Approval granted regardless of PD-L1 status,
based on tumor response rate and duration of response
IMFINZI is the cornerstone in an extensive
Immuno-Oncology program across multiple cancer types and stages of
disease
AstraZeneca and its global biologics research and development
arm, MedImmune, today announced that the US Food and Drug
Administration (FDA) has granted accelerated approval to IMFINZI™
(durvalumab). IMFINZI is indicated for the treatment of patients
with locally advanced or metastatic urothelial carcinoma (mUC) 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
durability of response. Continued approval for this indication may
be contingent upon verification and description of clinical benefit
in confirmatory trials.
Pascal Soriot, Chief Executive Officer of AstraZeneca, said: “We
are excited to offer IMFINZI as a breakthrough therapy for patients
with locally-advanced or metastatic bladder cancer. IMFINZI is the
cornerstone of our extensive Immuno-Oncology program, in
development across many tumor types, as monotherapy and in
combination. This first approval for IMFINZI is an important
milestone in our return to growth and brings us another step closer
to our goal of redefining the way cancer is treated.”
IMFINZI is also under investigation in the Phase III DANUBE
trial as first-line treatment in urothelial carcinoma as
monotherapy and in combination with tremelimumab.
Nicholas J. Vogelzang, MD, FACP, FASCO, Clinical Professor at
the University of Nevada School of Medicine; SWOG GU Vice Chair; US
Oncology Research GU Chair; Comprehensive Cancer Centers of Nevada,
said: “The usual course of treatment for patients with advanced
bladder cancer begins with a standard platinum-containing
chemotherapy. Patients who have disease progression during or
following chemotherapy are left with few other treatment options.
The approval of IMFINZI to treat this population of select patients
signifies hope for those who are currently suffering, or may find
themselves with limited options in the future.”
The recommended dose of IMFINZI is 10 mg/kg body weight
administered as an intravenous infusion over 60 minutes every two
weeks until disease progression or unacceptable toxicity.
The accelerated FDA approval of IMFINZI, a human monoclonal
antibody that blocks PD-L1, is based on data from Study 1108. This
Phase I/II trial evaluated the safety and efficacy of IMFINZI in
patients with locally advanced or metastatic urothelial carcinoma
of the bladder. Patients had progressed while on or after a
platinum-containing chemotherapy, including those who progressed
within 12 months of receiving therapy in a neoadjuvant or adjuvant
setting.
In the trial, IMFINZI demonstrated rapid and durable responses,
with an objective response rate (ORR) of 17.0% (95% confidence
interval [CI]: 11.9; 23.3) in all evaluable patients, regardless of
PD-L1 status, and 26.3% (95% CI: 17.8; 36.4) in patients with PD-L1
high-expressing tumors (as determined by the VENTANA PD-L1 (SP263)
Assay, Ventana Medical Systems Inc., a member of the Roche Group).
PD-L1 high was defined as ≥25% of tumor cells (TC) or
tumor-infiltrating immune cells (IC) expressing membrane PD-L1 if
ICs involved >1% of the tumor area, or TC≥25% or IC=100% if ICs
involved ≤1% of the tumor area. Additionally, approximately 14.3%
of all evaluable patients achieved partial response and 2.7%
achieved complete response. Of patients who had received only
neoadjuvant or adjuvant therapy prior to trial entry, 24% (n=9)
responded. Based on a secondary endpoint in this single-arm trial,
median time to response was six weeks. Among the total 31
responding patients, 14 patients (45%) had ongoing responses of six
months or longer and five patients (16%) had ongoing responses of
12 months or longer.
Efficacy results for Study 1 (bladder cancer cohort of Study
1108)
All Patients(N=182)
PD-L1High(N=95)
PD-L1Low/Negative(N=73)
PD-L1
NotEvaluable(N=14)
Objective ResponseRate (ORR) by
BICR*,n (%)(95% confidenceinterval
[CI])
31 (17.0%)(11.9; 23.3)
25 (26.3%)(17.8; 36.4)
3 (4.1%)(0.9; 11.5)
3 (21.4%)(4.7; 50.8)
CompleteResponse (CR)
5 3 1 1
PartialResponse (PR)
26 22 2 2
Median Duration ofResponse
(DoR),months (range)
Not reached(0.9+; 19.9+)
Not reached(0.9+; 19.9+)
12.3(1.9+; 12.3)
Not reached(2.3+; 2.6+)
*BICR=Blinded Independent Central Review+
Denotes a censored value
Patients should be monitored for immune-mediated adverse
reactions including pneumonitis, hepatitis, colitis,
endocrinopathies (including adrenal insufficiency, hypophysitis, or
Type 1 diabetes mellitus), nephritis, rash, thrombocytopenic
purpura, infection, infusion-related reactions, or embryo-fetal
toxicity. 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). Eight patients (4.4%)
who were treated with IMFINZI experienced Grade 5 adverse events of
cardiorespiratory arrest, general physical health deterioration,
sepsis, ileus, pneumonitis, or immune-mediated hepatitis. Three
additional patients were experiencing infection and disease
progression at the time of death. IMFINZI was discontinued for
adverse reactions in 3.3% of patients.
Clinical trials have demonstrated that patients with PD-L1
high-expressing tumors have a higher likelihood of response through
blockade of the PD-1/PD-L1 pathway. PD-L1 expression testing may be
a useful tool to help guide physicians in their treatment
decisions, but it is not required for use of IMFINZI.
AstraZeneca strives to ensure that appropriate patients and
their oncologists have access to IMFINZI and relevant support
resources. These include educational resources, an Oncology Nurse
Educator program and financial assistance programs. Additionally,
AstraZeneca has launched Lighthouse, a program that provides
support to patients during any immune-mediated adverse events they
may encounter during treatment, through medically trained
Lighthouse Advocates. The program aims to make patients’ treatment
experience as comfortable as possible.
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, and other
immune-mediated adverse reactions. 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. 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 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 is also being tested in the first-line treatment of
patients with unresectable and metastatic bladder cancer as a
monotherapy and in combination with tremelimumab, a checkpoint
inhibitor that targets CTLA-4, as part of the DANUBE Phase III
trial, which had the last patient commenced dosing during the first
quarter of 2017 (global trial, excluding China). Additional
clinical trials are ongoing to investigate durvalumab as
monotherapy or in combination with tremelimumab in multiple solid
tumors and blood cancers.
About bladder cancer
Urothelial bladder cancers arise from the epithelium of the
bladder and are the sixth most common form of cancer in the US. It
is estimated that in 2017, approximately 79,000 Americans will be
diagnosed with bladder cancer, and almost 17,000 will die from this
disease. Metastatic bladder cancer remains an area of unmet medical
need with five-year overall survival rates of approximately 5%.
The tumor microenvironment of urothelial carcinoma (UC)
significantly impairs lymphocyte function, helping the cancer to
evade immune detection by exploiting inhibitory checkpoint
pathways, such as PD-L1/PD-1. PD-L1 is widely expressed in
tumor and immune cells in UC patients and helps tumors to evade
detection from the immune system through binding to the PD-1
receptor on cytotoxic T lymphocytes.
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) as 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 majority 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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