Results showed that IMFINZI-based treatment
before and after surgery significantly increased the time patients
live without recurrence or progression events
Positive high-level results from a planned interim analysis of
the AEGEAN Phase III, placebo-controlled trial showed that
treatment with AstraZeneca’s IMFINZI® (durvalumab) in combination
with neoadjuvant chemotherapy before surgery and as adjuvant
monotherapy after surgery demonstrated a statistically significant
and clinically meaningful improvement in event-free survival (EFS)
versus neoadjuvant chemotherapy alone followed by surgery for
patients with resectable early-stage (IIA-IIIB) non-small cell lung
cancer (NSCLC).
Results from the final pathologic complete response (pCR) and
major pathologic response (mPR) analyses were consistent with
previously announced positive results. The trial will continue as
planned to assess key secondary endpoints including disease-free
survival (DFS) and overall survival (OS).
Each year there are an estimated 2.2 million people diagnosed
with lung cancer globally with 80-85% of patients diagnosed with
NSCLC, the most common form of lung cancer.1-3 Approximately 25-30%
of all patients with NSCLC are diagnosed early enough to have
surgery with curative intent.4-5 However, only around 56-65% of
patients with Stage II disease will survive for five years.6 This
decreases to 41% for patients with Stage IIIA and 24% for patients
with Stage IIIB disease, reflecting a high unmet medical need.6
John V. Heymach, MD, PhD. Professor and Chair Thoracic/Head and
Neck Medical Oncology, The University of Texas MD Anderson Cancer
Center, said: “Treating patients early with durvalumab both before
and after surgery delivers a significant and clinically meaningful
benefit in resectable non-small cell lung cancer, where new options
are urgently needed to offer patients the best chance of long-term
survival. The AEGEAN results provide compelling evidence that this
novel durvalumab regimen can drive improved outcomes in this
curative-intent setting.”
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “Patients with resectable non-small cell lung
cancer face unacceptably high rates of recurrence, despite
treatment with chemotherapy and surgery. We have shown that adding
IMFINZI both before and after surgery significantly increased the
time patients live without recurrence or progression events. We
will continue to follow patients for overall survival.”
IMFINZI was well tolerated and no new safety concerns were
observed in the neoadjuvant and adjuvant settings. Further, adding
IMFINZI to neoadjuvant chemotherapy was consistent with the known
profile for this combination and did not increase complications or
adverse events, or compromise patients' ability to undergo surgery
versus chemotherapy alone.
These data will be presented at a forthcoming medical meeting
and shared with global health authorities.
AstraZeneca has a comprehensive portfolio of approved and
potential new medicines in development for patients with lung
cancer. In addition to these results, the Company is also
announcing today that osimertinib met a secondary endpoint of OS in
the ADAURA Phase III trial in early-stage (IB, II and IIIA)
epidermal growth factor receptor-mutated (EGFRm) NSCLC after
complete tumor resection with curative intent.
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 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 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 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
The safety and effectiveness of IMFINZI have not been
established in pediatric patients.
Indication:
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.
Please refer to the full Prescribing Information
and Medication Guide for important dosage
modification and management information specific to adverse
reactions.
Notes
Lung cancer
Lung cancer is the leading cause of cancer death among both men
and women, accounting for about one-fifth of all cancer deaths.1
Lung cancer is broadly split into NSCLC and small cell lung cancer
(SCLC).2 The majority of NSCLC patients are diagnosed with advanced
disease while approximately 25-30% present with resectable disease
at diagnosis.4-5 Early-stage lung cancer diagnoses are often only
made when the cancer is found on imaging for an unrelated
condition.7-8
For patients with resectable tumors, the majority eventually
develop recurrence despite complete tumor resection and adjuvant
chemotherapy.9
AEGEAN
AEGEAN is a randomized, double-blind, multi-center,
placebo-controlled global Phase III trial evaluating IMFINZI as
perioperative treatment for patients with resectable Stage IIA-IIIB
(Eighth Edition AJCC Cancer Staging Manual) NSCLC, irrespective of
PD-L1 expression. Perioperative therapy includes treatment before
and after surgery, also known as neoadjuvant/adjuvant therapy. In
the trial, 802 patients were randomized to receive a 1500mg fixed
dose of IMFINZI plus chemotherapy or placebo plus chemotherapy
every three weeks for four cycles prior to surgery, followed by
IMFINZI or placebo every four weeks (for up to 12 cycles) after
surgery. Patients with known EGFR or ALK genomic tumor aberrations
were excluded from the primary efficacy analyses.
In the AEGEAN trial, the primary endpoints were pCR, defined as
no viable tumor in the resection specimen (including lymph nodes)
following neoadjuvant therapy, and EFS, defined as the time from
randomization to an event like tumor recurrence, progression
precluding definitive surgery, or death. Key secondary endpoints
were mPR, defined as residual viable tumor of less than or equal to
10% in the resected primary tumor following neoadjuvant therapy,
DFS, OS, safety and quality of life. The final pathologic response
analyses were performed after all patients had the opportunity for
surgery and pathology assessment per the trial protocol. The trial
enrolled participants in 264 centers in more than 25 countries
including in the US, Canada, Europe, South America and Asia.
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 and the global
standard of care in the curative-intent setting of unresectable,
Stage III NSCLC in patients whose disease has not progressed after
chemoradiation therapy 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 SCLC based on the CASPIAN Phase III trial. In an
exploratory analysis in 2021, updated results from the CASPIAN
trial showed IMFINZI plus chemotherapy tripled patient survival at
three years versus chemotherapy alone. Additionally, IMFINZI is
approved in combination with a short course of tremelimumab and
chemotherapy for the treatment of metastatic NSCLC in the US, EU
and Japan based on the POSEIDON Phase III trial.
In addition to its indications in lung cancer, IMFINZI is also
approved in combination with chemotherapy in locally advanced or
metastatic biliary tract cancer in the US, EU, Japan and several
other countries; in combination with tremelimumab in unresectable
hepatocellular carcinoma in the US, EU and Japan; and in previously
treated patients with advanced bladder cancer in several
countries.
Since the first approval in May 2017, more than 150,000 patients
have been treated with IMFINZI.
AstraZeneca has several ongoing registrational trials focused on
testing IMFINZI in earlier stages of lung cancer, including in
resectable NSCLC (ADJUVANT BR.31) and unresectable NSCLC
(PACIFIC-2, 4, 5, 8 and 9), and in limited-stage SCLC
(ADRIATIC).
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
gastrointestinal (GI) cancers, ovarian cancer, endometrial cancer
and other solid tumors.
AstraZeneca in lung cancer
AstraZeneca is working to bring patients with lung cancer closer
to cure through the detection and treatment of early-stage disease,
while also pushing the boundaries of science to improve outcomes in
the resistant and advanced settings. By defining new therapeutic
targets and investigating innovative approaches, the Company aims
to match medicines to the patients who can benefit most.
The Company's comprehensive portfolio includes leading lung
cancer medicines and the next wave of innovations, including
tremelimumab and gefitinib; IMFINZI and tremelimumab;
fam-trastuzumab deruxtecan-nxki and datopotamab deruxtecan in
collaboration with Daiichi Sankyo; savolitinib in collaboration
with HUTCHMED; as well as a pipeline of potential new medicines and
combinations across diverse mechanisms of action.
AstraZeneca is a founding member of the Lung Ambition Alliance,
a global coalition working to accelerate innovation and deliver
meaningful improvements for people with lung cancer, including and
beyond treatment.
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 aims to reimagine cancer care and help transform
outcomes for patients with IMFINZI as a single treatment and in
combination with tremelimumab as well as other novel
immunotherapies and modalities. The Company is also exploring
next-generation immunotherapies like bispecific antibodies and
therapeutics that harness different aspects of immunity to target
cancer.
AstraZeneca is boldly 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. 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 commercialisation
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
- World Health Organisation. International Agency for Research on
Cancer. Lung Fact Sheet. Available at:
https://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf.
Accessed March 2023.
- LUNGevity Foundation. Types of Lung Cancer. Available at:
https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer.
Accessed March 2023.
- Cheema PK, et al. Perspectives on treatment advances for stage
III locally advanced unresectable non-small-cell lung cancer. Curr
Oncol. 2019;26(1):37-42.
- Cagle PT, et al. Lung Cancer Biomarkers: Present Status and
Future Developments. Arch Pathol Lab Med.
2013;137(9):1191-1198.
- Le Chevalier T. Adjuvant Chemotherapy for Resectable
Non-Small-Cell Lung Cancer: Where is it Going? Ann Oncol.
2010;21:vii196-198.
- Goldstraw P, et al. The IASLC Lung Cancer Staging Project:
Proposals for Revision of the TNM Stage Groupings in the
Forthcoming (Eighth) Edition of the TNM Classification for Lung
Cancer. J Thorac Oncol. 2016;11(1):39-51.
- Sethi S, et al. Incidental Nodule Management – Should There Be
a Formal Process? J Thorac Onc. 2016:8;S494-S497.
- LUNGevity Foundation. Screening and Early Detection. Available
at:
https://lungevity.org/for-patients-caregivers/lung-cancer-101/screening-early-detection.
Accessed March 2023.
- Pignon JP, et al. Lung Adjuvant Cisplatin Evaluation: A Pooled
Analysis by the LACE Collaborative Group. J Clin Oncol.
2008;26(21):3552-3559.
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