- Five-year follow-up analysis of the Phase 3 CLL14 trial
(median follow-up of 65.4 months) continues to demonstrate longer
progression-free survival (PFS) after fixed-duration venetoclax
plus obinutuzumab compared to fixed-duration chlorambucil plus
obinutuzumab in previously untreated patients with chronic
lymphocytic leukemia and coexisting conditions
- PFS was significantly superior for venetoclax plus
obinutuzumab compared to chlorambucil plus obinutuzumab (median not
reached [NR] vs. 36.4 months, p<0.0001)
- A majority of patients treated with venetoclax and
obinutuzumab remain without relapse four years after completing the
venetoclax-based combination treatment
NORTH
CHICAGO, Ill., June 10,
2022 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced
five-year follow-up results from the Phase 3 CLL14 trial, finding
that over 60 percent of patients with previously untreated chronic
lymphocytic leukemia (CLL) who had received one-year fixed-duration
combination treatment of
VENCLYXTO®/VENCLEXTA® (venetoclax) plus
obinutuzumab (GAZYVA®) continued to show longer
progression-free survival (PFS) and higher rates of undetectable
minimal residual disease (MRD) after four years off
treatment.1 The findings were presented at the 2022
European Hematology Association (EHA) Annual Congress (Abstract
#S148).
"Long-term data from the CLL14 trial show that the one-year
fixed-duration combination regimen of venetoclax and obinutuzumab
offers patients the possibility of four years of CLL treatment-free
response without disease progression," said Mohamed Zaki, M.D., Ph.D., vice president and
global head of oncology clinical development, AbbVie. "Since its
approval, this chemotherapy-free combination option has helped
transform the therapeutic landscape for CLL."
Data shows that after more than five years of median follow-up
(65.4 months), PFS remained significantly superior among patients
treated with the VENCLYXTO/VENCLEXTA and obinutuzumab combination
compared to the chlorambucil and obinutuzumab chemotherapy regimen
(n=432; median NR vs 36.4 months; hazard ratio [HR] 0.35 [95% CI
0.26-0.46], p<0.0001). The therapies were administered for
a fixed-duration of 12 months for VENCLYXTO/VENCLEXTA in
combination with six cycles of obinutuzumab. At five years
after randomization, the estimated PFS rate after one-year
fixed-duration treatment was 62.6 percent for the
VENCLYXTO/VENCLEXTA-based combination compared to 27.0 percent for
the chlorambucil combination 1 The improvement
in PFS was maintained across all risk groups, including patients
with TP53 mutation/deletion and unmutated IGHV
status.1
Among the secondary endpoints, patients were assessed for MRD in
peripheral blood and/or bone marrow, using next generation
sequencing. Undetectable MRD (uMRD) was defined as less than one
CLL cell being identified per 10,000 lymphocytes sampled. Four
years after treatment completion, 18.1 percent of patients treated
with the VENCLYXTO/VENCLEXTA-based combination still had uMRD
compared to 1.9 percent of patients in the chlorambucil combination
study arm.1
The estimated overall survival (OS) rate was 81.9 percent in the
VENCLYXTO/VENCLEXTA-based combination and 77.0 percent in the
chlorambucil combination group (HR 0.72 [0.48-1.09], p=0.12) at
five years after randomization.1
No new safety signals were observed in the five-year follow-up
analysis. The most frequently occurring serious adverse reactions
(>=2%) in patients receiving the VENCLYXTO/VENCLEXTA-based
combination were pneumonia, sepsis, febrile neutropenia, and tumor
lysis syndrome.1
"Four years following treatment completion, we are pleased to
report that approximately three out of five patients who received
the fixed-duration combination treatment with venetoclax have
remained progression free," said Othman Al-Sawaf, M.D.,
investigator in the CLL14 study, hematologist-oncologist at the
University Hospital Cologne in Germany, and study physician at
the German CLL Study Group. "Additionally, it is notable that the
population of patients who received chlorambucil combination was
observed to have slightly more than twice the rate of
progression events, compared to the patients who received the
venetoclax combination."
VENCLYXTO/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 CLL14 Phase 3
Trial3,4,5
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 VENCLYXTO/VENCLEXTA and obinutuzumab (n=216)
versus obinutuzumab and chlorambucil (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
VENCLYXTO/VENCLEXTA 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 independent review committee.
Key secondary endpoints were rates of MRD in peripheral blood
and bone marrow, overall and complete response rates, MRD in
complete response in peripheral blood and bone marrow, and overall
survival.
In patients with CLL receiving venetoclax combination therapy
with obinutuzumab, serious adverse reactions (ARs) were most often
due to febrile neutropenia and pneumonia (5 percent each). The most
common ARs (≥20 percent) of any grade were neutropenia (60
percent), diarrhea (28 percent), and fatigue (21 percent). 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
percent (4/212) of patients, most often from infection.
About VENCLYXTO® (venetoclax)
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.
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
Information4
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 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.
AbbVie 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 2021 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
- Al-Sawaf O, et al. Venetoclax-Obinutuzumab for previously
untreated chronic lymphocytic leukemia: 5-year results of the
randomized CLL14 study. [Insert abstract no.]. Presented at
European Hematology Association 2022 Congress (EHA 2022),
June 9-12, 2022.
- Hallek M, et al. Guidelines for diagnosis, indications for
treatment, response assessment and supportive management of chronic
lymphocytic leukemia. Blood.
2018;131(25):2745-2760.
- Summary of Product Characteristics for VENCLYXTO (venetoclax).
Ludwigshafen, Germany: AbbVie Deutschland GmbH & Co.
KG.
- VENCLEXTA (venetoclax) [Package Insert]. North Chicago, Ill.: AbbVie Inc.
- 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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