Interim study findings further support safety,
efficacy and tolerability in squamous and elderly patients with
advanced NSCLC, consistent with results previously seen in the
pivotal Phase III trial
Celgene Corporation (NASDAQ:CELG) today announced interim
results from the ABOUND clinical trial program evaluating the use
of ABRAXANE® (paclitaxel protein-bound particles for injectable
suspension) (albumin-bound) in patients with advanced non-small
cell lung cancer (NSCLC). Interim data being presented from the
ABOUND trials during the IASLC 17th World Conference on Lung Cancer
(WCLC) reinforces the benefit of ABRAXANE/carboplatin doublet
therapy in first-line NSCLC.
Interim ABOUND.70+ data in 128 elderly patients (≥ 70
years old) receiving first-line treatment with ABRAXANE/carboplatin
for advanced NSCLC found that 91 (73%) patients experienced grade
≥2 peripheral neuropathy (PN) or grade ≥3 myelosuppression [primary
endpoint]. At the time of the analyses, the median overall survival
was 14.6 months and the median progression-free survival was 6.2
months, pooled across the two treatment arms [secondary endpoints].
Patients were randomized to receive first-line treatment with
ABRAXANE/carboplatin either continuous weekly or weekly every three
weeks with a one-week break.i Overall, 80 percent of patients
discontinued treatment and the majority did so due to adverse
events (24 percent) or disease progression (34 percent). Grade ≥2
PN was reported in 34% of patients, and grade ≥3 neutropenia,
anemia, and thrombocytopenia was observed in 52%, 21% and 21% of
patients, respectively. i
The interim ABOUND.sqm data in 284 patients receiving
first-line induction treatment with ABRAXANE/carboplatin for stage
IIIB/IV squamous NSCLC showed that the safety profile was
consistent with that previously reported for the squamous subset in
the pivotal Phase III trial.ii,iii During the induction phase, all
patients received four 21-day cycles of standard
ABRAXANE/carboplatin therapy.ii Overall, 119 patients (42 percent)
discontinued treatment during the induction phase. The majority of
patients discontinued treatment due to disease progression (34
percent) or adverse events (24 percent). The most common grade 3/4
treatment emergent adverse events (TEAEs) were hematologic and
included anemia (26 percent), neutropenia (43 percent) and
thrombocytopenia (15 percent).ii
Both ABOUND trials also evaluated quality of life utilizing the
Lung Cancer Symptom 3-item index Scale (LCSS), Symptom Burden
Index, Lung Cancer Symptom and Pulmonary Symptom Scores and the
EuroQol five dimensions, five level questionnaire (EQ-5D-5L). These
interim analyses suggest that quality of life was generally
maintained or improved in both patient populations.iv,v
"These early data from the ABOUND clinical trial program are
very encouraging, as they are consistent with the findings related
to these hard to treat non-small cell lung cancer patient subgroups
seen in the pivotal ABRAXANE Phase III trial," said Michael Pehl,
President, Hematology and Oncology for Celgene. "These data,
coupled with the ongoing studies of ABRAXANE in combination with
novel agents and immunotherapies, provide us with a deeper
understanding of how to treat challenging patient populations and
will help us continue to develop future treatment options."
With the rapidly evolving lung cancer treatment landscape,
Celgene remains committed to continuing to explore new combinations
that will benefit those living with lung cancer, including patients
who may not benefit from immunotherapy and targeted therapy.
ABRAXANE is being actively evaluated as a foundation therapy in
these patients.
Interim results of the phase I study of the immunotherapy agent
nivolumab in combination with ABRAXANE/carboplatin in 22 patients
with Stage IIIB/IV NSCLC will also be presented at WCLC. Patients
received four cycles of standard ABRAXANE/carboplatin therapy in
combination with nivolumab, followed by nivolumab monotherapy
starting at cycle 5. The primary endpoints were number of patients
with dose limiting toxicity and percentage of patients with grade
3/4 TEAEs or treatment discontinuation due to a TEAE. The interim
data suggests that combining ABRAXANE/carboplatin with nivolumab
may have promising anti-tumor activity in patients with advanced
NSCLC with no unexpected adverse events (AEs).vi
The most common grade 3/4 AEs observed during the study included
neutropenia (45 percent), anemia (35 percent), hypokalemia (15
percent), and vomiting (15 percent).vi The study has been expanded
and patients are currently enrolling in part 2. Additional data on
the safety and efficacy of this combination in multiple tumor types
will be presented at a future medical meeting.
Additional ABRAXANE Data Presented at
WCLC
There will also be an oral presentation at WCLC focused on new
findings from the phase III registration study for ABRAXANE
(Abstract 4460), which reports on the impact of depth of
response on survival in patients with advanced NSCLC treated with
first-line chemotherapy. Real-world analyses of US veterans with
NSCLC are also being presented at WCLC, evaluating prevalence of
squamous NSCLC in veterans vs. the general population (Abstract
4737) and the prevalence of autoimmune disease in veterans with
NSCLC (Abstract 4745).
Additional investigator initiated studies presented at WCLC also
evaluated ABRAXANE as first-line (Posters P2.03a-028 and
P2.06-018), second-line (Posters P2.03a-040,
P2.03a-054 and P2.03a-056) or third-line (Poster
P2.06-015) treatment for advanced NSCLC patients, as well as in
the adjuvant (Poster P2.03a-070) and neoadjuvant (Poster
P2.04-034) settings and in chemo-naïve patients with an EGFR
mutation (Poster P3.02b-061).
ABOUT ABOUND
ABOUND is a multi-phase, open-label, multicenter clinical trial
program evaluating the use of ABRAXANE in combination with
carboplatin or other novel agents, including immunotherapy, as
first- or second-line treatment of patients with advanced non-small
cell lung cancer (NSCLC). The ABOUND trials included patients 70
years and older, as well as those with poorer performance status or
squamous disease and those receiving second-line+
treatment.vii,viii,ix,x
ABOUT THE ABRAXANE/NIVOLUMAB STUDY
This is a phase I, open-label, multicenter, safety study of
ABRAXANE-based chemotherapy regimens administered prior to and/or
in combination with nivolumab in pancreatic cancer, NSCLC and
metastatic breast cancer. This is a six arm study assessing two
treatment arms per tumor-type/indication.
About ABRAXANE® (nab-paclitaxel)
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.
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 <1500cells/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
47% of patients with non–small cell lung cancer (NSCLC)
- Monitor for myelotoxicity by performing
complete blood cell counts frequently, including prior to dosing on
Days 1, 8, and 15
- 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 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
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 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 NSCLC, 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
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
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
- 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
- Myelosuppression, peripheral
neuropathy, and arthralgia were more frequent in patients
≥65 years of age treated with ABRAXANE and carboplatin in
NSCLC
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 NSCLC 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.
Please refer to the Summary of Product
Characteristics for full European prescribing
information.
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.
i Langer C, et al. Safety and Efficacy Results from ABOUND.70+:
nab-Paclitaxel + Carboplatin in Elderly Patients with Advanced
NSCLC. Abstract 4630. Presented at the 2016 World Conference of
Lung Cancer (WCLC), December 4-7, 2016.
ii McCleod M, et al. Interim Results from ABOUND.sqm: Safety of
nab-Paclitaxel + Carboplatin Induction Therapy in Squamous
Non-Small Cell Lung Cancer. Abstract 4391. Presented at the 2016
World Conference of Lung Cancer (WCLC), December 4-7, 2016.
iii Socinsky M, et al. Safety and efficacy of weekly
nab®-paclitaxel in combination with carboplatin as first-line
therapy in elderly patients with advanced non-small-cell lung
cancer. Annals of Oncology. 24: 314–321, 2013.
iv Weiss J, et al. ABOUND.70+: Interim Quality of Life Results
of nab-Paclitaxel + Carboplatin Treatment of Elderly Patients with
NSCLC. Abstract 4286. Presented at the 2016 World Conference of
Lung Cancer (WCLC), December 4-7, 2016.
v Thomas M, et al. nab-Paclitaxel + Carboplatin Induction
Therapy in Squamous Non-Small Cell Lung Cancer: Interim Quality of
Life Results from ABOUND.sqm. Abstract 4343. Presented at the 2016
World Conference of Lung Cancer (WCLC), December 4-7, 2016.
vi Goldman J, et al. Interim Results from the Phase I Study of
Nivolumab + nab-Paclitaxel + Carboplatin in Non-Small Cell Lung
Cancer. Abstract 4127. Presented at the 2016 World Conference of
Lung Cancer (WCLC), December 4-7, 2016.
vii ClinicalTrials.gov. Safety and Efficacy Study of
Nab®Paclitaxel With CC486 or Nab®Paclitaxel With Durvalumab, and
Nab®Paclitaxel Monotherapy as Second/Thirdline Treatment for
Advanced Nonsmall Cell Lung Cancer (abound2L+). Available at
https://www.clinicaltrials.gov/ct2/show/NCT02250326?term=ABOUNd&rank=3.
Accessed November 30, 2016.
viii ClinicalTrials.gov. Safety and Efficacy Study of Abraxane
in Combination With Carboplatin to Treat Advanced NSCL Cancer in
the Elderly (ABOUND 70+). Available at
https://www.clinicaltrials.gov/ct2/show/NCT02151149?term=ABOUNd&rank=2.
Accessed November 30, 2016.
ix ClinicalTrials.gov. Phase II Safety and Tolerability Trial
With NabPaclitaxel Plus Carboplatin Followed by NabPaclitaxel for
First Line Treatment of NSCLC Subjects With ECOG PS 2 (AboundPS2).
Available at
https://www.clinicaltrials.gov/ct2/show/NCT02289456?term=ABOUNd&rank=4.
Accessed November 30, 2016.
x ClinicalTrials.gov. Safety and Efficacy Study of Abraxane as
Maintenance Treatment After Abraxane Plus Carboplatin in 1st Line
Stage IIIB / IV Squamous Cell Non-small Cell Lung Cancer
(aboundsqm). Available at
https://www.clinicaltrials.gov/ct2/show/NCT02027428?term=ABOUNd&rank=6.
Accessed November 30, 2016.
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