Celgene Provides Update on ABRAXANE Combination Therapy in the Treatment of Metastatic Triple-Negative Breast Cancer and Pancreatic Cancer
Business Wire 12-Mar-2019 4:30 PM
TECENTRIQ® in Combination with ABRAXANE®
receives accelerated approval for people with PD-L1-Positive, Metastatic
Triple-Negative Breast Cancer
Top-line results announced from the international Phase 3 study
evaluating adjuvant therapy with ABRAXANE in combination with
gemcitabine vs. gemcitabine alone for patients with surgically resected
pancreatic cancer
Celgene Corporation (NASDAQ:CELG) today announced two updates for
ABRAXANE® (paclitaxel protein-bound particles for injectable
suspension) (albumin-bound) in the treatment of metastatic
triple-negative breast cancer and early stage pancreatic cancer.
Genentech, a member of the Roche Group, recently announced the
accelerated approval of TECENTRIQ® (atezolizumab) in
combination with ABRAXANE® for the treatment of adult
patients with unresectable locally advanced or metastatic
triple-negative breast cancer (TNBC) whose tumors express PD-L1 as
determined by an FDA-approved test. This indication is approved under
accelerated approval based on progression-free survival. Continued
approval for this indication may be contingent upon verification and
description of clinical benefit in a confirmatory trial(s). This
combination is the first cancer immunotherapy regimen approved for
breast cancer and is based on results from the Phase 3 IMpassion130
study, which demonstrated that the combination of TECENTRIQ plus
ABRAXANE compared to ABRAXANE monotherapy, as an initial (first-line)
treatment, significantly reduced the risk of disease worsening or death
(progression-free survival) in patients with metastatic or unresectable
locally advanced triple negative breast cancer (TNBC) in the PD-L1
positive populations who had not received chemotherapy for metastatic
disease.
"This is the second approval from the U.S. Food and Drug Administration
of a PD-1/PD-L1 antibody in combination with ABRAXANE," said Alise
Reicin, M.D., President, Global Clinical Development for Celgene.
"ABRAXANE continues to be studied with immunotherapy agents
as a combination partner across a range of solid tumors."
In addition, the Celgene-sponsored, pivotal, Phase 3 apact®
study evaluating the investigational use of ABRAXANE in combination with
gemcitabine following surgical resection (adjuvant treatment) in
patients with pancreatic cancer did not achieve the primary endpoint of
improvement in disease-free survival, as confirmed by independent
radiological review, compared to gemcitabine alone. Overall survival, a
secondary endpoint of the study, was improved, reaching nominal
statistical significance, with ABRAXANE in combination with gemcitabine
compared to gemcitabine alone. The safety profile observed in the apact
study was consistent with previously reported studies of ABRAXANE. Data
from apact will be submitted to a future medical meeting.
Currently, there are more than 130 studies evaluating the use of
ABRAXANE in patients with pancreatic cancer in combination with more
than 50 novel agents.
About apact
apact is an international, multicenter, randomized, open-label,
controlled Phase 3 study (ClinicalTrials.gov, NCT01964430) to assess the
efficacy of ABRAXANE in combination with gemcitabine versus gemcitabine
alone as adjuvant therapy for patients with surgically resected
pancreatic adenocarcinoma. The primary endpoint of the study was the
independent assessment of disease-free survival (DFS); secondary
endpoints included overall survival (OS) and safety. The study enrolled
866 patients randomized 1:1 to receive either ABRAXANE 125 mg/m2
followed by gemcitabine 1000 mg/m2, or gemcitabine 1000 mg/m2
monotherapy. Treatment was administered intravenously, weekly on Days 1,
8, and 15 of a 28-day cycle for a total of 6 cycles.
About Pancreatic Cancer
Each year, more than 350,000 people worldwide are diagnosed with
pancreatic cancer – one of the deadliest cancers – with the majority of
cases diagnosed in late stage. Despite advances in therapy over the past
two decades that have led to doubled 5-year survival rates, pancreatic
cancer 5-year survival is still only in the single digits – 8% – due to
the complex nature of the disease and lack of symptoms until the disease
has progressed.
Even among patients with localized pancreatic cancer, for whom surgery
is potentially curative, survival remains poor and the rate of relapse
is high. However, adjuvant chemotherapy has been proven to significantly
improve survival compared with surgery alone. Despite the noted
improvements with chemotherapy following surgery, recurrence rates of
pancreatic cancer are still high with 69 to 75% of patients having a
relapse within 2 years. There remains a high unmet medical need for more
effective adjuvant therapies.
About Triple Negative Breast Cancer
Breast cancer is the second most common cancer among women in the United
States. According to the American Cancer Society, it is estimated that
about 266,000 American women will be diagnosed with invasive breast
cancer in 2018, and nearly 41,000 will die from the disease.
Approximately 10-20 percent of breast cancers are triple negative breast
cancer (TNBC). TNBC is an aggressive form of the disease with a high
unmet need. It can be more difficult to treat because it is not
sensitive to hormone therapy or medicines that target HER2.
TECENTRIQ® is a registered trademark of Genentech, a member
of the Roche Group.
About ABRAXANE in Pancreatic Cancer
In September 2013, the U.S. Food and Drug Administration (FDA) approved
ABRAXANE in combination with gemcitabine as first-line treatment of
patients with metastatic pancreatic cancer. The current indication
remains unchanged and clinical trials continue building on the
foundation of ABRAXANE in combination with gemcitabine for a new wave of
potential treatments, such as an ongoing Phase 2 cooperative group trial
with SWOG S1505 (ClinicalTrials.gov, NCT02562716) investigating the
safety and effectiveness of ABRAXANE in combination with gemcitabine as
neoadjuvant treatment for localized pancreatic head adenocarcinoma.
ABRAXANE is not approved for the adjuvant treatment of pancreatic cancer.
About ABRAXANE
Indications
ABRAXANE is indicated for the treatment of breast cancer after
failure of combination chemotherapy for metastatic disease or relapse
within 6 months of adjuvant chemotherapy. Prior therapy should have
included an anthracycline unless clinically contraindicated.
ABRAXANE is indicated for the first-line treatment of locally
advanced or metastatic non–small cell lung cancer, in combination with
carboplatin, in patients who are not candidates for curative surgery or
radiation therapy.
ABRAXANE is indicated for the first-line treatment of patients with
metastatic adenocarcinoma of the pancreas, in combination with
gemcitabine.
Important Safety Information
WARNING - NEUTROPENIA
-
Do not administer ABRAXANE therapy to patients who have baseline
neutrophil counts of less than 1500 cells/mm3.
In order to monitor the occurrence of bone marrow suppression,
primarily neutropenia, which may be severe and result in infection, it
is recommended that frequent peripheral blood cell counts be performed
on all patients receiving ABRAXANE
-
Note: An albumin form of paclitaxel may substantially affect a
drug's functional properties relative to those of drug in solution. DO
NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS
CONTRAINDICATIONS
Neutrophil Counts
-
ABRAXANE should not be used in patients who have baseline neutrophil
counts of <1500 cells/mm3
Hypersensitivity
-
Patients who experience a severe hypersensitivity reaction to ABRAXANE
should not be rechallenged with the drug
WARNINGS AND PRECAUTIONS
Hematologic Effects
-
Bone marrow suppression (primarily neutropenia) is dose-dependent and
a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4
neutropenia occurred in 34% of patients with metastatic breast cancer
(MBC), 47% of patients with non–small cell lung cancer (NSCLC), and
38% of patients with pancreatic cancer
-
Monitor for myelotoxicity by performing complete blood cell counts
frequently, including prior to dosing on Day 1 (for MBC) and Days 1,
8, and 15 (for NSCLC and for pancreatic cancer)
-
Do not administer ABRAXANE to patients with baseline absolute
neutrophil counts (ANC) of less than 1500 cells/mm3
-
In the case of severe neutropenia (<500 cells/mm3 for 7
days or more) during a course of ABRAXANE therapy, reduce the dose of
ABRAXANE in subsequent courses in patients with either MBC or NSCLC
-
In patients with MBC, resume treatment with every-3-week cycles of
ABRAXANE after ANC recovers to a level >1500 cells/mm3
and platelets recover to a level >100,000 cells/mm3
-
In patients with NSCLC, resume treatment if recommended at permanently
reduced doses for both weekly ABRAXANE and every-3-week carboplatin
after ANC recovers to at least 1500 cells/mm3 and
platelet count of at least 100,000 cells/mm3 on Day 1 or to
an ANC of at least 500 cells/mm3 and platelet count of at
least 50,000 cells/mm3 on Days 8 or 15 of the cycle
-
In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and
gemcitabine if the ANC is less than 500 cells/mm3 or
platelets are less than 50,000 cells/mm3 and delay
initiation of the next cycle if the ANC is less than 1500 cells/mm3
or platelet count is less than 100,000 cells/mm3 on Day 1
of the cycle. Resume treatment with appropriate dose reduction if
recommended
Nervous System
-
Sensory neuropathy is dose- and schedule-dependent
-
The occurrence of Grade 1 or 2 sensory neuropathy does not generally
require dose modification
-
If = Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment
until resolution to Grade 1 or 2 for MBC or until resolution to
= Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction
for all subsequent courses of ABRAXANE
Sepsis
-
Sepsis occurred in 5% of patients with or without neutropenia who
received ABRAXANE in combination with gemcitabine
-
Biliary obstruction or presence of biliary stent were risk factors for
severe or fatal sepsis
-
If a patient becomes febrile (regardless of ANC), initiate treatment
with broad-spectrum antibiotics
-
For febrile neutropenia, interrupt ABRAXANE and gemcitabine until
fever resolves and ANC =1500 cells/mm3, then resume
treatment at reduced dose levels
Pneumonitis
-
Pneumonitis, including some cases that were fatal, occurred in 4% of
patients receiving ABRAXANE in combination with gemcitabine
-
Monitor patients for signs and symptoms and interrupt ABRAXANE and
gemcitabine during evaluation of suspected pneumonitis
-
Permanently discontinue treatment with ABRAXANE and gemcitabine upon
making a diagnosis of pneumonitis
Hypersensitivity
-
Severe and sometimes fatal hypersensitivity reactions, including
anaphylactic reactions, have been reported
-
Patients who experience a severe hypersensitivity reaction to ABRAXANE
should not be rechallenged with this drug
-
Cross-hypersensitivity between ABRAXANE and other taxane products has
been reported and may include severe reactions such as anaphylaxis.
Patients with a previous history of hypersensitivity to other taxanes
should be closely monitored during initiation of ABRAXANE therapy
Hepatic Impairment
-
Because the exposure and toxicity of paclitaxel can be increased with
hepatic impairment, administration of ABRAXANE in patients with
hepatic impairment should be performed with caution
-
Patients with hepatic impairment may be at an increased risk of
toxicity, particularly from myelosuppression, and should be monitored
for development of profound myelosuppression
-
For MBC and NSCLC, the starting dose should be reduced for patients
with moderate or severe hepatic impairment
-
For pancreatic adenocarcinoma, ABRAXANE is not recommended for
patients with moderate to severe hepatic impairment (total bilirubin
>1.5 x ULN and AST =10 x ULN)
Albumin (Human)
-
ABRAXANE contains albumin (human), a derivative of human blood
Embryo Fetal Toxicity
-
Based on mechanism of action and findings in animals, ABRAXANE can
cause fetal harm when administered to a pregnant woman
-
Advise females of reproductive potential of the potential risk to a
fetus.
-
Advise females of reproductive potential to use effective
contraception and avoid becoming pregnant during treatment with
ABRAXANE and for at least six months after the last dose of ABRAXANE
-
Advise male patients with female partners of reproductive potential to
use effective contraception and avoid fathering a child during
treatment with ABRAXANE and for at least three months after the last
dose of ABRAXANE
ADVERSE REACTIONS
Randomized Metastatic Breast Cancer (MBC) Study
-
The most common adverse reactions (=20%) with single-agent use of
ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%,
94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory
neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all
patients 60%, 52%; patients with normal baseline 35%, 30%),
fatigue/asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia
(any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline
phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%,
<1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%;
severe <1%, 1%) and infections (24%, 20%), respectively
-
Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229
(3%) patients
-
Other adverse reactions of note with the use of ABRAXANE vs paclitaxel
injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid
retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe
<1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%),
hypersensitivity reactions (any 4%, 12%; severe 0%, 2%),
thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis
(<1%, <1%), and injection site reactions (<1%, 1%), respectively.
Dehydration and pyrexia were also reported
-
Renal dysfunction (any 11%, severe 1%) was reported in patients
treated with ABRAXANE (n=229)
-
In all ABRAXANE-treated patients (n=366), ocular/visual disturbances
were reported (any 13%; severe 1%)
-
Severe cardiovascular events possibly related to single-agent ABRAXANE
occurred in approximately 3% of patients and included cardiac
ischemia/infarction, chest pain, cardiac arrest, supraventricular
tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary
emboli, and hypertension
-
Cases of cerebrovascular attacks (strokes) and transient ischemic
attacks have been reported
Non–Small Cell Lung Cancer (NSCLC) Study
-
The most common adverse reactions (=20%) of ABRAXANE in combination
with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia,
peripheral neuropathy, nausea, and fatigue
-
The most common serious adverse reactions of ABRAXANE in combination
with carboplatin for NSCLC are anemia (4%) and pneumonia (3%)
-
The most common adverse reactions resulting in permanent
discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia
(3%), and peripheral neuropathy (1%)
-
The most common adverse reactions resulting in dose reduction of
ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)
-
The most common adverse reactions leading to withholding or delay in
ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and
anemia (16%)
-
The following common (=10% incidence) adverse reactions were observed
at a similar incidence in ABRAXANE plus carboplatin–treated and
paclitaxel injection plus carboplatin–treated patients: alopecia
(56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia
(16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea
(12%), and rash (10%); incidence rates are for the ABRAXANE plus
carboplatin treatment group
-
Adverse reactions with a difference of =2%, Grade 3 or higher, with
combination use of ABRAXANE and carboplatin vs combination use of
paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%),
neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral
neuropathy (3%, 12%), respectively
-
Adverse reactions with a difference of =5%, Grades 1-4, with
combination use of ABRAXANE and carboplatin vs combination use of
paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%),
thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema
peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and
myalgia (10%, 19%), respectively
-
Neutropenia (all grades) was reported in 85% of patients who received
ABRAXANE and carboplatin vs 83% of patients who received paclitaxel
injection and carboplatin
Pancreatic Adenocarcinoma Study
-
Among the most common (=20%) adverse reactions in the phase III study,
those with a =5% higher incidence in the ABRAXANE/gemcitabine group
compared with the gemcitabine group are neutropenia (73%, 58%),
fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%,
48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%,
24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite
(36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)
-
Of these most common adverse reactions, those with a =2% higher
incidence of Grade 3-4 toxicity in the ABRAXANE/gemcitabine group
compared with the gemcitabine group, respectively, are neutropenia
(38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea
(6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%),
decreased appetite (5%, 2%), and dehydration (7%, 2%)
-
Thrombocytopenia (all grades) was reported in 74% of patients in the
ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group
-
The most common serious adverse reactions of ABRAXANE (with a =1%
higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%),
and vomiting (4%)
-
The most common adverse reactions resulting in permanent
discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue
(4%), and thrombocytopenia (2%)
-
The most common adverse reactions resulting in dose reduction of
ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%)
-
The most common adverse reactions leading to withholding or delay in
ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue
(8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)
-
Other selected adverse reactions with a =5% higher incidence for
all-grade toxicity in the ABRAXANE/gemcitabine group compared to the
gemcitabine group, respectively, are asthenia (19%, 13%), mucositis
(10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%,
7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection
(11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia
(10%, 4%), and depression (12%, 6%)
-
Other selected adverse reactions with a =2% higher incidence for Grade
3-4 toxicity in the ABRAXANE/gemcitabine group compared to the
gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%),
and hypokalemia (4%, 1%)
Postmarketing Experience With ABRAXANE and Other Paclitaxel
Formulations
-
Severe and sometimes fatal hypersensitivity reactions have been
reported with ABRAXANE. The use of ABRAXANE in patients previously
exhibiting hypersensitivity to paclitaxel injection or human albumin
has not been studied. In postmarketing experience,
cross-hypersensitivity between ABRAXANE and other taxanes has been
reported
-
There have been reports of congestive heart failure, left ventricular
dysfunction, and atrioventricular block with ABRAXANE, primarily among
individuals with underlying cardiac history or prior exposure to
cardiotoxic drugs
-
There have been reports of extravasation of ABRAXANE. Given the
possibility of extravasation, it is advisable to monitor closely the
ABRAXANE infusion site for possible infiltration during drug
administration
DRUG INTERACTIONS
-
Caution should be exercised when administering ABRAXANE concomitantly
with medicines known to inhibit or induce either CYP2C8 or CYP3A4
USE IN SPECIFIC POPULATIONS
Pregnancy
-
Based on the mechanism of action and findings in animals, ABRAXANE can
cause fetal harm when administered to a pregnant woman. Advise females
of the potential risk to a fetus and to avoid becoming pregnant while
receiving ABRAXANE
Lactation
-
Paclitaxel and/or its metabolites were excreted into the milk of
lactating rats. Nursing must be discontinued when receiving treatment
with ABRAXANE and for two weeks after the last dose
Females and Males of Reproductive Potential
-
Females of reproductive potential should have a pregnancy test prior
to starting treatment with ABRAXANE
-
Advise females of reproductive potential to use effective
contraception and avoid becoming pregnant during treatment with and
for at least six months after the last dose of ABRAXANE [see
Warnings and Precautions]
-
Advise males with female partners of reproductive potential to use
effective contraception and avoid fathering a child during treatment
with ABRAXANE and for at least three months after the last dose of
ABRAXANE [see Warnings and Precautions]
-
Based on findings in animals, ABRAXANE may impair fertility in females
and males of reproductive potential
Pediatric
-
The safety and effectiveness of ABRAXANE in pediatric patients have
not been evaluated
Geriatric
-
A higher incidence of epistaxis, diarrhea, dehydration, fatigue, and
peripheral edema was found in patients 65 years or older who received
ABRAXANE for MBC in a pooled analysis of clinical studies
-
Myelosuppression, peripheral neuropathy, and arthralgia were more
frequent in patients =65 years of age treated with ABRAXANE and
carboplatin in NSCLC
-
Diarrhea, decreased appetite, dehydration, and epistaxis were more
frequent in patients 65 years or older compared with patients younger
than 65 years old who received ABRAXANE and gemcitabine in
adenocarcinoma of the pancreas
Renal Impairment
-
There are insufficient data to permit dosage recommendations in
patients with severe renal impairment or end stage renal disease
(estimated creatinine clearance <30 mL/min)
DOSAGE AND ADMINISTRATION
-
Do not administer ABRAXANE to any patient with total bilirubin greater
than 5 x ULN or AST greater than 10 x ULN
-
For MBC and NSCLC, reduce starting dose in patients with moderate to
severe hepatic impairment
-
For adenocarcinoma of the pancreas, do not administer ABRAXANE to
patients who have moderate to severe hepatic impairment
-
Dose reductions or discontinuation may be needed based on severe
hematologic, neurologic, cutaneous, or gastrointestinal toxicity
-
Monitor patients closely
Please see full Prescribing
Information, including Boxed WARNING.
About Celgene
Celgene Corporation, headquartered in Summit, New Jersey, is an
integrated global biopharmaceutical company engaged primarily in the
discovery, development and commercialization of innovative therapies for
the treatment of cancer and inflammatory diseases through
next-generation solutions in protein homeostasis, immuno-oncology,
epigenetics, immunology and neuro-inflammation. For more information,
please visit www.celgene.com.
Follow Celgene on Social Media: Twitter,
Pinterest,
LinkedIn,
Facebook
and YouTube.
FORWARD-LOOKING STATEMENTS
This press release contains forward-looking statements, which are
generally statements that are not historical facts. Forward-looking
statements can be identified by the words "expects," "anticipates,"
"believes," "intends," "estimates," "plans," "will," "outlook" and
similar expressions. Forward-looking statements are based on
management's current plans, estimates, assumptions and projections, and
speak only as of the date they are made. We undertake no obligation to
update any forward-looking statement in light of new information or
future events, except as otherwise required by law. Forward-looking
statements involve inherent risks and uncertainties, most of which are
difficult to predict and are generally beyond our control. Actual
results or outcomes may differ materially from those implied by the
forward-looking statements as a result of the impact of a number of
factors, many of which are discussed in more detail in our Annual Report
on Form 10-K including factors related to the proposed transaction
between Bristol-Myers Squibb and Celgene, such as, but not limited to,
the risks that: management's time and attention is diverted on
transaction related issues; disruption from the transaction makes it
more difficult to maintain business, contractual and operational
relationships; pending legal proceedings or any future litigation
instituted against Bristol-Myers Squibb, Celgene or the combined company
could delay or prevent the proposed transaction; and Bristol-Myers
Squibb, Celgene or the combined company is unable to retain key
personnel.
Hyperlinks are provided as a convenience and for informational
purposes only. Celgene bears no responsibility for the security or
content of external websites.
View source version on businesswire.com: https://www.businesswire.com/news/home/20190312005846/en/