Approval based on TOPAZ-1 Phase III trial
results, which showed IMFINZI combination reduced risk of death by
20% vs. chemotherapy alone
AstraZeneca’s IMFINZI® (durvalumab) has been approved in the US
for the treatment of adult patients with locally advanced or
metastatic biliary tract cancer (BTC) in combination with
chemotherapy (gemcitabine plus cisplatin).
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The approval by the Food and Drug Administration (FDA) was based
on the results from the TOPAZ-1 Phase III trial. In an interim
analysis of TOPAZ-1, IMFINZI plus chemotherapy reduced the risk of
death by 20% versus chemotherapy alone (hazard ratio [HR] 0.80; 95%
confidence interval [CI] 0.66-0.97; p=0.021). An estimated one in
four (25%) patients treated with IMFINZI plus chemotherapy were
still alive at two years compared to one in 10 (10%) treated with
chemotherapy alone. Results were consistent across all prespecified
subgroups, regardless of PD-L1 expression or tumor location.
BTC is a group of rare and aggressive cancers that occur in the
bile ducts and gallbladder.1,2 Approximately 23,000 people in the
US are diagnosed with BTC each year.1 These patients have a poor
prognosis, with approximately 5% to 15% of patients with BTC
surviving five years.3
Aiwu Ruth He, MD, PhD, Associate Professor of Medicine, Leader
of the GI Cancer Program, Georgetown Lombardi Comprehensive Cancer
Center, Medstar Georgetown University Hospital, Washington DC, and
a lead investigator in the TOPAZ-1 Phase III trial, said: “This
approval represents a major step forward for patients with advanced
biliary tract cancer, who urgently need new, well-tolerated and
effective treatment options after more than a decade of limited
innovation. The combination of durvalumab and chemotherapy should
become a new standard of care in this setting, having demonstrated
significantly improved survival for these patients who have
historically faced a poor prognosis.”
Dave Fredrickson, Executive Vice President, Oncology Business
Unit, AstraZeneca, said: “For the first time, patients in the US
with advanced biliary tract cancer have an immunotherapy-based
treatment option that meaningfully extends survival and is
well-tolerated. This approval for IMFINZI and chemotherapy advances
our ambition to challenge treatment expectations and transform care
for patients with gastrointestinal cancers with high unmet
need.”
Stacie Lindsey, CEO, Cholangiocarcinoma Foundation, said:
“Patients have been waiting a long time for a new, first-line
treatment option for biliary tract cancer. The Foundation
congratulates AstraZeneca for engaging in rare cancer research,
which impacts patients and families nationwide. We are especially
grateful to the patients who participated in this trial making it
possible for the broader rare disease community to benefit from
this treatment.”
The TOPAZ-1 Phase III trial results were presented at the 2022
American Society of Clinical Oncology Gastrointestinal Cancers
(ASCO GI) Symposium and published in the New
England Journal of Medicine Evidence. IMFINZI plus
chemotherapy was generally well tolerated and did not increase the
discontinuation rate due to adverse events compared to chemotherapy
alone.
In July 2022, IMFINZI plus chemotherapy was added to the NCCN
Clinical Practice Guidelines in Oncology (NCCN Guidelines®) as a
Category 1 preferred regimen as 1st-line therapy for locally
advanced or metastatic BTC based on the data from TOPAZ-1.4
The US regulatory submission for TOPAZ-1 was reviewed under
Project Orbis, which provides a framework for concurrent submission
and review of oncology medicines among participating international
partners. As part of Project Orbis, IMFINZI plus chemotherapy is
also under regulatory review for the same indication by the
Australian Therapeutic Goods Administration, the Brazilian Health
Regulatory Agency (ANVISA), Health Canada, Israel’s Ministry of
Health Pharmaceutical Administration, Singapore’s Health Sciences
Authority, Switzerland’s Swissmedic and the UK’s Medicines and
Healthcare products Regulatory Agency.
The approval was granted after securing Priority Review and
Orphan Drug Designation for IMFINZI in the US in this setting.
Regulatory applications are also currently under review in Europe,
Japan and several other countries based on the TOPAZ-1 results.
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 or BTC 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 hyperthyroidism
occurred 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. In females of reproductive potential,
verify pregnancy status prior to initiating IMFINZI and advise them
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 locally advanced or metastatic BTC in the
TOPAZ-1 study receiving IMFINZI (n=338), the most common adverse
reactions (occurring in ≥20% of patients) were fatigue, nausea,
constipation, decreased appetite, abdominal pain, rash, and
pyrexia
- In patients with locally advanced or metastatic BTC in the
TOPAZ-1 study receiving IMFINZI (n=338), discontinuation due to
adverse reactions occurred in 6% of the patients receiving IMFINZI
plus chemotherapy. Serious adverse reactions occurred in 47% of
patients receiving IMFINZI plus chemotherapy. The most frequent
serious adverse reactions reported in at least 2% of patients were
cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%) and
acute kidney injury (2.4%). Fatal adverse reactions occurred in
3.6% of patients receiving IMFINZI plus chemotherapy. These include
ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients),
upper gastrointestinal hemorrhage (2 patients)
The safety and effectiveness of IMFINZI have not been
established in pediatric patients.
Indication: IMFINZI, in combination with gemcitabine and
cisplatin, is indicated for the treatment of adult patients with
locally advanced or metastatic biliary tract cancer (BTC).
Please see complete Prescribing Information, including
Medication Guide.
Notes
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).1,2
Cholangiocarcinoma is more common in China and South-East Asia
and is on the rise in Western countries.1,3 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.3,5,6
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.
In addition to the approval in BTC, 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 SCLC, NSCLC, bladder cancer, several
GI cancers, ovarian cancer, endometrial cancer, and other solid
tumors.
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 fam-trastuzumab
deruxtecan-nxki, a HER2-directed antibody drug conjugate, in the
two most common GI cancers, colorectal and gastric cancers.
Fam-trastuzumab deruxtecan-nxki is jointly developed and
commercialized by AstraZeneca and Daiichi Sankyo.
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. Olaparib is developed
and commercialized in collaboration with Merck & Co., Inc.,
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.
About 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 www.astrazeneca-us.com and follow
the Company on Twitter @AstraZenecaUS.
References
- Marcano-Bonilla L, et al. Biliary tract cancers: epidemiology,
molecular pathogenesis and genetic risk associations. CCO.
2016;5(5).
- 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 September 2022.
- Turkes F, et al. Contemporary Tailored Oncology Treatment of
Biliary Tract Cancers. Gastroenterol Res Pract. 2019:7698786.
- Referenced with permission from the NCCN Clinical Practice
Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer
V2.2022. © National Comprehensive Cancer Network, Inc. 2022. All
rights reserved. Accessed September 2022. To view the most recent
and complete version of the guideline, go online to NCCN.org. NCCN
makes no warranties of any kind whatsoever regarding their content,
use or application and disclaims any responsibility for their
application or use in any way.
- Rawla P, et al. Epidemiology of gallbladder cancer. Clin Exp
Hepatol. 2019;5(2):93-102.
- Banales JM, et al. Cholangiocarcinoma 2020: the next horizon in
mechanisms and management. Nat Rev Gastroenterol Hepatol.
2020;17:557-588.
US-66847 Last Updated 08/22
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Media Inquiries Brendan McEvoy, +1 302 885 2677 Jessica
McDuell, +1 302 885 2677 US Media Mailbox:
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