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,
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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.
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