Longest survival follow-up reported to date
for a Phase III trial in this setting
Updated results from the HIMALAYA Phase III trial showed
AstraZeneca’s IMFINZI® (durvalumab) plus IMJUDO®
(tremelimumab-actl) demonstrated a sustained, clinically meaningful
overall survival (OS) benefit at four years for patients with
unresectable hepatocellular carcinoma (HCC) who had not received
prior systemic therapy and were not eligible for localized
treatment.
These results from HIMALAYA will be presented today at the 2023
European Society for Medical Oncology (ESMO) World Congress on
Gastrointestinal Cancer in Barcelona, Spain (abstract #SO-15).
At four years of follow-up, these latest data show that a single
priming dose of IMJUDO added to IMFINZI, called the STRIDE regimen
(Single Tremelimumab Regular Interval Durvalumab), reduced the risk
of death by 22% compared to sorafenib (based on a hazard ratio [HR]
of 0.78; 95% confidence interval [CI] 0.67-0.92; 78% data
maturity). An estimated 25.2% of patients treated with the STRIDE
regimen were alive at four years versus 15.1% for those treated
with sorafenib. An ad-hoc exploratory analysis showed that the
treatment effects of the STRIDE regimen versus sorafenib were
consistent across all clinically relevant subgroups of patients, as
well as those surviving at least three years, regardless of the
underlying disease cause (hepatitis B virus [HBV], hepatitis C
virus [HCV] or nonviral) or other baseline demographics.
Bruno Sangro, MD, PhD, Director of the Liver Unit and Professor
of Internal Medicine at Clínica Universidad de Navarra, Pamplona,
Spain and a lead investigator in the trial, said: “Historically,
only seven percent of patients with advanced liver cancer have
survived five years, making the HIMALAYA long-term survival data
especially meaningful. One in four patients treated with the STRIDE
regimen were still alive at four years, reinforcing this novel
regimen as a standard of care in this setting.”
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “The remarkable four-year survival benefit shown
with IMFINZI and IMJUDO in this advanced liver cancer setting
supports the use of the STRIDE regimen to treat a broad, eligible
patient population globally. These latest results from HIMALAYA are
part of a series of clinical trials aiming to deliver innovative
treatments for patients at different stages of liver cancer.”
Summary of updated results: HIMALAYA
STRIDE regimen
Sorafenib
OSi, ii
(n=393)
(n=389)
Number of patients with events (%)
291 (74.0)
316 (81.2)
Median OS, in months (95% CI)
16.4 (14.2-19.6)
13.8 (12.3-16.1)
Median duration of follow-up in censored
patients, in months (95% CI)
49.12
(46.95-50.17)
47.31
(45.08-49.15)
Hazard ratio (95% CI)
0.78 (0.67-0.92)
p-value (2-sided)
0.0037
OS rate at 36 months
30.7%
19.8%
OS rate at 48 months
25.2%
15.1%
- Updated analysis data cut-off: 23 January 2023, with 78%
overall OS data maturity
- OS HRs and 95% CIs were calculated using a Cox proportional
hazards model adjusting for treatment, aetiology, ECOG performance
status, and macrovascular invasion. The OS rate at 36-months had a
nominal 2-sided p-value of 0.0006.
The safety profile of the STRIDE regimen was consistent with the
known profiles of each medicine, and no new safety signals were
observed with longer follow-up. Serious treatment-related adverse
events (TRAEs), defined as Grade 3 or 4 and including death, were
experienced by 17.5% of patients treated with the STRIDE regimen
versus 9.6% of patients treated with sorafenib, with no new events
occurring after the primary analysis for STRIDE (17.5%).
IMFINZI in combination with IMJUDO is approved for the treatment
of adults with advanced or unresectable HCC in the US, EU (in the
1st-line setting), Japan and several other countries. IMFINZI
monotherapy is also approved in Japan in this setting.
IMPORTANT SAFETY INFORMATION
There are no contraindications for IMFINZI® (durvalumab) or
IMJUDO® (tremelimumab-actl).
Severe and Fatal 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 clinical
chemistries including liver enzymes, creatinine,
adrenocorticotropic hormone (ACTH) level, and thyroid function at
baseline and before each dose. 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 and IMJUDO
depending on severity. See USPI Dosing and Administration for
specific details. In general, if combination of IMFINZI and IMJUDO
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 in combination with IMJUDO can cause immune-mediated
pneumonitis, which may be fatal. Immune‑mediated pneumonitis
occurred in 1.3% (5/388) of patients receiving IMFINZI and IMJUDO,
including fatal (0.3%) and Grade 3 (0.2%) adverse reactions.
Immune-Mediated Colitis
IMFINZI in combination with IMJUDO 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 or diarrhea occurred in 6% (23/388) of
patients receiving IMFINZI and IMJUDO, including Grade 3 (3.6%)
adverse reactions. Intestinal perforation has been observed in
other studies of IMFINZI and IMJUDO.
Immune-Mediated
Hepatitis
IMFINZI in combination with IMJUDO can cause immune-mediated
hepatitis, which may be fatal. Immune‑mediated hepatitis occurred
in 7.5% (29/388) of patients receiving IMFINZI and IMJUDO,
including fatal (0.8%), Grade 4 (0.3%) and Grade 3 (4.1%) adverse
reactions.
Immune-Mediated
Endocrinopathies
- Adrenal Insufficiency: IMFINZI in combination with
IMJUDO 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 1.5% (6/388) of
patients receiving IMFINZI and IMJUDO, including Grade 3 (0.3%)
adverse reactions.
- Hypophysitis: IMFINZI in combination with IMJUDO 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. Immune-mediated
hypophysitis/hypopituitarism occurred in 1% (4/388) of patients
receiving IMFINZI and IMJUDO.
- Thyroid Disorders (Thyroiditis, Hyperthyroidism, and
Hypothyroidism): IMFINZI in combination with IMJUDO 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.
- Immune-mediated thyroiditis occurred in 1.5% (6/388) of
patients receiving IMFINZI and IMJUDO.
- Immune-mediated hyperthyroidism occurred in 4.6% (18/388) of
patients receiving IMFINZI and IMJUDO, including Grade 3 (0.3%)
adverse reactions.
- Immune-mediated hypothyroidism occurred in 11% (42/388) of
patients receiving IMFINZI and IMJUDO.
- 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. Two patients 0.5% (2/388) had events of
hyperglycemia requiring insulin therapy that had not resolved at
last follow-up.
Immune-Mediated Nephritis with Renal
Dysfunction
IMFINZI in combination with IMJUDO can cause immune-mediated
nephritis. Immune-mediated nephritis occurred in 1% (4/388) of
patients receiving IMFINZI and IMJUDO, including Grade 3 (0.5%)
adverse reactions.
Immune-Mediated Dermatology
Reactions
IMFINZI in combination with IMJUDO 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 and CTLA-4 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 4.9% (19/388) of patients receiving IMFINZI
and IMJUDO, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse
reactions.
Immune-Mediated
Pancreatitis
IMFINZI in combination with IMJUDO can cause immune-mediated
pancreatitis. Immune-mediated pancreatitis occurred in 2.3% (9/388)
of patients receiving IMFINZI and IMJUDO, including Grade 4 (0.3%)
and Grade 3 (1.5%) 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 in combination with IMJUDO or were reported
with the use of other immune-checkpoint inhibitors.
- 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: 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 and IMJUDO 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 and IMJUDO 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 10
(2.6%) patients receiving IMFINZI and IMJUDO.
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,
both IMFINZI and IMJUDO 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 IMJUDO and advise them to
use effective contraception during treatment with IMFINZI and
IMJUDO and for 3 months after the last dose of IMFINZI and
IMJUDO.
Lactation
There is no information regarding the presence of either IMFINZI
or IMJUDO in human milk; however, because of the potential for
serious adverse reactions in breastfed infants from IMFINZI and
IMJUDO, advise women not to breastfeed during treatment and for 3
months after the last dose.
Adverse Reactions
- In patients with unresectable HCC in the HIMALAYA study
receiving IMFINZI and IMJUDO, the most common adverse reactions
(occurring in ≥20% of patients) were rash, diarrhea, fatigue,
pruritus, musculoskeletal pain, and abdominal pain.
- In patients with unresectable HCC in the HIMALAYA study
receiving IMFINZI and IMJUDO, serious adverse reactions occurred in
41% of patients. Serious adverse reactions in >1% of patients
included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia
(2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%),
and anemia (1.3%). Fatal adverse reactions occurred in 8% of
patients who received IMJUDO in combination with durvalumab,
including death (1%), hemorrhage intracranial (0.5%), cardiac
arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and
immune-mediated hepatitis (0.5%). Permanent discontinuation of
treatment regimen due to an adverse reaction occurred in 14% of
patients.
The safety and effectiveness of IMFINZI and IMJUDO have not been
established in pediatric patients.
Indication:
IMFINZI in combination with IMJUDO is indicated for the
treatment of adult patients with unresectable hepatocellular
carcinoma (uHCC).
Please see full Prescribing Information including Medication
Guide for IMFINZI and IMJUDO.
Notes
Liver cancer
Liver cancer is the third-leading cause of cancer death and the
sixth most commonly diagnosed cancer worldwide.1,2 About 75% of all
primary liver cancers in adults are HCC.3 Advanced-stage HCC
prognosis is poor, with a 5-year survival rate of only 7%.4 Between
80-90% of all patients with HCC also have cirrhosis.3 Chronic liver
diseases such as cirrhosis 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. 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 is a randomized, open-label, multicenter, global Phase
III trial of IMFINZI monotherapy and a regimen comprising a single
priming dose of IMJUDO 300mg added to IMFINZI 1500mg followed by
IMFINZI every four weeks (STRIDE regimen) versus sorafenib, a
standard-of-care multi-kinase inhibitor.
The trial included a total of 1,324 randomized 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 was OS for the combination versus sorafenib and
key secondary endpoints included OS for IMFINZI versus sorafenib,
objective response rate and PFS for the combination 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 approved in combination with chemotherapy
(gemcitabine plus cisplatin) in locally advanced or metastatic
biliary tract cancer (BTC) and in combination with IMJUDO®
(tremelimumab-actl) in unresectable hepatocellular carcinoma (HCC)
in the US, EU, Japan and several other countries based on the
TOPAZ-1 and HIMALAYA Phase III trials, respectively.
In addition to its indications in gastrointestinal (GI) cancers,
IMFINZI is the only approved immunotherapy and the global standard
of care in the curative-intent setting of unresectable, Stage III
non-small cell lung cancer (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 small-cell lung cancer (SCLC) based on the CASPIAN
Phase III trial. Additionally, IMFINZI is approved in combination
with a short course of IMJUDO and chemotherapy for the treatment of
metastatic NSCLC in the US, EU and Japan based on the POSEIDON
Phase III trial. IMFINZI is approved in previously treated patients
with advanced bladder cancer in a small number of countries.
Since the first approval in May 2017, more than 200,000 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. In 2023, AstraZeneca announced positive results for Phase
III trials including combinations with IMFINZI in ovarian (DUO-O)
and endometrial (DUO-E) cancers, as well as in resectable NSCLC
(AEGEAN).
In GI cancers specifically, AstraZeneca has several ongoing
registrational trials investigating IMFINZI across multiple liver
cancer settings (EMERALD-1, EMERALD-2 and EMERALD-3), in resectable
gastric and gastroesophageal junction cancers (MATTERHORN) and in
locally advanced esophageal cancer (KUNLUN). In June 2023, IMFINZI
added to standard-of-care neoadjuvant chemotherapy met a key
secondary endpoint of pathologic complete response in the
MATTERHORN Phase III trial.
IMJUDO
IMJUDO® (tremelimumab-actl) is a human monoclonal antibody that
targets the activity of cytotoxic T-lymphocyte-associated protein 4
(CTLA-4). IMJUDO blocks the activity of CTLA-4, contributing to
T-cell activation, priming the immune response to cancer and
fostering cancer cell death.
In addition to its approved indications in liver and lung
cancers, IMJUDO is being tested in combination with IMFINZI across
multiple tumor types including locoregional HCC (EMERALD-3), SCLC
(ADRIATIC) and bladder cancer (VOLGA and NILE).
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.7
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 IMJUDO, in liver,
esophageal and gastric cancers in an extensive development program
spanning early to late-stage disease across settings.
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. 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 by AstraZeneca and Merck & Co., Inc., known as
MSD outside the US and Canada.
AstraZeneca also recently entered into a global exclusive
license agreement with KYM Biosciences Inc. for CMG901. CMG901 is a
potential first-in-class antibody drug conjugate targeting Claudin
18.2, a promising therapeutic target in gastric cancer, currently
in Phase I development.
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 IMJUDO 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 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. For more
information, please visit www.astrazeneca-us.com and follow us on
Twitter @AstraZenecaUS.
References
- ASCO. Liver Cancer: View All Pages. Available at:
https://www.cancer.net/cancer-types/liver-cancer/view-all. Accessed
June 2023.
- WHO. Liver Cancer Fact Sheet. Available at:
https://gco.iarc.fr/today/data/factsheets/cancers/11-Liver-fact-sheet.pdf.
Accessed June 2023.
- ASCO. Liver Cancer: View All Pages. Available at:
https://www.cancer.net/cancer-types/liver-cancer/view-all. Accessed
June 2023.
- Sayiner M, et al. Disease Burden of Hepatocellular Carcinoma: A
Global Perspective. Digestive Diseases and Sciences. 2019; 64:
910-917.
- 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/populations/900-world-fact-sheets.pdf.
Accessed June 2023.
US-77474 Last Updated 06/23
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Media Inquiries Brendan McEvoy, +1 302 885 2677 Chelsea
Ford, +1 302 885 2677 US Media Mailbox:
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