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IMFINZI® (durvalumab) plus transarterial chemoembolization (TACE) and bevacizumab reduced the risk of disease progression or death by 23% vs. TACE in liver cancer eligible for embolization

EMERALD-1 is first global Phase III trial to show improved clinical outcome for systemic therapy in combination with TACE in this setting

Positive results from the EMERALD-1 Phase III trial showed AstraZeneca’s IMFINZI® (durvalumab) in combination with TACE and bevacizumab demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of progression-free survival (PFS) compared to TACE alone in patients with hepatocellular carcinoma (HCC) eligible for embolization.

These results will be presented today at the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI) in San Francisco, California (#LBA432).

Approximately 20-30% of patients with HCC, the most common type of liver cancer, are eligible for embolization, a procedure that blocks the blood supply to the tumor and can also deliver chemotherapy or radiation therapy directly to the liver.1-8 Despite being the standard of care in this setting, most patients who receive embolization experience disease progression or recurrence within eight months.9-11

In EMERALD-1, treatment with IMFINZI plus TACE and bevacizumab reduced the risk of disease progression or death by 23% compared to TACE alone (based on a hazard ratio [HR] of 0.77; 95% confidence interval [CI] 0.61-0.98; p=0.032). Median PFS was 15 months in patients treated with the IMFINZI combination versus 8.2 months with TACE. The PFS benefit observed was generally consistent across key prespecified subgroups. The secondary endpoint of time to progression (TTP) further supports the clinical benefit of IMFINZI plus TACE and bevacizumab in this setting, with a median TTP of 22 months versus 10 months for TACE (HR 0.63; 95% CI 0.48-0.82).

The trial will continue as planned to assess the key secondary endpoint of overall survival (OS).

Bruno Sangro, MD, PhD, Director of the Liver Unit and Professor of Medicine at Clínica Universidad de Navarra, Pamplona, Spain and a lead investigator in the EMERALD-1 trial, said: “In this earlier liver cancer setting, embolization alone has been the standard of care for more than 20 years, and rates of disease progression have remained high. Adding durvalumab and bevacizumab to TACE reduced the risk of disease progression or death by twenty-three per cent for patients with liver cancer eligible for embolization, showing for the first time that combining a systemic treatment with TACE meaningfully improves this clinically relevant outcome in earlier-stage disease.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “With IMFINZI-based treatment, patients with liver cancer eligible for embolization lived nearly seven additional months before their disease progressed. We are discussing these positive EMERALD-1 data with global regulatory authorities while awaiting the final overall survival results from the trial.”

Summary of results: EMERALD-1i

 

IMFINZI plus TACE and bevacizumab

(n=204)

Placebo plus TACE

(n=205)

Median PFS (months; 95% CI)ii, iii

15.0 (11.1-18.9)

8.2 (6.9-11.1)

PFS HR (95% CI)ii, iv

0.77 (0.61-0.98)

p-valuev

0.032

PFS rate at 12 months (%)iii

55.5

39.8

PFS rate at 18 months (%)iii

43.1

28.3

Median TTP (months; 95% CI)iii, v

22.0 (16.6-24.9)

10.0 (7.1-13.6)

TTP HR (95% CI)iv, v

0.63 (0.48-0.82)

Subjects with measurable disease

IMFINZI plus TACE and bevacizumab

(n=202)

Placebo plus TACE

(n=203)

Objective Response Rate (ORR) (%)iii

43.6

29.6

i The data cut-off date was Sept 11, 2023.

ii PFS, TTP and ORR by Blinded Independent Central Review (BICR) per RECIST v1.1

iii Calculated using Kaplan-Meier method

iv Calculated from stratified Cox proportional hazards method

v The threshold of significance for this analysis was 0.0435 based on the alpha spend at the PFS interim analysis (2.27%) and the actual number of events at PFS final analysis.

 

The safety profile for IMFINZI plus TACE and bevacizumab was generally manageable and consistent with the known profile of each medicine. The number of TACE procedures was consistent across arms. No new safety signals were observed. Grade 3 and 4 adverse events due to any cause occurred in 45.5% of patients treated with IMFINZI plus TACE and bevacizumab and 23% of patients treated with TACE alone.

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, 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 (n=388), the most common adverse reactions (occurring in ≥20% of patients) were rash (32%), diarrhea (27%), fatigue (26%), pruritus (23%), musculoskeletal pain (22%), and abdominal pain (20%).
  • In patients with unresectable HCC in the HIMALAYA study receiving IMFINZI and IMJUDO (n=388), 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, of which HCC is the most common type, is the third-leading cause of cancer death, with an estimated 900,000 people worldwide diagnosed each year and a high prevalence in certain regions of Asia.12-14 An estimated 80-90% of all patients with HCC also have cirrhosis.15 Chronic liver diseases such as cirrhosis are associated with inflammation that over time can lead to the development of HCC.15 Immunotherapy is a proven treatment modality in HCC with approved options available for patients in later-line settings.16

EMERALD-1

EMERALD-1 is a randomized, double-blind, placebo-controlled, multicenter, global Phase III trial of IMFINZI plus TACE concurrently, followed by IMFINZI with or without bevacizumab until progression versus TACE alone in a total of 616 patients with unresectable HCC eligible for embolization.

The trial was conducted in 157 centers across 18 countries, including in North America, Australia, Europe, South America and Asia. The primary endpoint was PFS for IMFINZI plus TACE and bevacizumab versus TACE alone, and secondary endpoints include PFS for IMFINZI plus TACE, OS, patient-reported outcomes and ORR.

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 HCC in the US, EU, Japan, China and many other countries based on the TOPAZ-1 and HIMALAYA Phase III trials, respectively. Following HIMALAYA in the advanced setting, EMERALD-1 is AstraZeneca’s second positive Phase III trial in HCC.

In non-small cell lung cancer (NSCLC), 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 also 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, the results of which have been confirmed in the real-world setting in the PACIFIC-R study. In 2023, AstraZeneca announced positive results from the AEGEAN Phase III trial evaluating IMFINZI in combination with neoadjuvant chemotherapy before surgery and as adjuvant monotherapy after surgery in resectable NSCLC.

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. 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, breast cancer and other solid tumors. In 2023, AstraZeneca announced positive results for several Phase III trials evaluating IMFINZI in various combinations, including in ovarian (DUO-O) and endometrial (DUO-E) cancers with olaparib.

In GI cancers specifically, AstraZeneca has an extensive clinical development program further assessing IMFINZI across multiple settings. In addition to EMERALD-1, IMFINZI is also being investigated in combination with bevacizumab in adjuvant HCC (EMERALD-2), in combination with IMJUDO, lenvatinib and TACE in embolization-eligible HCC (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.

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.17

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 with IMJUDO in 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 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, that is 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 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. Please visit www.astrazeneca-us.com and follow us on social media @AstraZeneca.

References

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  2. Park JW, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int. 2015;35(9):2155-2166.
  3. Henriksson M, et al. Treatment patterns and survival in patients with hepatocellular carcinoma in the Swedish national registry SweLiv. BJS Open. 2020;4(1):109-117.
  4. Wehling C, et al. Treatment stage migration and treatment sequences in patients with hepatocellular carcinoma: drawbacks and opportunities. J Cancer Res Clin Oncol. 2021;147(8):2471-2481.
  5. Fukuda H, et al. Differences in healthcare expenditure estimates according to statistical approach: A nationwide claims database study on patients with hepatocellular carcinoma. PLoS ONE. 2020;15(8):e0237316.
  6. Akada K, et al. Database analysis of patients with hepatocellular carcinoma and treatment flow in early and advanced stages. Pharmacol Res Perspect. 2019;7(4):e00486.
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  8. National Cancer Institute. Embolization. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/embolization. Accessed January 2024.
  9. Lencioni R, et al. Lipiodol transarterial chemoembolization for hepatocellular carcinoma: A systematic review of efficacy and safety data. Hepatology. 2016;64:106-116.
  10. Young S, et al. Local recurrence following complete radiologic response in patients treated with transarterial chemoembolization for hepatocellular carcinoma. Diagn Interv Imaging. 2022;103(3):143-149.
  11. Llovet JM, et al. Trial design and endpoints in hepatocellular carcinoma: AASLD consensus conference. Hepatology. 2021;73(Suppl 1):158-191.
  12. ASCO. Liver Cancer: View All Pages. Available at: https://www.cancer.net/cancer-types/liver-cancer/view-all. Accessed January 2024.
  13. WHO. Liver Cancer Fact Sheet. Available at: https://gco.iarc.fr/today/data/factsheets/cancers/11-Liver-fact-sheet.pdf. Accessed January 2024.
  14. Liu Y, et al. Changes in the Epidemiology of Hepatocellular Carcinoma in Asia. Cancers (Basel). 2022;14(18):4473.
  15. 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.
  16. Colagrande S, et al. Challenges of advanced hepatocellular carcinoma. World J Gastroenterol. 2016;22(34):7645-7659.
  17. World Health Organization. World Fact Sheet. Available at: https://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf. Accessed January 2024.

US-84597 Last Updated 01/24

 

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