Diarrhea is a common side effect in people who take IMBRUVICA^®. Drink plenty of fluids during treatment with IMBRUVICA^® to help reduce your risk of losing too much fluid (dehydration) due to diarrhea. Tell your healthcare provider if you have diarrhea that does not go away.

These are not all the possible side effects of IMBRUVICA^®. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of IMBRUVICA^® 

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use IMBRUVICA^® for a condition for which it was not prescribed. Do not give IMBRUVICA^® to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about IMBRUVICA^® that is written for health professionals.

Please click here for full Prescribing Information.

About VENCLEXTA® (venetoclax) 
VENCLEXTA® (venetoclax) is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells from undergoing their natural death or self-destruction process, called apoptosis. VENCLEXTA targets the BCL-2 protein and works to help restore the process of apoptosis.

VENCLEXTA/VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers. VENCLEXTA/VENCLYXTO is approved in more than 50 countries, including the U.S.

Uses and Important VENCLEXTA® (venetoclax) U.S. Safety Information¹⁰

Uses
VENCLEXTA is a prescription medicine used:

• to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
• in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) who:
• are 75 years of age or older, or
• have other medical conditions that prevent the use of standard chemotherapy.

It is not known if VENCLEXTA is safe and effective in children.

Important Safety Information
What is the most important information I should know about VENCLEXTA?
VENCLEXTA can cause serious side effects, including:
Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your healthcare provider will do tests to check your risk of getting TLS before you start taking VENCLEXTA. You will receive other medicines before starting and during treatment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive intravenous (IV) fluids into your vein. Your healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with VENCLEXTA.It is important to keep your appointments for blood tests. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Drink plenty of water during treatment with VENCLEXTA to help reduce your risk of getting TLS. Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased.

Your healthcare provider may delay, decrease your dose, or stop treatment with VENCLEXTA if you have side effects.

Who should not take VENCLEXTA?
Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased TLS.

• Tell your healthcare provider about all the medicines you take, including prescription and over-the counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other causing serious side effects.
• Do not start new medicines during treatment with VENCLEXTA without first talking with your healthcare provider.

Before taking VENCLEXTA, tell your healthcare provider about all of your medical conditions, including if you:

• have kidney or liver problems.
• have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium.
• have a history of high uric acid levels in your blood or gout.
• are scheduled to receive a vaccine. You should not receive a "live vaccine" before, during, or after
• treatment with VENCLEXTA, until your healthcare provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA.
• are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for at least 30 days after the last dose of VENCLEXTA. If you become pregnant or think you are pregnant, tell your healthcare provider right away.
• are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment with VENCLEXTA and for 1 week after the last dose.

What should I avoid while taking VENCLEXTA?
You should not drink grapefruit juice or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood.

What are the possible side effects of VENCLEXTA?
VENCLEXTA can cause serious side effects, including:

• Low white blood cell counts (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your healthcare provider will do blood tests to check your blood counts during treatment with VENCLEXTA and may pause dosing.
• Infections. Death and serious infections such as pneumonia and blood infection (sepsis) have happened during treatment with VENCLEXTA. Your healthcare provider will closely monitor and treat you right away if you have a fever or any signs of infection during treatment with VENCLEXTA.

Tell your healthcare provider right away if you have a fever or any signs of an infection during treatment with VENCLEXTA.

The most common side effects of VENCLEXTA when used in combination with obinutuzumab or rituximab or alone in people with CLL or SLL include low white blood cell counts; low platelet counts; low red blood cell counts; diarrhea; nausea; upper respiratory tract infection; cough; muscle and joint pain; tiredness; and swelling of your arms, legs, hands, and feet.

The most common side effects of VENCLEXTA in combination with azacitidine or decitabine or low-dose cytarabine in people with AML include nausea; diarrhea; low platelet count; constipation; low white blood cell count; fever with low white blood cell count; tiredness; vomiting; swelling of arms, legs, hands, or feet; fever; infection in lungs; shortness of breath; bleeding; low red blood cell count; rash; stomach (abdominal) pain; infection in your blood; muscle and joint pain; dizziness; cough; sore throat; and low blood pressure.

VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. Call your doctor for medical advice about side effects.

You are encouraged to report side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

If you cannot afford your medication, contact genentech-access.com/patient/brands/venclexta for assistance.

The full U.S. prescribing information, including Medication Guide, for VENCLEXTA can be found here. 
Globally, prescribing information varies; refer to the individual country product label for complete information.

About AbbVie in Oncology
At AbbVie, we strive to discover and develop medicines that deliver transformational improvements in cancer treatment by uniquely combining our deep knowledge in core areas of biology with cutting-edge technologies, and by working together with our partners – scientists, clinical experts, industry peers, advocates, and patients. We remain focused on delivering these transformative advances in treatment across some of the most debilitating and widespread cancers. We are also committed to exploring solutions to help patients obtain access to our cancer medicines. AbbVie's oncology portfolio now consists of marketed medicines and a pipeline containing multiple new molecules being evaluated worldwide in more than 300 clinical trials and more than 20 different tumor types. For more information, please visit http://www.abbvie.com/oncology.

About AbbVie
AbbVie's mission is to discover and deliver innovative medicines that solve serious health issues today and address the medical challenges of tomorrow. We strive to have a remarkable impact on people's lives across several key therapeutic areas: immunology, oncology, neuroscience, eye care, virology, women's health and gastroenterology, in addition to products and services across its Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook, Instagram, YouTube and LinkedIn.

Forward-Looking Statements
Some statements in this news release are, or may be considered, forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, failure to realize the expected benefits from AbbVie's acquisition of Allergan plc ("Allergan"), failure to promptly and effectively integrate Allergan's businesses, competition from other products, challenges to intellectual property, difficulties inherent in the research and development process, adverse litigation or government action, changes to laws and regulations applicable to our industry and the impact of public health outbreaks, epidemics or pandemics such as COVID-19. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," of AbbVie's 2019 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission, as updated by its subsequent Quarterly Reports on Form 10-Q. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

References:

¹ American Society of Hematology. Leukemia. http://www.hematology.org/Patients/Cancers/Leukemia.aspx Accessed December 2018. 

² IMS Database [Data on File].

³ National Cancer Institute. Cancer Stat Facts: Leukemia - Chronic Lymphocytic Leukemia (CLL). https://seer.cancer.gov/statfacts/html/clyl.html. Accessed December 2018. 

⁴ Shanafelt, et al. Age at Diagnosis and the Utility of Prognostic Testing in Patients with Chronic Lymphocytic Leukemia (CLL). Cancer. 2010; 116(20): 4777–4787. 

⁵ Leukemia and Lymphoma Society Minimal Residual Disease (MRD) Fact Sheet https://www.lls.org/sites/default/files/National/USA/Pdf/Publications/FS35_MRD_Final_2019.pdf 

⁶ Genetics Home Reference. Isolated growth hormone deficiency. http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed November 2020.

⁷ Turetsky, et al. Single cell imaging of Bruton's Tyrosine Kinase using an irreversible inhibitor. Scientific Reports. volume 4, Article number: 4782 (2014).

⁸ de Rooij MF, Kuil A, Geest CR, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119(11):2590-2594.

⁹ IMBRUVICA U.S. Prescribing Information, April 2020.

¹⁰  VENCLEXTA (venetoclax) [Package Insert]. North Chicago, IL.: AbbVie Inc.

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