AbbVie Presents Extended Follow-Up Data for Fixed Duration Treatment VENCLEXTA®/VENCLYXTO® (venetoclax) in Chronic Lymphocytic Leukemia (CLL)

NORTH CHICAGO, Ill., Dec. 5, 2020 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced new, updated results from the Phase 3 MURANO and CLL14 clinical trials evaluating VENCLEXTA^®/VENCLYXTO^® (venetoclax) fixed duration treatment combinations at the virtual 62^nd American Society of Hematology (ASH) Annual Meeting & Exposition (abstracts 125, 127, and 1310, respectively). These findings add to the growing body of data supporting the use of VENCLEXTA/VENCLYXTO in first-line or previously treated chronic lymphocytic leukemia (CLL) patients.

"MURANO and CLL14 provide a look at the benefits of fixed duration VENCLEXTA combinations in helping many patients to achieve sustained progression-free survival," said John Hayslip, M.D., M.S.C.R., executive medical director, AbbVie. "These responses reinforce that with VENCLEXTA/VENCLYXTO, it is possible for CLL patients to complete treatment and live longer without their disease progressing."

Data from the MURANO and CLL14 trials presented at ASH reinforce that CLL patients who have relapsed or have not started treatment and receive a VENCLEXTA/VENCLYXTO regimen can experience long-lasting responses, even after stopping treatment, compared to standard of care treatment options.

MURANO Five-Year Analysis¹
The results of the final, descriptive analysis of the MURANO trial (median follow-up of 59.2 months with all patients off VENCLEXTA/VENCLYXTO in combination with rituximab [VenR] treatment for at least three years; Abstract 125) demonstrated the following:

• Investigator (INV)-assessed progression-free survival (PFS): Patients with relapsed or refractory (R/R) CLL on fixed duration VenR had a median PFS of 53.6 months (95% CI: 48.4-57.0) compared to 17.0 months (95% CI: 15.5-21.7) with bendamustine plus rituximab (BR; HR 0.19, 95% CI: 0.15-0.26).
• Overall survival (OS): The OS estimate was 82.1% (95% CI: 76.4-87.8) with VenR compared to 62.2% (95% CI: 54.8-69.6) for BR (HR 0.40, 95% CI: 0.26-0.62), median not reached in either arm.
• Minimal residual disease (MRD) status at completion of VenR treatment: Patients who achieved MRD-negativity without disease progression at the end of their treatment course had improved PFS and OS compared to patients with MRD. MRD refers to the small number of cancer cells that remain in the body after treatment. 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.⁴
• Consistent safety profile: The safety profile of the VenR combination is consistent with the known safety profile of each individual therapy alone. No new, serious safety issues were observed in the five-year MURANO updated analysis.

According to the Leukemia & Lymphoma Society, MRD refers to the small number of cancer cells that remain in the body after treatment.⁴ 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.

CLL14 Analyses^2,3
Data from descriptive analyses of the Phase 3 CLL14 trial was also presented today evaluating the role of MRD measurements in clinical trials.

One analysis showed that patients with previously untreated CLL and co-existing medical conditions who had partial response (PR) after treatment with VENCLEXTA/VENCLYXTO in combination with obinutuzumab (Ven-Obi) had a similar outcome as patients with complete response (CR) when uMRD levels were achieved. These data suggest that patients on the VENCLEXTA/VENCLYXTO combination with uMRD levels and PR had longer PFS than patients with MRD and CR. This is significant because patients with CLL who show a PR to chemoimmunotherapy have a poorer prognosis than patients with CR.² These results were not tested for statistical significance. (Abstract 1310) 

The second analysis looked at clonal growth patterns – or how quickly cancer cells grow and spread – in patients treated within the CLL14 trial. The findings from the analysis shed light on which patient group may be at risk of relapsing despite initial MRD response.³ (Abstract 127)

The four-year, follow-up analysis showed an OS rate of 85.3% with Ven-Obi versus 83.1% with chlorambucil in combination with obinutuzumab (Obi-Clb; HR 0.85, 95% CI [0.54-1.35]; P=0.4929).

VENCLEXTA 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.

About the MURANO Trial^5,6,7
A total of 389 patients with R/R CLL who had received at least one prior therapy were enrolled in the international, multicenter, open-label, randomized Phase 3 MURANO trial. The trial was designed to evaluate the efficacy and safety of VenR (n=194) compared with BR (n=195). The median age of patients in the trial was 65 years (range: 22 to 85).

The trial met its primary efficacy endpoint of INV-assessed PFS. At the time of the primary analysis, median PFS with VenR was not reached compared with 17.0 months for BR (HR: 0.17; 95% CI: 0.11- 0.25; p<0.0001). In the primary efficacy analysis, the median follow-up for PFS was 23.8 months (range: 0 to 37.4). Additional efficacy endpoints included independent review committee (IRC)-assessed PFS, INV- and IRC-assessed overall response rate (defined as complete response + complete response with incomplete marrow recovery + partial response + nodular partial response), OS and rates of MRD-negativity. 

In patients with CLL receiving combination therapy with rituximab, the most frequent serious adverse reaction (AR; ≥5%) was pneumonia (9%). The most common ARs (≥20%) of any grade were neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), fatigue (22%), and nausea (21%). Fatal ARs that occurred in the absence of disease progression and within 30 days of the last venetoclax treatment and/or 90 days of the last rituximab were reported in 2% (4/194) of patients.

About the CLL14 Trial^6,7,8
The prospective, multicenter, open-label, randomized Phase 3 CLL14 trial, which was conducted in close collaboration with the German CLL Study Group (DCLLSG), evaluated the efficacy and safety of a combined regimen of Ven-Obi (n=216) versus Obi-Clb (n=216) in previously untreated patients with CLL and coexisting medical conditions (total Cumulative Illness Rating Scale [CIRS] score >6 or creatinine clearance <70 mL/min). The therapies were administered for a fixed duration of 12 months for venetoclax in combination with six cycles of obinutuzumab. The trial enrolled 432 patients, all of whom were previously untreated according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. Efficacy was based on PFS as assessed by an IRC. 

Key secondary endpoints were MRD-negativity in peripheral blood and bone marrow, overall and complete response rates, MRD-negativity in complete response in peripheral blood and bone marrow, and OS. 

In patients with CLL receiving combination therapy with obinutuzumab, serious ARs were most often due to febrile neutropenia and pneumonia (5% each). The most common ARs (≥20%) of any grade were neutropenia (60%), diarrhea (28%), and fatigue (21%). Fatal ARs that occurred in the absence of disease progression and with onset within 28 days of the last study treatment were reported in 2% (4/212) of patients, most often from infection.

About VENCLEXTA^®/VENCLYXTO^® (venetoclax) 
VENCLEXTA^®/VENCLYXTO^® (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/VENCLYXTO 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 Information⁷

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. When restarting VENCLEXTA after stopping for 1 week or longer, your healthcare provider may again check for your risk of TLS and change your dose.

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 and for 1 week after the last dose of VENCLEXTA.

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. 

See VENCLYXTO full summary of product characteristics (SmPC) at https://www.ema.europa.eu/en/documents/product-information/venclyxto-epar-product-information_en.pdf. 

Globally, prescribing information varies; refer to the individual country product label for complete information.

About AbbVie in Oncology
At AbbVie, we are committed to transforming standards of care for multiple blood cancers while advancing a dynamic pipeline of investigational therapies across a range of cancer types. Our dedicated and experienced team joins forces with innovative partners to accelerate the delivery of potentially breakthrough medicines. We are evaluating more than 20 investigational medicines in over 300 clinical trials across some of the world's most widespread and debilitating cancers. As we work to have a remarkable impact on people's lives, we are committed to exploring solutions to help patients obtain access to our cancer medicines. 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.

¹ Kater AP, et al. Abstract 125: Five-Year Analysis of Murano Study Demonstrates Enduring Undetectable Minimal Residual Disease (uMRD) in a Subset of Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Patients (Pts) Following Fixed-Duration Venetoclax-Rituximab (VenR) Therapy (Tx). Presented at the 2020 American Society of Hematology Annual Meeting & Exposition: December 5, 2020.
² Al-Sawaf O, et al. Abstract 1310: Characteristics and Outcome of Patients with Chronic Lymphocytic Leukaemia and Partial Response to Venetoclax-Obinutuzumab. Presented at the 2020 American Society of Hematology Annual Meeting & Exposition: December 5, 2020.
³ Al-Sawaf O, et al. Abstract 127: Clonal Dynamics after Venetoclax-Obinutuzumab Therapy: Novel Insights from the Randomized, Phase 3 CLL14 Trial. Presented at the 2020 American Society of Hematology Annual Meeting & Exposition: December 5, 2020. 
⁴ 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  
⁵ Seymour JF, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120
⁶ Summary of Product Characteristics for VENCLYXTO (venetoclax). Ludwigshafen, Germany: AbbVie Deutschland GmbH & Co. KG.
⁷ VENCLEXTA (venetoclax) [Package Insert]. North Chicago, Ill.: AbbVie Inc.
⁸ Fischer K, et al. Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. N Engl J Med. 2019;380:2225-2236.

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