Longest survival follow-up ever reported for
immunotherapy treatment in this setting
Updated exploratory results from the TOPAZ-1 Phase III trial
showed AstraZeneca’s IMFINZI® (durvalumab) in combination with
standard-of-care chemotherapy demonstrated a clinically meaningful
long-term overall survival (OS) benefit at three years for patients
with advanced biliary tract cancer (BTC).
These results from TOPAZ-1, which are the longest survival
follow-up ever reported for a global, randomized Phase III trial in
this setting, will be presented on April 18 at the 2024
Cholangiocarcinoma Foundation Conference in Salt Lake City,
Utah.
At more than three years (median follow-up of 41.3 months),
results showed IMFINZI plus chemotherapy reduced the risk of death
by 26% versus chemotherapy alone (based on a hazard ratio [HR] of
0.74; 95% confidence interval [CI], 0.63-0.87). The median OS was
12.9 months for IMFINZI plus chemotherapy versus 11.3 months for
chemotherapy alone. More than twice as many patients on the
IMFINZI-based regimen were alive at three years versus chemotherapy
alone (14.6% versus 6.9%).
The TOPAZ-1 trial met the primary endpoint of OS in October 2021
at a planned interim analysis, showing that the combination reduced
the risk of death by 20% versus chemotherapy alone (based on a HR
of 0.80; 95% CI, 0.66-0.97; 2-sided p=0.021 at a statistical
significance threshold of 0.03).
Do-Youn Oh, MD, PhD, Professor, Division of Medical Oncology,
Department of Internal Medicine at Seoul National University
Hospital and Seoul National University College of Medicine, and
principal investigator in the trial, said: “The latest data from
TOPAZ-1 show that twice as many patients with advanced biliary
tract cancer were still alive at three years with durvalumab and
chemotherapy, an especially meaningful advance in a setting where
historically the prognosis has been poor. These results reinforce
the long-term benefit of this immunotherapy-based combination as a
standard of care for patients with this devastating disease.”
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “TOPAZ-1 raised the bar for the treatment of
advanced biliary tract cancer, showing a remarkable survival
benefit for IMFINZI added to chemotherapy with a well-tolerated
regimen. These data represent the longest survival follow-up
reported for immunotherapy in this setting, and the three-year
landmark survival improvement underscores our commitment to
improving long-term outcomes in gastrointestinal cancers.”
Stacie Lindsey, CEO, Cholangiocarcinoma Foundation said:
“AstraZeneca’s longer survival data in advanced biliary tract
cancer represents a meaningful milestone in that we are seeing
three-year survival data for the first time for these patients. The
data spurs hope that research will continue to improve outcomes for
patients living with these challenging and rare cancers.”
Summary of updated survival results: TOPAZ-1i
OSi,ii
IMFINZI+ chemotherapy
(n=341)
Chemotherapy
(n=344)
Median OS (95% CI in months)
12.9
(11.6-14.1)
11.3
(10.1-12.5)
HR (95% CI)iii
0.74 (0.63-0.87)
OS rate at 36 months (95% CI) (%)iv
14.6
(11.0-18.6)
6.9
(4.5-10.0)
i. 26 months of additional follow-up (data
cut-off: 23 October 2023) after the primary analysis, with 89%
overall OS event maturity
ii. At data cut-off for this analysis,
median (95% CI) follow-up time in all patients calculated using
reverse Kaplan-Meier technique was 42.9 (39.8-44.3) months for
IMFINZI plus chemotherapy and 41.8 (36.7-46.2) months for
chemotherapy
iii. HR and 95% CI calculated using Cox
proportional hazards model
iv. OS rates calculated using Kaplan-Meier
technique
IMFINZI plus chemotherapy continued to be well-tolerated, with
no new safety signals observed with longer follow-up. Results
showed 15.4% of patients experienced treatment-related serious
adverse events with IMFINZI plus chemotherapy versus 17.3% with
chemotherapy alone.
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 USPI 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 given 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), has 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 USPI 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 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 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 (42%),
nausea (40%), constipation (32%), decreased appetite (26%),
abdominal pain (24%), rash (23%), and pyrexia (20%).
- 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),
and 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 Full Prescribing Information including Medication
Guide for IMFINZI.
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).1,2 Approximately 50,000 people in the US, Europe and
Japan and about 210,000 people worldwide are diagnosed with BTC
each year.3-5 These patients historically have a poor prognosis,
with approximately 5% to 15% of patients with BTC surviving five
years. For patients with metastatic disease, the five-year survival
rate drops to less than 5%.6
Cholangiocarcinoma is more common in China and Thailand and is
on the rise in Western countries.1,7 Gallbladder cancer is more
common in certain regions of South America, India and Japan.8
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.7-9
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 adult
patients with unresectable, locally 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® (durvalumab)
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 its indications in unresectable, Stage III NSCLC
and ES-SCLC, IMFINZI is currently approved in a number of countries
in combination with a short course of tremelimumab-actl and
chemotherapy for the treatment of metastatic NSCLC.
IMFINZI is also approved in a number of countries in combination
with chemotherapy in locally advanced or metastatic biliary tract
cancer and in combination with tremelimumab-actl in unresectable
hepatocellular carcinoma (HCC). IMFINZI is also approved as a
monotherapy in unresectable HCC in Japan and the EU and in
previously treated patients with advanced bladder cancer in a small
number of countries.
Since the first approval in May 2017, more than 220,000 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, breast cancer, several
gastrointestinal cancers and other solid tumors.
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.10
Within this program, the Company is committed to improving
outcomes in gastric, liver, biliary tract, esophageal, pancreatic
and colorectal cancers.
In addition to its indications in BTC and HCC, IMFINZI is being
assessed in combinations, including with tremelimumab-actl, in
liver, esophageal and gastric cancers in an extensive development
program spanning early to late-stage disease across settings.
The Company is also assessing rilvegostomig (AZD2936), a
PD-1/TIGIT bispecific antibody, in combination with chemotherapy as
an adjuvant therapy in biliary tract cancer.
Fam-trastuzumab deruxtecan-nxki, a HER2-directed antibody drug
conjugate, is approved in the US and several other countries for
HER2-positive advanced gastric cancer and is being assessed in
colorectal cancer. It also has been assessed in multiple GI
settings including biliary tract cancer in the DESTINY-PanTumor02
Phase II trial, and it was recently approved in the US for the
treatment of unresectable or metastatic HER2-positive solid tumors
who have received prior systemic treatment and have no satisfactory
alternative treatment options. Fam-trastuzumab deruxtecan-nxki is
jointly developed and commercialized by AstraZeneca and Daiichi
Sankyo.
Olaparib, a first-in-class PARP inhibitor, is approved in the US
and several other countries for the treatment of BRCA-mutated
metastatic pancreatic cancer. Olaparib is developed and
commercialized in collaboration with Merck & Co., Inc., known
as MSD outside the US and Canada.
AstraZeneca is advancing multiple modalities that provide
complementary mechanisms for targeting Claudin 18.2, a promising
therapeutic target in gastric cancer. These include AZD0901, a
potential first-in-class antibody drug conjugate licensed from KYM
Biosciences Inc., currently in Phase II development, AZD5863, a
novel Claudin 18.2/CD3 T-cell engager bispecific antibody licensed
from Harbour Biomed in Phase I development, and AZD6422, an armored
autologous chimeric antigen receptor T-cell (CAR-T) therapy,
currently being evaluated in an Investigator Initiated Trial (IIT)
in collaboration with AbelZeta in China.
In early development, AstraZeneca is developing two Glypican 3
(GPC3) armored CAR-Ts in HCC. AZD5851, currently in Phase I
development, is being developed globally, and C-CAR031 / AZD7003 is
being co-developed with AbelZeta in China where it is under
evaluation in an IIT.
AstraZeneca in immuno-oncology (IO)
AstraZeneca is a pioneer in introducing the concept of
immunotherapy into dedicated clinical areas of high unmet medical
need. The Company has a comprehensive and diverse IO portfolio and
pipeline anchored in immunotherapies designed to overcome evasion
of the anti-tumor immune response and stimulate the body’s immune
system to attack tumors.
AstraZeneca strives to redefine cancer care and help transform
outcomes for patients with IMFINZI as a monotherapy and in
combination with tremelimumab-actl as well as other novel
immunotherapies and modalities. The Company is also investigating
next-generation immunotherapies like bispecific antibodies and
therapeutics that harness different aspects of immunity to target
cancer, including cell therapy and T cell engagers.
AstraZeneca is pursuing an innovative clinical strategy to bring
IO-based therapies that deliver long-term survival to new settings
across a wide range of cancer types. The Company is focused on
exploring novel combination approaches to help prevent treatment
resistance and drive longer immune responses. With an extensive
clinical program, the Company also champions the use of IO
treatment in earlier disease stages, where there is the greatest
potential for cure.
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 us on social media
@AstraZeneca.
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 March 2024.
- Siegel RL. Cancer statistics, 2020. CA Cancer J Clin.
2020;70:7-30.
- ECIS - European Cancer Information System. Available:
https://ecis.jrc.ec.europa.eu/explorer.php Accessed March
2024.
- Kohei Nakachi, et al. Hepatobiliary and Pancreatic Oncology
Group of the Japan Clinical Oncology Group, A randomized Phase III
trial of adjuvant S-1 therapy vs. observation alone in resected
biliary tract cancer: Japan Clinical Oncology Group Study
(JCOG1202, ASCOT), Japanese Journal of Clinical Oncology.
2018,48:392-395.
- American Cancer Society. Survival Rates for Bile Duct Cancer.
Available at:
https://www.cancer.org/cancer/types/bile-duct-cancer/detection-diagnosis-staging/survival-by-stage.html.
Accessed March 2024.
- Turkes F, et al. Contemporary Tailored Oncology Treatment of
Biliary Tract Cancers. Gastroenterol Res Pract.
2019;2019:7698786.
- 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. Nature Reviews Gastroenterology &
Hepatology. 2020; 17: 557-588.
- WHO. World Cancer Fact Sheet. Available at:
https://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf.
Accessed September 2022.
US-88271 Last Updated 04/24
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Media Inquiries Brendan McEvoy, +1 302 885 2677 Chelsea
Tressler, +1 302 885 2677 US Media Mailbox:
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