IMpassion130 reports first positive Phase III
study results for a chemotherapy/immunotherapy (ABRAXANE plus
atezolizumab) combination in first-line metastatic triple negative
breast cancer (TNBC) patients
IMpower130 demonstrated significant overall
survival (OS) and progression-free survival (PFS) benefit of
ABRAXANE/carboplatin plus atezolizumab in advanced non-squamous
non-small cell lung cancer (NSCLC) patients
Celgene Corporation (NASDAQ:CELG) today announced the first
results from the IMpassion130 study evaluating ABRAXANE®
(paclitaxel protein-bound particles for injectable suspension)
(albumin-bound) in combination with atezolizumab (Tecentriq®) in
patients with first-line locally advanced triple negative breast
cancer (TNBC) and the IMpower130 study evaluating
ABRAXANE/carboplatin in combination with atezolizumab in first-line
advanced non-squamous non-small cell lung cancer. These findings
were presented at the European Society for Medical Oncology (ESMO)
2018 Congress, taking place from October 19-23 in Munich, Germany.
Both studies were sponsored by Roche.
IMpassion130 Demonstrated a PFS Benefit
of ABRAXANE plus Atezolizumab Combination as Initial Treatment in
Locally Advanced or Metastatic TNBC
Results from the Phase 3 Impassion study showed that the
investigational combination of ABRAXANE plus atezolizumab
significantly reduced the risk of disease worsening or death (PFS)
in first-line metastatic or unresectable locally advanced TNBC
patients compared to ABRAXANE alone (7.2 months vs. 5.5 months
[p=0.0025; HR=0.80 (95% CI: 0.69,0.92)]) in all randomized patients
and in the PD-L1 positive subgroup population (median PFS=7.5
months vs. 5.0 months; HR=0.62(95% CI: 0.49-0.78, p<0.0001).
At this first interim analysis, statistical significance was not
met for overall survival (OS) in the ITT population (median OS=21.3
months in the ABRAXANE plus atezolizumab arm vs. 17.6 months in the
ABRAXANE monotherapy arm; HR=0.84, 95% CI 0.69-1.02, p=0.0840). In
the PD-L1-positive population (which was not tested due to
hierarchal design), the ABRAXANE plus atezolizumab arm demonstrated
a 9.5-month OS improvement (median OS=25.0 vs. 15.5 months;
HR=0.62, 95% CI 0.45-0.86). Follow-up will continue until the next
planned analysis. The safety findings were consistent with the
known profiles of the individual regimens investigated.
IMpassion130 is the first phase III study to demonstrate a
statistically significant PFS improvement in first-line metastatic
or unresectable locally advanced TNBC.
“The findings of the IMpassion130 trial illustrate that the
ABRAXANE plus atezolizumab regimen has activity in an aggressive
type of breast cancer with few viable treatments,” said Jay
Backstrom, M.D., Chief Medical Officer and Head of Global
Regulatory Affairs for Celgene. “We are particularly excited about
these findings because triple negative breast cancer is such a
difficult disease to treat and patients are in need of additional
treatment options.”
The most common Grade 3/4 treatment-emergent adverse events
(TEAE) were neutropenia (8% in both treatment arms), decreased
neutrophil count (ABRAXANE plus atezolizumab: 5%; ABRAXANE plus
placebo: 3%), peripheral neuropathy (ABRAXANE plus atezolizumab:
6%; ABRAXANE plus placebo: 3%), fatigue (ABRAXANE plus
atezolizumab: 4%; ABRAXANE plus placebo: 3%) and anemia (3% in both
treatment groups). A higher proportion of patients in the ABRAXANE
plus atezolizumab arm reported serious AEs (23% vs. 18%).
IMpower130 Demonstrated Significant OS
and PFS Benefit of ABRAXANE/Carboplatin plus Atezolizumab in
Advanced Non-Squamous NSCLC
Results from the Phase III IMpower130 study showed that
first-line treatment with the investigational combination of
ABRAXANE/carboplatin plus atezolizumab significantly improved
overall survival of patients with previously untreated metastatic
non-squamous NSCLC compared to ABRAXANE/carboplatin alone (median
OS= 18.6 versus 13.9 months; HR= 0.79; 95 percent CI: 0.64–0.98;
p=0.033) in the intention-to-treat wild-type (ITT-WT) population.
The ABRAXANE/carboplatin plus atezolizumab combination also
significantly reduced the risk of disease worsening or death (PFS)
compared to ABRAXANE/carboplatin alone (median PFS=7.0 versus 5.5
months; HR=0.64; 95 percent CI: 0.54–0.77; p<0.0001) in the
ITT-WT population.
Safety for the ABRAXANE/carboplatin plus atezolizumab
combination appeared consistent with the known safety profile of
the individual medicines. Grade 3/4 TEAEs were reported in 73.2
percent of people receiving ABRAXANE/carboplatin plus atezolizumab
compared to 60.3 percent of people receiving ABRAXANE/carboplatin
alone. The most common Grade 3/4 AEs in people receiving
ABRAXANE/carboplatin plus atezolizumab were: an abnormal low count
of a certain type of white blood cell (neutropenia, 32.1 percent),
a decrease in red blood cells (anemia, 29.2 percent) and a
decreased neutrophil count (12.1 percent).
“Data from these studies continue to shape our understanding of
the current and future treatment landscapes in areas where
historically there have been limited treatment options available to
patients,” said Nadim Ahmed, President, Hematology and Oncology for
Celgene. “We are very encouraged by the findings of these studies
as they add to the growing body of research evaluating the
potential of ABRAXANE as a backbone therapy in combination with
immunotherapy.”
ABRAXANE alone or in combination with atezolizumab is not
approved for the first-line treatment of triple negative breast
cancer, and ABRAXANE/carboplatin in combination with atezolizumab
is not approved for the treatment of advanced NSCLC.
Tecentriq® (atezolizumab) is a registered trademark of
Genentech, a member of the Roche Group.
About the IMpassion130 study
IMpassion130 is a Phase III multicenter, randomized,
double-blind study evaluating the efficacy, safety, and
pharmacokinetics of ABRAXANE and atezolizumab compared with placebo
in combination with ABRAXANE alone in patients with locally
advanced or metastatic TNBC who have not received prior systemic
therapy for metastatic breast cancer (mBC). The study enrolled 902
people who were randomized equally (1:1). The co-primary endpoints
were PFS (RECIST 1.1) in all randomized participants, as well as in
those who disease expressed PD-L1, and OS in all randomized
participants. Secondary endpoints included overall response rate,
duration of response and time to deterioration in Global Health
Status/Health-Related Quality of Life.
During the treatment duration, people in:
- Arm A received atezolizumab at a fixed
dose of 840 milligrams via intravenous (IV) infusion on Days 1 and
15 of each 28-day cycle and ABRAXANE at a dose of 100 milligrams
per square meter via IV infusion on Days 1, 8, and 15 of each
28-day cycle. ABRAXANE was administered for a target of at least 6
cycles, with no maximum. Participants received both agents until
unacceptable toxicity or disease progression.
- Arm B received ABRAXANE at a dose of
100 milligrams per square meter via IV infusion on Days 1, 8, and
15 of each 28-day cycle. ABRAXANE was administered for a target of
at least 6 cycles, with no maximum, and placebo was administered
via IV infusion on Days 1 and 15 of each 28-day cycle. Participants
assigned to placebo plus ABRAXANE received both agents until
unacceptable toxicity or disease progression.
About the IMpower130 study
IMpower130 is a Phase III, multicenter, open-label, randomized
study evaluating the efficacy and safety of atezolizumab in
combination with carboplatin and ABRAXANE versus chemotherapy
(carboplatin and ABRAXANE) alone for chemotherapy-naïve patients
with stage IV non-squamous NSCLC. The study enrolled 723 people who
were randomized (2:1) to receive:
- Atezolizumab (1200 mg via IV every 3
weeks) plus carboplatin (AUC 6 mg/mL/min via IV every 3 weeks) and
ABRAXANE (100 mg/m2 via IV every 3 weeks) (Arm A), or
- Carboplatin (AUC 6 mg/mL/min via IV
every 3 weeks) and ABRAXANE (100 mg/m2 via IV every 3 weeks) (Arm
B, control arm)
During the treatment-induction phase, people in Arm A received
atezolizumab and carboplatin on day 1 of each 21-day cycle, and
ABRAXANE on days 1, 8 and 15 of each 21-day cycle for 4 or 6 cycles
or until loss of clinical benefit, whichever occurs first. People
received atezolizumab during the maintenance treatment phase until
loss of clinical benefit was observed.
During the treatment-induction phase, people in Arm B received
carboplatin on day 1 and ABRAXANE on days 1, 8 and 15 of each
21-day cycle for 4 or 6 cycles or until disease progression,
whichever occurred first. People received best supportive care
during the maintenance treatment phase. Switch maintenance to
pemetrexed was also permitted. People who were consented prior to a
protocol revision were given the option to crossover to receive
atezolizumab as monotherapy until disease progression.
The co-primary endpoints were:
- PFS as determined by the investigator
using RECIST v1.1 in the ITT-WT population
- OS in the ITT-WT population
About ABRAXANE
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.
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) and 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
Day 1 (for MBC) and Days 1, 8, and 15 for NSCLC
- 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
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
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
- 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
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
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
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
- 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 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.
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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
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and speak only as of the date they are made. We undertake no
obligation to update any forward-looking statement in light of new
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Forward-looking statements involve inherent risks and
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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
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