Fourth Breakthrough Therapy designation for
an AstraZeneca New Oncology medicine in three years
AstraZeneca and MedImmune, its global biologics research and
development arm, today announced that the US Food and Drug
Administration (FDA) has granted Breakthrough Therapy Designation
for IMFINZI™ (durvalumab), an anti-PD-L1 monoclonal antibody, being
investigated for the treatment of patients with locally advanced,
unresectable non-small cell lung cancer (NSCLC) whose disease has
not progressed following platinum-based chemoradiation therapy.
Sean Bohen, Executive Vice President, Global Medicines
Development and Chief Medical Officer at AstraZeneca, said: “For
patients who have not progressed following chemoradiation therapy
the only current option is active monitoring. Unfortunately, for
the majority of patients, their cancer will progress to metastatic
disease, typically within 12 months. IMFINZI is the first
immuno-oncology medicine to show a clinically significant benefit
in this earlier, non-metastatic setting, so following Breakthrough
Designation we hope to bring it to patients as soon as
possible.”
The Breakthrough Therapy Designation is designed to expedite the
development and regulatory review of new medicines that are
intended to treat a serious condition and that have shown
encouraging early clinical results, which demonstrate substantial
improvement on a clinically significant endpoint over available
therapies and when there is significant unmet medical need. Use of
durvalumab in patients with locally advanced, unresectable NSCLC is
not yet FDA-approved.
The Breakthrough Therapy Designation for durvalumab was granted
on the basis of interim results from the Phase III PACIFIC trial, a
randomized, double-blinded, placebo-controlled multi-center trial
of durvalumab as sequential treatment in patients with
locally-advanced, unresectable (Stage III) NSCLC who had not
progressed following standard platinum-based chemotherapy
concurrent with radiation therapy. This achievement is the fourth
Breakthrough Therapy Designation AstraZeneca has received from the
FDA for medicines in Oncology over the past three years and the
second for durvalumab. 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.
Data from the PACIFIC trial have been submitted for presentation
at a forthcoming medical meeting.
Durvalumab is also being tested in for the treatment of NSCLC in
the adjuvant setting in the ADJUVANT Phase III trial. In the Stage
IV 1st-line setting for patients with advanced NSCLC, durvalumab as
monotherapy and in combination with tremelimumab, an anti-CTLA-4
monoclonal antibody, is being tested in the MYSTIC, NEPTUNE and
PEARL Phase III trials. The POSEIDON trial is evaluating durvalumab
with and without tremelimumab in combination with chemotherapy.
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) NSCLC, who have not progressed following
platinum-based chemotherapy concurrent with radiation therapy.
The trial is being conducted in 235 centers across 26 countries,
including the US, Canada, Europe, South and Central America, Japan,
Korea, Taiwan, South Africa and Australia. The primary endpoints of
the trial are PFS and OS, and secondary endpoints include landmark
PFS and OS, objective response rate and duration of response.
About IMFINZI™ (durvalumab)
IMFINZI™ (durvalumab, previously known as MEDI4736) 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
urothelial cancer and in head and neck squamous cell carcinoma
(HNSCC). The combination of durvalumab and tremelimumab is being
assessed in Phase III trials in urothelial cancer, NSCLC, SCLC 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 two stages (IIIA and
IIIB), 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 NSCLC
Lung cancer is the leading cause of cancer death among both men
and women, accounting for about one-third of all cancer deaths and
more than breast, prostate and colorectal cancers combined.
AstraZeneca has a comprehensive portfolio of approved and
potential new medicines in late-stage clinical development for the
treatment of non-small cell lung cancer (NSCLC) across all stages
of disease and lines of therapy. We aim to address unmet needs of
patients with EGFR-mutated tumors as a genetic driver of disease,
which occur in 10% to 15% of NSCLC patients in the US and Europe
and 30% to 40% of NSCLC patients in Asia, with our approved
medicines IRESSA and TAGRISSO and ongoing FLAURA and ADAURA trials.
Our extensive late-stage Immuno-Oncology program focuses on 75% to
80% of patients with NSCLC without a known genetic mutation. Our
portfolio includes IMFINZI (durvalumab), an anti-PD-L1 monoclonal
antibody, which is in development as monotherapy (ADJUVANT,
PACIFIC, MYSTIC, PEARL and ARCTIC trials) and in combination with
tremelimumab, an anti-CTLA-4 monoclonal antibody (MYSTIC, NEPTUNE
and POSEIDON trials).
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) monotherapy and in combination
with tremelimumab (anti-CTLA-4) 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.
US-12590 Last Updated 7/17
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