-- Phase III Secondary Endpoint Results
Demonstrate A Significantly Higher Disease-free Survival Rate
following ABRAXANE as Investigational Therapy in Neoadjuvant Breast
Cancer --
The German Breast Group (GBG) and Celgene Corporation
(NASDAQ:CELG) today announced long-term invasive disease-free
survival results from the GeparSepto clinical trial comparing the
investigational use of ABRAXANE® (paclitaxel albumin-bound
particles for injectable suspension) to paclitaxel in early
high-risk breast cancer patients at the 2017 San Antonio Breast
Cancer Symposium (SABCS). The results from the 1,206 patient study
found that ABRAXANE demonstrated a significantly higher
disease-free survival rate, a secondary efficacy endpoint, in high
risk early breast cancer patients when compared to conventional
solvent-based paclitaxel.
In this large Phase III study, of which disease-free survival
was a secondary endpoint, the investigational use of ABRAXANE
(N=600) was compared to conventional solvent-based paclitaxel
(N=606) followed by epirubicin/cyclophosphamide in both arms given
all before surgery. The study found a significantly higher
disease-free survival (DFS) rate in patients receiving ABRAXANE
compared to those receiving paclitaxel as part of a neoadjuvant
treatment regimen [HR=0.69, 95% CI (0.54-0.89); p=0.0044]). The
rates of DFS were 87.1% vs. 80.7% at 3 years and 83.5% vs. 76.2% at
4 years, respectively. A treatment effect was observed in the
predefined subset of patients with triple negative tumors and
hormone receptor-positive (HR+), human epidermal growth factor
receptor 2 negative (HER2-) tumors. Patients with triple negative
breast cancer (n=276) had DFS rates of 83.1% vs. 73.4% at 3 years,
and 78.7% vs. 68.6% at 4 years. DFS was not significantly different
in the TNBC subgroup [HR=0.66, 95% CI (0.42-1.04), p=0.0694].
HR+/HER2- patients had DFS rates of 86.3% vs. 78.6% at 3 years and
80.8% vs. 72.8% at 4 years [HR=0.71, 95% CI (0.49-1.02); p=0.0660].
Another secondary endpoint measure evaluated in the study was
overall survival (OS). No difference in OS was observed, however
the OS findings are not yet mature.
“These long-term findings show that weekly nab-paclitaxel
followed by epirubicin/cyclophosphamide helped to significantly
delay the progression of disease compared to solvent-based
paclitaxel followed by epirubicin/cyclophosphamide in early
high-risk breast cancer patients,” stated Sibylle Loibl, Chair of
GBG. “These findings are consistent with our previous findings and
are very exciting, as they help us evaluate another potential
treatment option for this high-risk patient group.”
The primary endpoint of GeparSepto was pCR (pathological
complete response) which has been reported previously and found a
statistically significant and clinically meaningful 9% absolute
improvement from 29% to 38% (p=<0.001) when neoadjuvant
(preoperative) chemotherapy was started with ABRAXANE instead of
conventional solvent-based paclitaxel followed by
epirubicin/cyclophosphamide given prior to surgery.
The most common adverse events (>30%) that were previously
reported included anemia, alopecia, peripheral sensory neuropathy
neutropenia, leukopenia, fatigue, lymphopenia, increased alanine
aminotransferase, increased aspartate aminotransferase, headache,
nausea, mucositis/stomatitis/ esophagitis, diarrhea, infection,
arthralgia, epistaxis, skin rash maculopapular, and myalgia.
Follow-up data regarding long-term neurotoxicity and quality of
life will be collected during the study follow-up period. These
results will be forthcoming in future analyses.
“These latest results are very encouraging, illustrating that an
ABRAXANE-containing investigational regimen may have activity in
high-risk breast cancer patients in the neoadjuvant setting,” said
Nadim Ahmed, President, Hematology and Oncology for Celgene. “The
long-term outcomes from this study offer researchers additional
insight into how to potentially treat patients more effectively at
an earlier stage of the disease.”
ABRAXANE is not approved for neoadjuvant treatment of breast
cancer, or for the treatment regimens studied in GeparSepto in any
country. See label excerpts below for more information.
About GeparSepto
GeparSepto is a phase III clinical trial evaluating the safety
and efficacy of the investigational use of a weekly treatment
regimen of nab-paclitaxel compared to a solvent-based paclitaxel,
both followed by epirubicin/cyclophosphamide given all before
surgery to treat high-risk early breast cancer.
The trial evaluated 1,206 patients with high risk early breast
cancer. Patients received either nab-paclitaxel 150 mg/m2 or
paclitaxel 80 mg/m2 weekly for 12 weeks followed by epirubicin 90
mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks for 12 weeks.
HER2 positive patients also received trastuzumab 8 (6) mg/kg and
pertuzumab 840 (420) mg every 3 weeks during neoadjuvant treatment.
The nab-paclitaxel dose was reduced to 125 mg/m2 after recruitment
of 464 patients because of the evaluation of an interim safety
analysis. The median age in each treatment arm was 49
(nab-paclitaxel) and 48 (paclitaxel) years. The primary endpoint of
the trial was pathological complete response (pCR). Secondary
endpoints evaluated in the study included invasive disease-free
survival (DFS), distant disease-free survival (DDFS) and overall
survival (OS).
Grade 3 and 4 neutropenia occurred in 23% and 38% of patients,
respectively, in the nab-paclitaxel arm compared to 25% and 36% in
the solvent-based paclitaxel arm. Peripheral sensory neuropathy was
more common with nab-paclitaxel (8% for the 125 mg/m2 dose and 15%
for the 150 mg/m2 dose) compared with solvent-based paclitaxel 80
mg/m2. Taxane discontinuation due to an adverse event occurred in
16% of patients on nab-paclitaxel and 6% on solvent-based
paclitaxel.
Overall, 23% of patients were noted to have at least one serious
adverse event based on the study drug received (26% in the
nab-paclitaxel group and 21% in the solvent-based paclitaxel group
[p=0.057]). There were three deaths (during epirubicin plus
cyclophosphamide treatment) in the nab-paclitaxel group due to
sepsis, diarrhea, and an accident unrelated to the trial, compared
to one death in the solvent-based paclitaxel group (during
paclitaxel treatment) due to cardiac failure.
GeparSepto is the largest randomized Phase III study ever
completed with ABRAXANE and the first one completed in high risk
early breast cancer. Celgene provided funding support for the
GeparSepto trial.
ABOUT ABRAXANE
ABRAXANE® for Injectable Suspension (paclitaxel
protein-bound particles for injectable suspension) (albumin-bound)
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.
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
CONTRADINDICATIONS
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 a clinical study, Grade 3-4 neutropenia occurred in
34% of patients with metastatic breast cancer (MBC)
- Monitor for myelotoxicity by performing
complete blood cell counts frequently, including prior to dosing on
Day 1
- Do not administer ABRAXANE to patients
with baseline absolute neutrophil counts (ANC) of less than 1,500
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 MBC
- Resume treatment with every-3-week
cycles of ABRAXANE after ANC recovers to a level > 1500
cells/mm3 and platelets recover to > 100,000 cells/mm3
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 until resolution to Grade 1 or 2 followed by a
dose reduction for all subsequent courses of ABRAXANE
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
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, the starting dose should be
reduced for patients with moderate or severe hepatic
impairment
Albumin (Human)
- ABRAXANE contains albumin (human), a
derivative of human blood
Use in Pregnancy: Pregnancy Category D
- ABRAXANE can cause fetal harm when
administered to a pregnant woman
- If this drug is used during pregnancy,
or if the patient becomes pregnant while receiving this drug, the
patient should be apprised of the potential hazard to the
fetus
- Women of childbearing potential should
be advised to avoid becoming pregnant while receiving ABRAXANE
Use in Men
- Men should be advised not to father a
child while receiving 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
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 to human albumin has not been
studied
- 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
Nursing Mothers
- It is not known whether paclitaxel is
excreted in human milk. Because many drugs are excreted in human
milk and because of the potential for serious adverse reactions in
nursing infants, a decision should be made to discontinue nursing
or to discontinue the drug, taking into account the importance of
the drug to the mother
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
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
- Reduce starting dose in MBC patients
with moderate to severe hepatic impairment
- Dose reductions or discontinuation may
be needed based on severe hematologic or neurologic toxicity
- Monitor patients closely
Please see full Prescribing Information,
including Boxed WARNING.
About the German Breast Group
GBG is a large independent academic network of over 500 study
centers in Germany with the world- wide largest experience in
conducting neoadjuvant breast cancer trials. Since 1998, with
joined forces from AGO-B, over 10.000 patients participated in the
neoadjuvant “Gepardo” trial series. GBG has recruited at totality
of over 35.000 patients to trials in breast cancer of all
indications. Reports on these trials were previously published in
the New England Journal of Medicine, The Lancet Oncology, the
Journal of Clinical Oncology and the Journal of the National Cancer
Institute (for more information go to www.germanbreastgroup.de).
The GBG Research Institute received unrestricted grants and the
provision of medication from Celgene and Roche for the conduct of
the GeparSepto study. ABRAXANE is approved in the US and Europe for
patients with metastatic breast cancer.
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: @Celgene, 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 and our other reports filed with the Securities
and Exchange Commission.
Hyperlinks are provided as a convenience and for informational
purposes only. Neither Celgene nor the German Breast Group bears
responsibility for the security or content of external websites or
websites outside of their respective control.
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For the German Breast Group:Mara
EichenaubMara.Eichenlaub@gbg.deorFor
Celgene:Investors:908-673-9628investors@celgene.comorMedia:908-673-2275media@celgene.com
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