STRIDE regimen of a single priming dose of
tremelimumab added to Imfinzi is the first dual immune checkpoint
blockade regimen to improve overall survival in a Phase III trial
in this setting
AstraZeneca’s Biologics License Application (BLA) for
tremelimumab has been accepted for Priority Review in the US,
supporting the indication of a single priming dose of the
anti-CTLA4 antibody added to Imfinzi (durvalumab) for the treatment
of patients with unresectable hepatocellular carcinoma (HCC). A
supplemental BLA (sBLA) also has been submitted for Imfinzi in this
indication. This novel dose and schedule of the combination is
called the STRIDE regimen (Single Tremelimumab Regular Interval
Durvalumab).
The Prescription Drug User Fee Act date, the Food and Drug
Administration (FDA) action date for their regulatory decision, is
during the fourth quarter of 2022 following the use of a priority
review voucher.
Liver cancer, of which HCC is the most common type, is the
third-leading cause of cancer death and the sixth most commonly
diagnosed cancer worldwide.1,2 Approximately 26,000 people in the
US present with advanced, unresectable HCC each year.3
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “The HIMALAYA Phase III trial showed an
unprecedented three-year overall survival in this setting with a
single priming dose of tremelimumab added to Imfinzi, highlighting
the potential for this regimen to improve longer-term survival
outcomes. Patients with advanced liver cancer are in great need of
new treatment options, and we are working closely with the FDA to
bring this novel approach to patients in the US as soon as
possible.”
The BLA for tremelimumab and sBLA for Imfinzi are based on final
results from the HIMALAYA Phase III trial presented at the 2022
American Society of Clinical Oncology Gastrointestinal Cancers
Symposium.
In this trial, patients treated with the STRIDE regimen
experienced a 22% reduction in the risk of death versus sorafenib
(based on a hazard ratio [HR] of 0.78, 96.02% confidence interval
[CI] 0.65-0.93; p=0.0035).4 Nearly one in three (31%) patients were
still alive at three years versus one in five (20%) for
sorafenib.4
The safety profiles of the STRIDE regimen and for Imfinzi alone
were consistent with the known profiles of each medicine, and no
new safety signals were identified.
Imfinzi and tremelimumab were granted Orphan Drug Designation in
the US for the treatment of HCC in January 2020.
As part of its extensive clinical development program in
gastrointestinal (GI) cancers, AstraZeneca is further assessing
Imfinzi across multiple liver cancer settings, including
locoregional HCC (EMERALD-1, EMERALD-3) and adjuvant HCC
(EMERALD-2).
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 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. 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%)
t
- 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
Liver Cancer
About 75% of all primary liver cancers are HCC.1 Between 80-90%
of all patients with HCC also have cirrhosis.5 Chronic liver
diseases are associated with inflammation that over time can lead
to the development of HCC.5
More than half of patients are diagnosed at advanced stages of
the disease, often when symptoms first appear.6 A critical unmet
need exists for patients with HCC who face limited treatment
options.6 The unique immune environment of liver cancer provides
clear rationale for investigating medications that harness the
power of the immune system to treat HCC.6
HIMALAYA
HIMALAYA was a randomized, open-label, multicenter, global Phase
III trial of Imfinzi monotherapy and the STRIDE regimen, comprising
a single priming dose of tremelimumab 300mg added to Imfinzi 1500mg
followed by Imfinzi every four weeks versus sorafenib, a
standard-of-care multi-kinase inhibitor.
The trial included a total of 1,324 patients with unresectable,
advanced HCC who had not been treated with prior systemic therapy
and were not eligible for locoregional therapy (treatment localized
to the liver and surrounding tissue).
The trial was conducted in 181 centers across 16 countries,
including in the US, Canada, Europe, South America and Asia. The
primary endpoint is OS for STRIDE versus sorafenib and key
secondary endpoints included OS for Imfinzi versus sorafenib,
objective response rate and progression-free survival (PFS) for
STRIDE and for Imfinzi alone.
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.
In the past year, Imfinzi has demonstrated clinical benefit in
multiple additional cancer settings with positive Phase III trials
in advanced biliary tract cancer (TOPAZ-1), unresectable advanced
liver cancer (HIMALAYA) and metastatic NSCLC (POSEIDON).
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, NSCLC, bladder
cancer, several gastrointestinal cancers, ovarian cancer,
endometrial cancer, and other solid tumors.
Tremelimumab
Tremelimumab is a human monoclonal antibody and potential new
medicine that targets the activity of cytotoxic
T-lymphocyte-associated protein 4 (CTLA-4). Tremelimumab blocks the
activity of CTLA-4, contributing to T-cell activation, priming the
immune response to cancer and fostering cancer cell death.
Beyond HIMALAYA, tremelimumab is being tested in combination
with Imfinzi across multiple tumor types including locoregional HCC
(EMERALD-3), SCLC (ADRIATIC) and bladder cancer (VOLGA and
NILE).
Tremelimumab is also under review by global regulatory
authorities in combination with Imfinzi and chemotherapy in
1st-line metastatic NSCLC based on the results of the POSEIDON
Phase III trial, which showed the addition of a short course of
tremelimumab to Imfinzi plus chemotherapy improved both overall and
progression-free survival compared to chemotherapy alone.
AstraZeneca in GI cancers
AstraZeneca has a broad development program for the treatment of
GI cancers across several medicines spanning a variety of tumor
types and stages of disease. In 2020, GI cancers collectively
represented approximately 5.1 million new diagnoses leading to
approximately 3.6 million deaths.7
Within this program, the Company is committed to improving
outcomes in gastric, liver, BTC, esophageal, pancreatic, and
colorectal cancers.
Imfinzi (durvalumab) is being assessed in combinations including
with tremelimumab in HCC, biliary tract, esophageal and gastric
cancers in an extensive development program spanning early to
late-stage disease across settings. In January 2022, results of the
TOPAZ-1 Phase III trial in 1st-line advanced BTC demonstrated a
significant improvement in OS with Imfinzi plus standard-of-care
chemotherapy versus chemotherapy alone.
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 with MSD (Merck &
Co., Inc. inside 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 (LSE/STO/Nasdaq: AZN) 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.com and follow the
Company on Twitter @AstraZeneca.
References
- ASCO. Liver Cancer: View All Pages. Available at:
https://www.cancer.net/cancer-types/liver-cancer/view-all. Accessed
March 2022.
- WHO. Liver Cancer Fact Sheet. Available at:
https://gco.iarc.fr/today/data/factsheets/cancers/11-Liver-fact-sheet.pdf.
Accessed March 2022.
- AstraZeneca data on file. Kantar Health. 2021.
- Abou-Alfa GK, et al. Phase 3 randomized, open-label,
multicenter study of tremelimumab and durvalumab as first-line
therapy in patients with unresectable hepatocellular carcinoma:
HIMALAYA. Presented at ASCO Gastrointestinal Cancers Symposium
2022.
- Tarao K, et al. Real impact of liver cirrhosis on the
development of hepatocellular carcinoma in various liver
diseases—meta‐analytic assessment. Cancer Med.
2019;8(3):1054-1065.
- Colagrande S, et al. Challenges of advanced hepatocellular
carcinoma. World J Gastroenterol. 2016;22(34):7645-7659.
- WHO. World Cancer Fact Sheet. Available at:
https://gco.iarc.fr/today/data/factsheets/cancers/39-All-cancers-fact-sheet.pdf.
Accessed March 2022.
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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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