News

• CANOVA study evaluated venetoclax plus dexamethasone in patients with t(11;14)-positive multiple myeloma compared to pomalidomide plus dexamethasone
• Results are being presented at the International Myeloma Society Annual Meeting in Athens, Greece
• AbbVie will discuss the data with health authorities in the near future to further understand the potential of venetoclax as a biomarker-driven therapy in multiple myeloma

NORTH CHICAGO, Ill., Sept. 29, 2023 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced data from its Phase 3 CANOVA study evaluating the safety and efficacy of venetoclax (VENCLEXTA^®/ VENCLYXTO^®) plus dexamethasone (VenDex) for patients with t(11;14)-positive relapsed or refractory (R/R) multiple myeloma who have received two or more prior treatments. Data did not demonstrate that the treatment combination significantly improved progression-free survival (PFS), the primary endpoint of the trial. Patients receiving VenDex showed improvement in median PFS of 9.9 months compared to 5.8 months with the combination of study comparator pomalidomide and dexamethasone (PomDex); however, the results did not reach statistical significance [HR = 0.823, 95% CI: (0.596, 1.136); p-value of 0.237]. 

Select prespecified secondary endpoints from the CANOVA trial include the following:

• Overall response rate (ORR): 62% in VenDex vs. 35% in PomDex (nominal p-value of <0.001)
• Rate of very good partial response or better (VGPR) at 39% in VenDex vs. 14% in PomDex (nominal p-value of <0.001)
• Median overall survival (OS) was 32.4 months in VenDex vs. 24.5 months in PomDex [HR of 0.697 (95% CI: 0.472, 1.029); nominal p-value of 0.067]

Additional prespecified analyses include:

• PFS per investigator which resulted in a median PFS of 9.1 months with VenDex vs 4.9 months with PomDex [HR = 0.737, (95% CI: 0.543, 1.000); nominal p-value of 0.050]
• Median time to next treatment (TTNT) which was longer in the VenDex arm 21.2 months vs. 8.3 months in the PomDex arm [HR of 0.546 (95% CI: 0.385, 0.776); nominal p-value of 0.001]

The safety profile of the combination of venetoclax and dexamethasone in the trial was generally consistent with the known safety profiles when used as single agents and no new safety signals have emerged. The most common adverse events (AEs) experienced by patients (>20%) treated with VenDex included any infection (61%), diarrhea (41%), lymphopenia (24%) and nausea (22%). The most common AEs experienced by subjects treated with PomDex included neutropenia (63%), any infection (57%), thrombocytopenia (39%) and anemia (35%). 

Multiple myeloma is the second most common blood cancer in the world.¹ Many patients experience poor outcomes as most eventually relapse despite recent treatment advances. A subset of patients have the t(11;14) biomarker, the most common chromosomal translocation in multiple myeloma, that can signal an overexpression of the BCL-2 protein.² 

"While the CANOVA trial did not meet its primary endpoint, given the potential favorable trends seen in the study, we will discuss these data with health authorities in the near future," said Mariana Cota Stirner, M.D., Ph.D., therapeutic area head oncology hematology, AbbVie. "We remain committed to elevating the standard of care for blood cancer patients around the world including patients with multiple myeloma."

Venetoclax is currently approved for patients with previously untreated and treated chronic lymphocytic leukemia (CLL) and newly diagnosed acute myeloid leukemia (AML). Venetoclax is not approved by any regulatory authority in any country for the treatment of multiple myeloma. 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 CANOVA Study³
CANOVA is a Phase 3, multicenter, randomized, open label study of either venetoclax or pomalidomide in combination with dexamethasone in patients with t(11;14)-positive R/R multiple myeloma. The study was initiated in 2018 and enrolled 263 patients 18 years and older with a documented diagnosis of multiple myeloma with t(11;14)-positive disease based on standard International Myeloma Working Group (IMWG) criteria, who had received at least two prior lines of therapy.

The primary endpoint of the trial was IRC-assessed PFS. Secondary endpoints include ORR, VGPR or better response rate, OS and MRD negativity rate defined at 10^-5 threshold, as measured by centralized testing of bone marrow aspirate samples by next generation sequencing.

About Multiple Myeloma
Multiple myeloma is a type of blood cancer that affects plasma cells, which grow out of control and accumulate in the body's bone marrow.^1,4 Multiple myeloma is the second most common blood cancer in the world.¹ An estimated 176,000 people globally were diagnosed with multiple myeloma in 2020, and 117,000 people died from the disease.⁵ In approximately 16% to 24% of people with multiple myeloma, t(11;14) is the most frequently seen chromosomal translocation.²

Nearly all multiple myeloma patients eventually relapse, which is associated with poor outcomes, and each remission is typically shorter than the previous one.⁶

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. 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. Venetoclax is approved in more than 80 countries, including the U.S.

Indication and Important VENCLYXTO^® ▼ (venetoclax) EU Safety Information⁷

Indications

Venclyxto in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL).

Venclyxto in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy.

Venclyxto monotherapy is indicated for the treatment of CLL:

• In the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor, or
• In the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.

Venclyxto in combination with a hypomethylating agent is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy.

Contraindications

Hypersensitivity to the active substance or to any of the excipients is contraindicated. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumour lysis syndrome (TLS). Concomitant use of preparations containing St. John's wort as Venclyxto efficacy may be reduced.

Special Warnings & Precautions for Use

Tumour Lysis syndrome, including fatal events, has occurred in patients when treated with Venclyxto. For CLL and AML, please refer to the indication-specific recommendations for prevention of TLS in the Venclyxto summary of product characteristic (SmPC).

Patients should be assessed for risk and should receive appropriate prophylaxis, monitoring, and management for TLS. The risk of TLS is a continuum based on multiple factors, including comorbidities. Venclyxto poses a risk for TLS at initiation and during the dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of Venclyxto and at each dose increase.

Neutropenia (grade 3 or 4) has been reported. Complete blood counts should be monitored throughout the treatment period.

In patients with AML, neutropenia (grade 3 or 4) is common before starting treatment. The neutrophil counts can worsen with Venetoclax in combination with a hypomethylating agent. Neutropenia can recur with subsequent cycles of therapy. Dose modification and interruptions for cytopenias are dependent on remission status.

For CLL and AML, please refer to the indication-specific recommendations for dose modifications for toxicities in the Venclyxto SmPC.

Serious infections including sepsis with fatal outcome have been reported. Monitoring of any signs and symptoms of infection is required. Suspected infections should receive prompt treatment including antimicrobials and dose interruption or reduction as appropriate.

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions

In CLL and AML CYP3A inhibitors may increase Venclyxto plasma concentrations.

In CLL, at initiation and dose-titration phase, Strong CYP3A inhibitors are contraindicated due to increased risk for TLS and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, please refer to the recommendations for dose modifications in the Venclyxto SmPC.

In AML, please refer to the AML-specific recommendation for dose modifications for potential interactions with CYP3A inhibitors, in the VENCLYXTO SmPC.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.

CYP3A4 inducers may decrease Venclyxto plasma concentrations.  Avoid coadministration with strong or moderate CYP3A inducers. These agents may decrease venetoclax plasma concentrations. 

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions

CLL

The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in the combination studies with obinutuzumab or rituximab were neutropenia, diarrhoea, and upper respiratory tract infection. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhoea, nausea, anaemia, fatigue, and upper respiratory tract infection.

The most frequently occurring serious adverse reactions (>=2%) in patients receiving venetoclax in combination with obinutuzumab or rituximab were pneumonia, sepsis, febrile neutropenia, and TLS.  In the monotherapy studies, the most frequently reported serious adverse reactions (>=2%) were pneumonia and febrile neutropenia.

Discontinuations due to adverse reactions occurred in 16% of patients treated with venetoclax in combination with obinutuzumab or rituximab in the CLL14 and Murano studies, respectively.  In the monotherapy studies with venetoclax, 11% of patients discontinued due to adverse reactions. 

Dosage reductions due to adverse reactions occurred in 21% of patients treated with the combination of venetoclax and obinutuzumab in CLL14, in 15% of patients treated with the combination of venetoclax and rituximab in Murano, and in 14% of patients treated with venetoclax in the monotherapy studies. The most common adverse reaction that led to dose interruptions was neutropenia. 

AML

The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in combination with azacitidine or decitabine in the VIALE-A and M14-358, respectively, were thrombocytopenia, neutropenia, febrile neutropenia, nausea, diarrhoea, vomiting, anaemia, fatigue, pneumonia, hypokalaemia, and decreased appetite, haemorrhage, dizziness/syncope, hypotension, headache, abdominal pain, and anaemia.

The most frequently reported serious adverse reactions (≥5%) in patients receiving venetoclax in combination with azacitidine were febrile neutropenia, pneumonia, sepsis and haemorrhage. In M14-358, the most frequently reported serious adverse reactions (≥5%) were febrile neutropenia, pneumonia, bacteraemia and sepsis.

Discontinuations due to adverse reactions occurred in 24% of patients treated with venetoclax in combination with azacitidine in the VIALE-A study, and 26% of patients treated with venetoclax in combination with decitabine in the M14-358 study, respectively.

Dosage reductions due to adverse reactions occurred in 2% of patients in VIALE-A, and in 6% of patients in M14-358. Venetoclax dose interruptions due to adverse reactions occurred in 72% and 65% of patients, respectively. The most common adverse reaction that led to dose interruption (>10%) of Venetoclax in VIALE-A, were febrile neutropenia, neutropenia, pneumonia, and thrombocytopenia.  The most common adverse reactions that led to dose interruption (≥5%) of venetoclax in M14-358 were febrile neutropenia, neutropenia/neutrophil count decreased, pneumonia, platelet count decreased, and white blood cell count decreased.

Special Populations

Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS at initiation and during the dose-titration phase.  Safety in patients with severe renal impairment (CrCl <30 mL/min) or on dialysis has not been established, and a recommended dose for these patients has not been determined.

For patients with severe (Child-Pugh C) hepatic impairment, a dose reduction of at least 50% throughout treatment is recommended.

Venclyxto may cause embryo-fetal harm when administered to a pregnant woman. Advise nursing women to discontinue breastfeeding during treatment.

This is not a complete summary of all safety information. See Venclyxto (venetoclax) SmPC at www.ema.europa.eu. 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 www.abbvie.com/oncology and our Blood Cancer Press Kit page.

About AbbVie
AbbVie's mission is to discover and deliver innovative medicines and solutions 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, and eye care – and products and services in our Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on LinkedIn, Facebook, Instagram, X (formerly Twitter), and YouTube. 

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 and uses of future or conditional verbs, 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 expressed or implied in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. 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 2022 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, and specifically declines, to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.  

References:

1. International Myeloma Foundation. What is Multiple Myeloma? https://www.myeloma.org/what-is-multiple-myeloma. Accessed September 2023.
2. Bal S, et al. Am J Cancer Res. 2022;12:2950-2965.
3. Clinicaltrials.gov (2023). NCT 03539744: A Study of Venetoclax and Dexamethasone Compared With Pomalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma (CANOVA). https://www.clinicaltrials.gov/study/NCT03539744?cond=NCT03539744&rank=1. Accessed September 2023.
4. Multiple Myeloma Research Foundation. Understanding Multiple Myeloma. https://themmrf.org/multiple-myeloma/. Accessed September 2023.
5. Cancer.Net. Multiple Myeloma: Statistics. https://www.cancer.net/cancer-types/multiple-myeloma/statistics. Accessed September 2023.
6. Myeloma UK. Infopack for relapsed and/or refractory myeloma patients. https://www.myeloma.org.uk/documents/infopack-for-relapsed-and-or-refractory-myeloma-patients/. Accessed September 2023.
7. Summary of Product Characteristics for VENCLYXTO (venetoclax). Ludwigshafen, Germany: AbbVie Deutschland GmbH & Co. KG.

SOURCE AbbVie