First Phase III trial in this setting to
show improved overall survival with an immunotherapy added
to chemotherapy over standard-of-care chemotherapy alone
AstraZeneca’s supplemental Biologics License Application (sBLA)
for Imfinzi (durvalumab), in combination with standard-of-care
chemotherapy, has been accepted and granted Priority Review in the
US for patients with locally advanced or metastatic biliary tract
cancer (BTC).
The Food and Drug Administration (FDA) grants Priority Review to
applications for medicines that, if approved, would offer
significant improvements over available options by demonstrating
safety or efficacy improvements, preventing serious conditions, or
enhancing patient compliance.1 The Prescription Drug User Fee Act
date, the FDA action date for their regulatory decision, is during
the third quarter of 2022.
BTC is a group of rare and aggressive cancers that occur in the
bile ducts and gallbladder. 2,3 Approximately 23,000 people in the
US are diagnosed with BTC each year.2 These patients have a poor
prognosis, with approximately 5% to 15% of patients with BTC
surviving five years.4
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “People with advanced biliary tract cancer have
faced poor outcomes and limited treatment options for too long, and
today’s news for the TOPAZ-1 trial underscores the urgency to
deliver new, effective therapies in this setting. We are working
closely with the FDA to bring the first immunotherapy-based option
to patients with this devastating cancer and potentially set a new
standard of care with Imfinzi plus chemotherapy.”
The sBLA was based on results from an interim analysis of the
TOPAZ-1 Phase III trial presented during the 2022 American Society
of Clinical Oncology Gastrointestinal Cancers (ASCO GI) Symposium.
The data showed Imfinzi plus chemotherapy (gemcitabine plus
cisplatin) reduced the risk of death by 20% versus chemotherapy
alone (based on a hazard ratio [HR] of 0.80; 95% confidence
interval [CI], 0.66-0.97; 2-sided p=0.021). An estimated one in
four (25%) patients treated with Imfinzi plus chemotherapy were
alive at two years compared to one in 10 (10%) treated with
chemotherapy alone.
Results also showed a statistically significant 25% reduction in
the risk of disease progression or death with Imfinzi plus
chemotherapy (HR, 0.75; 95% CI, 0.64-0.89; 2-sided p=0.001). The
Imfinzi combination was generally well tolerated and did not
increase the discontinuation rate due to adverse events compared to
chemotherapy alone.
In December 2020, Imfinzi was granted Orphan Drug Designation in
the US for the treatment of BTC.
IMPORTANT SAFETY INFORMATION
There are no contraindications for IMFINZI® (durvalumab).
Immune-Mediated Adverse Reactions
Important immune-mediated adverse reactions listed under
Warnings and Precautions may not include all possible severe and
fatal immune-mediated reactions. Immune-mediated adverse reactions,
which may be severe or fatal, can occur in any organ system or
tissue. Immune-mediated adverse reactions can occur at any time
after starting treatment or after discontinuation. Monitor patients
closely for symptoms and signs that may be clinical manifestations
of underlying immune-mediated adverse reactions. Evaluate liver
enzymes, creatinine, and thyroid function at baseline and
periodically during treatment. In cases of suspected
immune-mediated adverse reactions, initiate appropriate workup to
exclude alternative etiologies, including infection. Institute
medical management promptly, including specialty consultation as
appropriate. Withhold or permanently discontinue IMFINZI depending
on severity. See Dosing and Administration for specific details. In
general, if IMFINZI requires interruption or discontinuation,
administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day
prednisone or equivalent) until improvement to Grade 1 or less.
Upon improvement to Grade 1 or less, initiate corticosteroid taper
and continue to taper over at least 1 month. Consider
administration of other systemic immunosuppressants in patients
whose immune-mediated adverse reactions are not controlled with
corticosteroid therapy.
Immune-Mediated Pneumonitis
IMFINZI can cause immune-mediated pneumonitis. The incidence of
pneumonitis is higher in patients who have received prior thoracic
radiation. In patients who did not receive recent prior radiation,
the incidence of immune-mediated pneumonitis was 2.4% (34/1414),
including fatal (<0.1%), and Grade 3-4 (0.4%) adverse reactions.
In patients who received recent prior radiation, the incidence of
pneumonitis (including radiation pneumonitis) in patients with
unresectable Stage III NSCLC following definitive chemoradiation
within 42 days prior to initiation of IMFINZI in PACIFIC was 18.3%
(87/475) in patients receiving IMFINZI and 12.8% (30/234) in
patients receiving placebo. Of the patients who received IMFINZI
(475), 1.1% were fatal and 2.7% were Grade 3 adverse reactions. The
frequency and severity of immune-mediated pneumonitis in patients
who did not receive definitive chemoradiation prior to IMFINZI were
similar in patients who received IMFINZI as a single agent or with
ES-SCLC when in combination with chemotherapy.
Immune-Mediated Colitis
IMFINZI can cause immune-mediated colitis that is frequently
associated with diarrhea. Cytomegalovirus (CMV)
infection/reactivation has been reported in patients with
corticosteroid-refractory immune-mediated colitis. In cases of
corticosteroid-refractory colitis, consider repeating infectious
workup to exclude alternative etiologies. Immune-mediated colitis
occurred in 2% (37/1889) of patients receiving IMFINZI, including
Grade 4 (<0.1%) and Grade 3 (0.4%) adverse reactions.
Immune-Mediated Hepatitis
IMFINZI can cause immune-mediated hepatitis. Immune-mediated
hepatitis occurred in 2.8% (52/1889) of patients receiving IMFINZI,
including fatal (0.2%), Grade 4 (0.3%) and Grade 3 (1.4%) adverse
reactions.
Immune-Mediated Endocrinopathies
- Adrenal Insufficiency: IMFINZI can cause primary or
secondary adrenal insufficiency. For Grade 2 or higher adrenal
insufficiency, initiate symptomatic treatment, including hormone
replacement as clinically indicated. Immune-mediated adrenal
insufficiency occurred in 0.5% (9/1889) of patients receiving
IMFINZI, including Grade 3 (<0.1%) adverse reactions.
- Hypophysitis: IMFINZI can cause immune-mediated
hypophysitis. Hypophysitis can present with acute symptoms
associated with mass effect such as headache, photophobia, or
visual field cuts. Hypophysitis can cause hypopituitarism. Initiate
symptomatic treatment including hormone replacement as clinically
indicated. Grade 3 hypophysitis/hypopituitarism occurred in
<0.1% (1/1889) of patients who received IMFINZI.
- Thyroid Disorders: IMFINZI can cause immune-mediated
thyroid disorders. Thyroiditis can present with or without
endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate
hormone replacement therapy for hypothyroidism or institute medical
management of hyperthyroidism as clinically indicated.
- Thyroiditis: Immune-mediated thyroiditis occurred in
0.5% (9/1889) of patients receiving IMFINZI, including Grade 3
(<0.1%) adverse reactions.
- Hyperthyroidism: Immune-mediated hyperthyroidismoccurred
in 2.1% (39/1889) of patients receiving IMFINZI.
- Hypothyroidism: Immune-mediated hypothyroidism occurred
in 8.3% (156/1889) of patients receiving IMFINZI, including Grade 3
(<0.1%) adverse reactions.
- Type 1 Diabetes Mellitus, which can present with diabetic
ketoacidosis: Monitor patients for hyperglycemia or other signs
and symptoms of diabetes. Initiate treatment with insulin as
clinically indicated. Grade 3 immune-mediated type 1 diabetes
mellitus occurred in <0.1% (1/1889) of patients receiving
IMFINZI.
Immune-Mediated Nephritis with Renal Dysfunction
IMFINZI can cause immune-mediated nephritis. Immune-mediated
nephritis occurred in 0.5% (10/1889) of patients receiving IMFINZI,
including Grade 3 (<0.1%) adverse reactions.
Immune-Mediated Dermatology Reactions
IMFINZI can cause immune-mediated rash or dermatitis.
Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS),
drug rash with eosinophilia and systemic symptoms (DRESS), and
toxic epidermal necrolysis (TEN), have occurred with PD-1/L-1
blocking antibodies. Topical emollients and/or topical
corticosteroids may be adequate to treat mild to moderate
non-exfoliative rashes. Immune-mediated rash or dermatitis occurred
in 1.8% (34/1889) of patients receiving IMFINZI, including Grade 3
(0.4%) adverse reactions.
Other Immune-Mediated Adverse Reactions
The following clinically significant, immune-mediated adverse
reactions occurred at an incidence of less than 1% each in patients
who received IMFINZI or were reported with the use of other
PD-1/PD-L1 blocking antibodies.
- Cardiac/vascular: Myocarditis, pericarditis,
vasculitis.
- Nervous system: Meningitis, encephalitis, myelitis and
demyelination, myasthenic syndrome/myasthenia gravis (including
exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune
neuropathy.
- Ocular: Uveitis, iritis, and other ocular inflammatory
toxicities can occur. Some cases can be associated with retinal
detachment. Various grades of visual impairment to include
blindness can occur. If uveitis occurs in combination with other
immune-mediated adverse reactions, consider a
Vogt-Koyanagi-Harada-like syndrome, as this may require treatment
with systemic steroids to reduce the risk of permanent vision
loss.
- Gastrointestinal: Pancreatitis including increases in
serum amylase and lipase levels, gastritis, duodenitis.
- Musculoskeletal and connective tissue disorders:
Myositis/polymyositis, rhabdomyolysis and associated sequelae
including renal failure, arthritis, polymyalgia rheumatic.
- Endocrine: Hypoparathyroidism
- Other (hematologic/immune): Hemolytic anemia, aplastic
anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory
response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi
lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ
transplant rejection.
Infusion-Related Reactions
IMFINZI can cause severe or life-threatening infusion-related
reactions. Monitor for signs and symptoms of infusion-related
reactions. Interrupt, slow the rate of, or permanently discontinue
IMFINZI based on the severity. See Dosing and Administration for
specific details. For Grade 1 or 2 infusion-related reactions,
consider using pre-medications with subsequent doses.
Infusion-related reactions occurred in 2.2% (42/1889) of patients
receiving IMFINZI, including Grade 3 (0.3%) adverse reactions.
Complications of Allogeneic HSCT after IMFINZI
Fatal and other serious complications can occur in patients who
receive allogeneic hematopoietic stem cell transplantation (HSCT)
before or after being treated with a PD-1/L-1 blocking antibody.
Transplant-related complications include hyperacute
graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic
veno-occlusive disease (VOD) after reduced intensity conditioning,
and steroid-requiring febrile syndrome (without an identified
infectious cause). These complications may occur despite
intervening therapy between PD-1/L-1 blockade and allogeneic HSCT.
Follow patients closely for evidence of transplant-related
complications and intervene promptly. Consider the benefit versus
risks of treatment with a PD-1/L-1 blocking antibody prior to or
after an allogeneic HSCT.
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.
Advise pregnant women of the potential risk to a fetus. Advise
females of reproductive potential to use effective contraception
during treatment with IMFINZI and for at least 3 months after the
last dose of IMFINZI.
Lactation
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 women not to breastfeed
during treatment and for at least 3 months after the last dose.
Adverse Reactions
- In patients with Stage III NSCLC in the PACIFIC study receiving
IMFINZI (n=475), the most common adverse reactions (≥20%) were
cough (40%), fatigue (34%), pneumonitis or radiation pneumonitis
(34%), upper respiratory tract infections (26%), dyspnea (25%), and
rash (23%). The most common Grade 3 or 4 adverse reactions (≥3%)
were pneumonitis/radiation pneumonitis (3.4%) and pneumonia
(7%)
- In patients with Stage III NSCLC in the PACIFIC study receiving
IMFINZI (n=475), discontinuation due to adverse reactions occurred
in 15% of patients in the IMFINZI arm. Serious adverse reactions
occurred in 29% of patients receiving IMFINZI. The most frequent
serious adverse reactions (≥2%) were pneumonitis or radiation
pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis or radiation
pneumonitis and fatal pneumonia occurred in <2% of patients and
were similar across arms
- In patients with extensive-stage SCLC in the CASPIAN study
receiving IMFINZI plus chemotherapy (n=265), the most common
adverse reactions (≥20%) were nausea (34%), fatigue/asthenia (32%),
and alopecia (31%). The most common Grade 3 or 4 adverse reaction
(≥3%) was fatigue/asthenia (3.4%)
- In patients with extensive-stage SCLC in the CASPIAN study
receiving IMFINZI plus chemotherapy (n=265), IMFINZI was
discontinued due to adverse reactions in 7% of the patients
receiving IMFINZI plus chemotherapy. Serious adverse reactions
occurred in 31% of patients receiving IMFINZI plus chemotherapy.
The most frequent serious adverse reactions reported in at least 1%
of patients were febrile neutropenia (4.5%), pneumonia (2.3%),
anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%), and COPD
(1.1%). Fatal adverse reactions occurred in 4.9% of patients
receiving IMFINZI plus chemotherapy
The safety and effectiveness of IMFINZI have not been
established in pediatric patients.
Indications:
IMFINZI is indicated for the treatment of adult patients with
unresectable Stage III non-small cell lung cancer (NSCLC) whose
disease has not progressed following concurrent platinum-based
chemotherapy and radiation therapy.
IMFINZI, in combination with etoposide and either carboplatin or
cisplatin, is indicated for the first-line treatment of adult
patients with extensive-stage small cell lung cancer (ES-SCLC).
Please see complete Prescribing Information, including
Medication Guide.
Notes
Biliary tract cancer
Biliary tract cancer (BTC) is a group of rare and aggressive
gastrointestinal (GI) cancers that form in the cells of the bile
ducts (cholangiocarcinoma), gallbladder or ampulla of Vater (where
the bile duct and pancreatic duct connect to the small
intestine).2,3
Cholangiocarcinoma is more common in China and South-East Asia
and is on the rise in Western countries.2,4 Gallbladder cancer is
more common in certain regions of South America, India and
Japan.5
Early-stage BTC affecting the bile ducts and gallbladder often
presents without clear symptoms and most new cases of BTC are
therefore diagnosed at an advanced stage, when treatment options
are limited and the prognosis is poor.4-6
TOPAZ-1
TOPAZ-1 is a randomized, double-blind, placebo controlled,
multicenter, global Phase III trial of Imfinzi in combination with
chemotherapy (gemcitabine plus cisplatin) versus placebo in
combination with chemotherapy as a 1st-line treatment in 685
patients with unresectable advanced or metastatic BTC including
intrahepatic and extrahepatic cholangiocarcinoma, and gallbladder
cancer. Patients with ampullary carcinoma were excluded.
The primary endpoint is overall survival and key secondary
endpoints included progression-free survival, objective response
rate and safety. The trial was conducted in 105 centers across 17
countries including in the US, Europe, South America and several
countries in Asia including South Korea, Thailand, Japan and
China.
Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds
to the PD-L1 protein and blocks the interaction of PD-L1 with the
PD-1 and CD80 proteins, countering the tumor’s immune-evading
tactics and releasing the inhibition of immune responses.
Imfinzi is the only approved immunotherapy in the
curative-intent setting of unresectable, Stage III non-small cell
lung cancer (NSCLC) in patients whose disease has not progressed
after chemoradiotherapy, and is the global standard of care in this
setting based on the PACIFIC Phase III trial.
Imfinzi is also approved in the US, EU, Japan, China and many
other countries around the world for the treatment of
extensive-stage small cell lung cancer (ES-SCLC) based on the
CASPIAN Phase III trial. In 2021, updated results from the CASPIAN
trial showed Imfinzi plus chemotherapy tripled patient survival at
three years versus chemotherapy alone.
Imfinzi is also approved for previously treated patients with
advanced bladder cancer in several countries.
Since the first approval in May 2017, more than 100,000 patients
have been treated with Imfinzi.
As part of a broad development program, Imfinzi is being tested
as a single treatment and in combinations with other anti-cancer
treatments for patients with small cell lung cancer (SCLC), NSCLC,
bladder cancer, several GI cancers, ovarian cancer, endometrial
cancer, and other solid tumors.
In the past year, Imfinzi combinations have demonstrated
clinical benefit in multiple additional cancer settings with
positive Phase III trials in unresectable advanced liver cancer
(HIMALAYA) and metastatic NSCLC (POSEIDON).
AstraZeneca in GI cancers
AstraZeneca has a broad development program for the treatment of
GI cancers across several medicines and a variety of tumor types
and stages of disease. In 2020, GI cancers collectively represented
approximately 5.1 million new cancer cases leading to approximately
3.6 million deaths.6
Within this program, the Company is committed to improving
outcomes in gastric, liver, BTC, esophageal, pancreatic, and
colorectal cancers.
Imfinzi is being assessed in combinations in liver, BTC,
esophageal and gastric cancers in an extensive development program
spanning early to late-stage disease.
The Company aims to understand the potential of Enhertu
(trastuzumab deruxtecan), a HER2-directed antibody drug conjugate,
in the two most common GI cancers, colorectal and gastric cancers.
Enhertu is jointly developed and commercialized by AstraZeneca and
Daiichi Sankyo.
Lynparza (olaparib) is a first-in-class PARP inhibitor with a
broad and advanced clinical trial program across multiple GI tumor
types including pancreatic and colorectal cancers. Lynparza is
developed and commercialized in collaboration Merck & Co.,
Inc., Kenilworth, NJ, US (known as MSD outside the US and
Canada).
AstraZeneca in immunotherapy
Immunotherapy is a therapeutic approach designed to stimulate
the body’s immune system to attack tumors. The Company’s
Immuno-Oncology (IO) portfolio is anchored in immunotherapies that
have been designed to overcome evasion of the anti-tumor immune
response. AstraZeneca is invested in using IO approaches that
deliver long-term survival for new groups of patients across tumor
types.
The Company is pursuing a comprehensive clinical-trial program
that includes Imfinzi as a single treatment and in combination with
tremelimumab and other novel antibodies in multiple tumor types,
stages of disease, and lines of treatment, and where relevant 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 the IO portfolio with
radiation, chemotherapy, and targeted small molecules from across
AstraZeneca’s oncology pipeline, and from research partners, may
provide new treatment options across a broad range of tumors.
AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the
ambition to provide cures for cancer in every form, following the
science to understand cancer and all its complexities to discover,
develop and deliver life-changing medicines to patients.
The Company's focus is on some of the most challenging cancers.
It is through persistent innovation that AstraZeneca has built one
of the most diverse portfolios and pipelines in the industry, with
the potential to catalyze changes in the practice of medicine and
transform the patient experience.
AstraZeneca has the vision to redefine cancer care and, one day,
eliminate cancer as a cause of death.
AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company
that focuses on the discovery, development, and commercialization
of prescription medicines in Oncology, Rare Diseases, and
BioPharmaceuticals, including Cardiovascular, Renal &
Metabolism, and Respiratory & Immunology. Based in Cambridge,
UK, AstraZeneca operates in over 100 countries and its innovative
medicines are used by millions of patients worldwide. Please visit
astrazeneca-us.com and follow the Company on Twitter
@AstraZenecaUS.
References
1. FDA. Priority Review. Available at:
https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review.
Accessed May 2022. 2. Marcano-Bonilla L, et al. Biliary tract
cancers: epidemiology, molecular pathogenesis and genetic risk
associations. CCO. 2016;5(5). 3. ESMO. What is Biliary Tract
Cancer. Available at:
https://www.esmo.org/content/download/266801/5310983/1/EN-Biliary-Tract-Cancer-Guide-for-Patients.pdf.
Accessed May 2022. 4. Turkes F, et al. Contemporary Tailored
Oncology Treatment of Biliary Tract Cancers. Gastroenterol Res
Pract. 2019; 2019:7698786. 5. Rawla P, et al. Epidemiology of
gallbladder cancer. Clin Exp Hepatol. 2019;5(2):93-102. 6. Banales
JM, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms
and management. Nat Rev Gastroenterol Hepatol. 2020;17:557-588.
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Media Inquiries Brendan McEvoy +1 302 885 2677 Jessica
McDuell +1 302 885 2677
US Media Mailbox: usmediateam@astrazeneca.com
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