IMFINZI improves progression-free survival
(PFS) by more than 11 months compared to standard of care following
chemoradiation therapy (CRT) and is the first medicine to show
superior PFS in this setting
Data presented at ESMO 2017 Congress follows
FDA’s recent Breakthrough Therapy Designation for IMFINZI in
locally-advanced, unresectable lung cancer
The PACIFIC trial continues to evaluate overall
survival, the other primary endpoint
AstraZeneca and MedImmune, its global biologics research and
development arm, today announced the full progression-free survival
(PFS) data from a planned interim analysis of the investigational
Phase III PACIFIC trial. Results show that IMFINZI® (durvalumab)
demonstrated a statistically-significant and clinically-meaningful
improvement in PFS compared to current standard of care with active
surveillance in patients with locally-advanced (Stage III),
unresectable non-small cell lung cancer (NSCLC) who had not
progressed following standard platinum-based chemotherapy
concurrent with radiation therapy (CRT).
Results of the trial, included in the Presidential Symposium I
of the European Society of Medical Oncology (ESMO) 2017 Congress in
Madrid, Spain, show an improvement in PFS of more than 11 months in
patients treated with durvalumab compared to placebo (HR 0.52; 95%
CI, 0.42-0.65; p<0.0001) (see full details below). The PFS
improvement with durvalumab was observed across all pre-specified
subgroups, including PD-L1 expression status (assessed at time of
diagnosis). Patients receiving IMFINZI also had a lower incidence
of metastases than those receiving placebo. The PACIFIC trial
continues to evaluate overall survival (OS), the other primary
endpoint.
Sean Bohen, Executive Vice President, Global Medicines
Development and Chief Medical Officer at AstraZeneca, said: “The
Phase III PACIFIC results are incredibly encouraging for a patient
population that until now has been without treatment options. As
the first Immuno-Oncology medicine to achieve improvement in
progression-free survival in this setting, IMFINZI is showing clear
potential to become the new standard of care for patients with
locally advanced, unresectable NSCLC who have not progressed
following chemoradiation.”
Dr. Luis Paz-Ares, Principal Investigator of the PACIFIC trial,
from the Hospital Universitario Doce de Octubre in Madrid, Spain,
said: “For patients with locally advanced, unresectable NSCLC who
have completed chemoradiation therapy, IMFINZI represents a
potential new treatment option in the context of clear unmet
clinical need. Durvalumab overtly prolongs the period in which the
disease is controlled with reasonable side effects. In addition, it
offers hope to increase the cure rate in this setting, but more
mature follow-up is needed to assess its impact on survival.”
Summary of additional key efficacy
results:
Endpoint
TreatmentArm
Results
Hazard ratio (HR)/Confidence
interval (CI), p-value
PFS*(first primaryendpoint)
IMFINZI
16.8 months(median)
HR 0.5295% CI, 0.42-0.65, p<0.0001
Placebo
5.6 months(median)
Median Duration ofresponse (DoR)**
IMFINZI Not reached N/A Placebo 13.8 months
Objective ResponseRate (ORR)** asmeasured
frombaseline scan post-CRT completion
IMFINZI 28.4% 95% CI, 24.28-32.89, p<0.001
Placebo 16.0% 95% CI, 11.31-21.59, p<0.001
* Time from randomization to the first documented tumor
progression or death in the absence of progression. Randomization
in the PACIFIC trial occurred up to 6 weeks after concurrent
chemoradiation therapy (cCRT) and cCRT typically lasted at least 6
weeks.** Assessed in patients with measurable disease at
baseline.
Among patients receiving durvalumab, the most frequent adverse
events (AEs) vs placebo were cough (35.4% vs 25.2%),
pneumonitis/radiation pneumonitis (33.9% vs 24.8%), fatigue (23.8%
vs 20.5%), dyspnea (22.3% vs 23.9%) and diarrhea (18.3% vs 18.8%).
29.9% of patients experienced a grade 3 or 4 AE vs 26.1% for
placebo, and 15.4% of patients discontinued treatment due to AEs,
compared to 9.8% of patients on placebo. See below for additional
important safety information for IMFINZI.
On July 31, 2017, durvalumab received Breakthrough Therapy
Designation from the US Food and Drug Administration (FDA) as a
potential treatment for patients with locally advanced,
unresectable NSCLC whose disease had not progressed following
platinum-based chemoradiation therapy. This indication is not
FDA-approved.
AstraZeneca is in discussions with global health authorities
regarding regulatory submissions for durvalumab based on the
PACIFIC data. A status of regulatory submissions is usually
provided with the Company’s quarterly results announcement.
In May 2017, AstraZeneca received accelerated approval from the
FDA for IMFINZI for the treatment of patients with locally advanced
or metastatic urothelial carcinoma, who have disease progression
during or following platinum-containing chemotherapy, or whose
disease has progressed within 12 months of receiving
platinum-containing chemotherapy before (neoadjuvant) or after
(adjuvant) surgery. IMFINZI is approved under the FDA’s accelerated
approval pathway, based on tumor response rate and duration of
response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in
confirmatory trials.
IMPORTANT SAFETY INFORMATION
There are no contraindications for IMFINZI® (durvalumab).
Monitor patients for clinical signs and symptoms of
immune-mediated pneumonitis, hepatitis, colitis or diarrhea,
endocrinopathies, nephritis, rash or dermatitis, other
immune-mediated adverse reactions, and infection. Please refer to
the full Prescribing Information for important dose management
information specific to adverse reactions.
Immune-Mediated Pneumonitis
In the combined safety database (n=1414), immune-mediated
pneumonitis occurred in 32 patients (2.3%), including 1 fatal case
(0.1%) and 6 Grade 3–4 cases (0.4%). In Study 1 (n=182), 1 patient
(0.5%) died from immune-mediated pneumonitis. Monitor patients for
signs and symptoms of pneumonitis and evaluate with radiographic
imaging when suspected. Administer corticosteroids for ≥Grade 2
pneumonitis. Withhold IMFINZI for Grade 2 pneumonitis; permanently
discontinue for Grade 3–4 pneumonitis.
Immune-Mediated Hepatitis
In the combined safety database (n=1414), immune-mediated
hepatitis occurred in 16 patients (1.1%), including 1 fatal case
(<0.1%) and 9 Grade 3 cases (0.6%). Grade 3–4 elevations in ALT
occurred in 40/1342 patients (3.0%), AST in 58/1336 patients
(4.3%), and total bilirubin in 37/1341 patients (2.8%). In Study 1
(n=182), 1 patient (0.5%) died from immune-mediated hepatitis, and
2 patients (1.1%) experienced immune-mediated hepatitis, including
1 Grade 3 case (0.5%). Monitor patients for abnormal liver tests in
each cycle during treatment with IMFINZI. Administer
corticosteroids and withhold IMFINZI for Grade 2–3 ALT or AST
>3–5X ULN or ≤8X ULN or total bilirubin >1.5–3X ULN or ≤5X
ULN. Permanently discontinue IMFINZI in patients with Grade 3 ALT
or AST >8X ULN or total bilirubin >5X ULN, or in patients
with concurrent ALT or AST >3X ULN and total bilirubin >2X
ULN with no other cause.
Immune-Mediated Colitis
In the combined safety database (n=1414), immune-mediated
colitis or diarrhea occurred in 18 patients (1.3%), including 1
Grade 4 case (<0.1%) and 4 Grade 3 cases (0.3%). In Study 1
(n=182), 23 patients (12.6%) experienced colitis or diarrhea,
including 2 Grade 3–4 cases (1.1%). Monitor patients for signs and
symptoms of colitis or diarrhea. Administer corticosteroids for
≥Grade 2 colitis or diarrhea. Withhold IMFINZI for Grade 2 colitis
or diarrhea; permanently discontinue for Grade 3–4 colitis or
diarrhea.
Immune-Mediated Endocrinopathies
- Immune-mediated thyroid disorders,
adrenal insufficiency, type 1 diabetes mellitus and
hypophysitis/hypopituitarism have occurred with IMFINZI. Monitor
patients for clinical signs and symptoms of endocrinopathies. For
Grade 2–4 endocrinopathies (except hypothyroidism) withhold dose
until clinically stable and offer symptomatic management for
hyperthyroidism. For Grade 2–4 hypothyroidism, initiate thyroid
hormone replacement as needed
- Thyroid disorders— In the combined
safety database (n=1414), immune-mediated hypothyroidism and
hyperthyroidism occurred in 136 patients (9.6%) and 81 patients
(5.7%), respectively. Thyroiditis occurred in 10 patients (0.7%),
including 1 Grade 3 case (<0.1%) in a patient who had a
myocardial infarction. In 9 patients with thyroiditis, transient
hyperthyroidism preceded hypothyroidism. Treatment with a
beta-blocker and/or thioamide was administered for hyperthyroidism
in five of these patients. In Study 1 (n=182), Grade 1–2
hypothyroidism or thyroiditis occurred in 10 patients (5.5%). Grade
1–2 hyperthyroidism or thyroiditis leading to hyperthyroidism
occurred in 9 patients (4.9%). Monitor patients for abnormal
thyroid function tests prior to and periodically during
treatment
- Immune-mediated adrenal
insufficiency—In the combined safety database (n=1414),
immune-mediated adrenal insufficiency occurred in 13 patients
(0.9%), including 2 Grade 3 cases (0.1%). In Study 1 (n=182), Grade
1 adrenal insufficiency occurred in 1 patient (0.5%). Administer
corticosteroids and hormone replacement as clinically
indicated
- Type 1 diabetes mellitus—In the
combined safety database (n=1414), new onset type 1 diabetes
mellitus without an alternative etiology occurred in 1 patient
(<0.1%). For type 1 diabetes mellitus, initiate insulin as
indicated and withhold IMFINZI until clinically stable
- Hypophysitis—In the combined safety
database (n=1414), hypopituitarism leading to adrenal insufficiency
and diabetes insipidus occurred in 1 patient (<0.1%). Administer
corticosteroids and hormone replacement as clinically
indicated
Other Immune-Mediated Adverse Reactions
- IMFINZI has caused immune-mediated
rash. Other immune-related adverse reactions, including aseptic
meningitis, hemolytic anemia, immune thrombocytopenic purpura,
myocarditis, myositis, nephritis, and ocular inflammatory toxicity
including uveitis and keratitis, have occurred in ≤1.0% of patients
treated with IMFINZI
- Immune-mediated rash or dermatitis—In
the combined safety database (n=1414), immune-mediated rash or
dermatitis occurred in 220 patients (15.6%) and 4 patients (0.3%)
developed vitiligo. In Study 1 (n=182), 20 patients (11.0%)
developed rash, including 1 Grade 3 case (0.5%). Patients should be
monitored for signs and symptoms of rash or dermatitis. Administer
corticosteroids if indicated. Withhold IMFINZI for Grade 3 rash or
dermatitis or Grade 2 rash or dermatitis lasting >1 week.
Permanently discontinue IMFINZI in patients with Grade 4 rash or
dermatitis
- Immune thrombocytopenic purpura—In the
combined safety database (n=1414), 1 fatal case (<0.1%) of
immune thrombocytopenic purpura occurred. Monitor patients for
signs and symptoms of immune thrombocytopenic purpura
- Nephritis—In the combined safety
database (n=1414), immune-mediated nephritis occurred in 3 patients
(0.2%), including 2 Grade 3 cases (0.1%). Monitor patients for
abnormal renal function tests prior to and during each cycle of
IMFINZI. Administer corticosteroids for ≥Grade 2 nephritis
(creatinine >1.5X ULN). Withhold IMFINZI for Grade 2 nephritis;
permanently discontinue for ≥Grade 3 nephritis (creatinine >3X
ULN)
Infection
Severe infections, including sepsis, necrotizing fasciitis, and
osteomyelitis, occurred in patients receiving IMFINZI. In the
combined safety database (n=1414), infections occurred in 531
patients (37.6%). In Study 1 (n=182), infections occurred in 54
patients (29.7%). 11 patients (6.0%) experienced Grade 3–4
infection and 5 patients (2.7%) were experiencing infection at the
time of death. 8 patients (4.4%) experienced urinary tract
infection, the most common ≥Grade 3 infection. Monitor patients for
signs and symptoms of infection and treat with anti-infectives for
suspected or confirmed infections. Withhold IMFINZI for ≥Grade 3
infection.
Infusion-Related Reactions
In the combined safety database (n=1414), severe
infusion-related reactions occurred in 26 patients (1.8%). In Study
1 (n=182), infusion-related reactions occurred in 3 patients
(1.6%). There were 5 Grade 3 (0.4%) and no Grade 4 or 5 reactions.
Patients should be monitored for signs and symptoms of
infusion-related reactions. Interrupt or slow the rate of infusion
for Grade 1–2 infusion-related reactions and permanently
discontinue for Grade 3–4 infusion-related reactions.
Embryo-Fetal Toxicity
Based on its mechanism of action and data from animal studies,
IMFINZI can cause fetal harm when administered to a pregnant woman.
There are no data on the use of IMFINZI in pregnant women. Advise
pregnant women of the potential risk to a fetus and advise women of
reproductive potential to use effective contraception during
treatment and for at least 3 months after the last dose of
IMFINZI.
Nursing Mothers
There is no information regarding the presence of IMFINZI in
human milk; however, because of the potential for adverse reactions
in breastfed infants from IMFINZI, advise a lactating woman not to
breastfeed during treatment and for at least 3 months after the
last dose.
Most Common Adverse Reactions
- The most common adverse reactions
(≥15%) were fatigue (39%), musculoskeletal pain (24%), constipation
(21%), decreased appetite (19%), nausea (16%), peripheral edema
(15%), and urinary tract infection (15%). The most common Grade 3
or 4 adverse reactions (≥3%) were fatigue, urinary tract infection,
musculoskeletal pain, abdominal pain, dehydration, and general
physical health deterioration
- Adverse reactions leading to
discontinuation of IMFINZI occurred in 3.3% of patients. Serious
adverse reactions occurred in 46% of patients. The most frequent
serious adverse reactions (>2%) were acute kidney injury (4.9%),
urinary tract infection (4.4%), musculoskeletal pain (4.4%), liver
injury (3.3%), general physical health deterioration (3.3%),
sepsis, abdominal pain, and pyrexia/tumor associated fever (2.7%
each)
The safety and effectiveness of IMFINZI have not been
established in pediatric patients.
Please see complete Prescribing Information
including Patient Information.
NOTES TO EDITORS
About PACIFIC
The PACIFIC trial is a randomized, double-blinded,
placebo-controlled multi-center trial of durvalumab as sequential
treatment in unselected patients with locally advanced,
unresectable (Stage III) non-small cell lung cancer (NSCLC) who
have not progressed following platinum-based chemotherapy
concurrent with radiation therapy.
The trial is being conducted in 235 centers across 26 countries,
involving approximately 700 patients. The primary endpoints of the
trial are progression-free survival (PFS) and overall survival
(OS), and secondary endpoints include landmark PFS and OS,
objective response rate and duration of response.
About IMFINZI® (durvalumab)
IMFINZI® (durvalumab) is a human monoclonal antibody directed
against PD-L1, which blocks the interaction of PD-L1 with PD-1 and
CD80.
Durvalumab continues to be studied in multiple monotherapy
trials and combination trials with tremelimumab and other potential
new medicines in Immuno-Oncology. Durvalumab is being assessed in
Phase III trials as a monotherapy in various stages of non-small
cell lung cancer (NSCLC), in small-cell lung cancer (SCLC), in
metastatic urothelial cancer (mUC) and in head and neck squamous
cell carcinoma (HNSCC). The combination of durvalumab and
tremelimumab is being assessed in Phase III trials in NSCLC, SCLC,
mUC and HNSCC and in Phase I/II trials in hepatocellular carcinoma
and hematological malignancies.
About Locally Advanced (Stage III) NSCLC
Stage III lung cancer is divided into three sub-categories
(IIIA, IIIB and IIIC), which are defined by how much the cancer has
spread locally and the possibility of surgery. This differentiates
it from Stage IV disease, when the cancer has metastasized to other
organs.
Stage III lung cancer represents approximately one-third of
non-small cell lung cancer incidence and is estimated to affect
over 43,000 patients in the United States. About half of these
patients have tumors that are unresectable. The current standard of
care is chemotherapy and radiation followed by active surveillance
to monitor for progression. The prognosis remains poor and
long-term survival rates are low.
About AstraZeneca in Lung Cancer
AstraZeneca is committed to developing therapies to help every
patient with lung cancer. We have two approved therapies and a
growing pipeline that targets genetic changes in tumor cells and
boosts the power of the immune response against cancer. Our
unrelenting pursuit of science aims to deliver more breakthrough
therapies with the goal of extending and improving the lives of
patients across all stages of disease and lines of therapy.
About AstraZeneca’s approach to Immuno-Oncology (IO)
Immuno-Oncology (IO) is a therapeutic approach designed to
stimulate the body’s immune system to attack tumors. At AstraZeneca
and MedImmune, our biologics research and development arm, our IO
portfolio is anchored by immunotherapies that have been designed to
overcome anti-tumor immune suppression. We believe that IO-based
therapies will offer the potential for life-changing cancer
treatments for the vast majority of patients.
We are pursuing a comprehensive clinical trial program that
includes durvalumab (anti-PD-L1 antibody) monotherapy and in
combination with tremelimumab (anti-CTLA-4 antibody) in multiple
tumor types, stages of disease, and lines of therapy, using the
PD-L1 biomarker as a decision-making tool to define the best
potential treatment path for a patient. In addition, the ability to
combine our IO portfolio with small targeted molecules from across
our oncology pipeline, and with those of our research partners, may
provide new treatment options across a broad range of tumors.
About AstraZeneca in Oncology
AstraZeneca has a deep-rooted heritage in Oncology and offers a
quickly growing portfolio of new medicines that has the potential
to transform patients’ lives and the Company’s future. With at
least six new medicines to be launched between 2014 and 2020, and a
broad pipeline of small molecules and biologics in development, we
are committed to advance New Oncology as one of AstraZeneca’s five
Growth Platforms focused on lung, ovarian, breast and blood
cancers. In addition to our core capabilities, we actively pursue
innovative partnerships and investments that accelerate the
delivery of our strategy as illustrated by our investment in Acerta
Pharma in hematology.
By harnessing the power of four scientific platforms –
Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response
and Antibody Drug Conjugates – and by championing the development
of personalized combinations, AstraZeneca has the vision to
redefine cancer treatment and one day eliminate cancer as a cause
of death.
About MedImmune
MedImmune is the global biologics research and development arm
of AstraZeneca, a global, innovation-driven biopharmaceutical
business that focuses on the discovery, development and
commercialization of small molecule and biologic prescription
medicines. MedImmune is pioneering innovative research and
exploring novel pathways across Oncology; Respiratory,
Cardiovascular & Metabolic Diseases; and Infection and
Vaccines. The MedImmune headquarters is located in Gaithersburg,
MD, one of AstraZeneca’s three global R&D centers, with
additional sites in Cambridge, UK, and Mountain View, CA. For more
information, please visit www.medimmune.com.
About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company
that focuses on the discovery, development and commercialization of
prescription medicines, primarily for the treatment of diseases in
three main therapy areas – Oncology, Cardiovascular & Metabolic
Diseases and Respiratory. The Company also is selectively active in
the areas of autoimmunity, neuroscience and infection. AstraZeneca
operates in over 100 countries and its innovative medicines are
used by millions of patients worldwide. For more information,
please visit www.astrazeneca-us.com and follow us on Twitter
@AstraZenecaUS.
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