Results from the global Phase II Study 22 trial testing AstraZeneca’s tremelimumab, an anti-CTLA4 antibody and potential new medicine, added to IMFINZI® (durvalumab) demonstrated promising clinical activity and tolerability in patients with advanced hepatocellular carcinoma (HCC). HCC is the most common type of liver cancer.1
In the primary endpoint of the trial evaluating safety, all experimental arms demonstrated an acceptable profile and no new safety signals were identified. Patients treated with a single, priming dose of tremelimumab 300mg added to durvalumab every four weeks (T300+D regimen) achieved a median overall survival (OS) of 18.7 months in a key secondary endpoint. The OS result for the T300+D regimen was the longest among treatments tested in the trial, which included IMFINZI monotherapy, tremelimumab monotherapy and two regimens of the two combined.
In other key secondary endpoints, objective response rate (ORR) confirmed by independent central review was 24% with the T300+D regimen, and median duration of response (DoR) was not yet reached at the time of data cut-off. A unique T-cell profile for patients in the T300+D arm was associated with treatment response, suggesting complementary biological activity.
R. Kate Kelley, MD, Associate Professor of Clinical Medicine, Department of Medicine, University of California San Francisco and principal investigator said, “In Study 22, we were able to induce a stronger immune response and enhance the clinical activity of IMFINZI in patients with advanced liver cancer by combining with a single dose of tremelimumab, a novel approach designed to prime the immune response using CTLA-4 inhibition at the start of therapy. These exciting results suggest that dual checkpoint blockade with tremelimumab and IMFINZI may have a role in a challenging cancer where patients have few treatment options.”
José Baselga, Executive Vice President, Oncology R&D, said, “Based on these compelling results, we see the potential for a single, priming dose of tremelimumab plus IMFINZI to change the treatment landscape and improve outcomes for patients with advanced liver cancer, a setting where new treatments are urgently needed. The Study 22 data are also an encouraging sign for our Phase III HIMALAYA trial testing this regimen in liver cancer, with data expected later this year.”
Summary of Results
Study 22 Safety and Efficacy
T300i mg x 1 dose + D1500ii mg Q4W
D1500ii mg Q4W
T750i mg Q4W x 7 doses, Q12W thereafter
T75i mg x 4 doses + D1500ii mg Q4W
Median Total Treatment Duration, months (min.-max.)
Grade 3/4 trAEsiii, n (%)
Serious trAEsiii, n (%)
Grade 5 trAEsiii, n (%)
Discontinuation due to trAEsiii, n (%)
Median OS, months (95% CI)
ORR, % (95% CI)
Median DoR, months
- Treatment-related adverse events
- Not reached
Results evaluating safety and efficacy from parts two and three of the Phase II Study 22 trial were presented during the 2020 American Society of Clinical Oncology ASCO20 Virtual Scientific Program on Friday, May 29, 2020.
IMFINZI is not currently approved to treat HCC in any country, alone or in combination with tremelimumab. In January 2020, IMFINZI and tremelimumab were granted Orphan Drug Designation in the US for the treatment of HCC.
Important Safety Information
There are no contraindications for IMFINZI® (durvalumab).
IMFINZI can cause serious, potentially fatal adverse reactions including immune-mediated pneumonitis, hepatitis, colitis, endocrinopathies, nephritis, dermatologic reactions, other immune-mediated adverse reactions, infection, and infusion-related reactions. Please refer to the full Prescribing Information for important dosage modification and management information specific to adverse reactions.
IMFINZI can cause immune-mediated pneumonitis, defined as requiring use of corticosteroids. Fatal cases have been reported. Monitor patients for signs and symptoms of pneumonitis and evaluate with radiographic imaging when suspected. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold IMFINZI for Grade 2 pneumonitis; permanently discontinue for Grade 3 or 4 pneumonitis.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, pneumonitis occurred in 5% of patients, including Grade 3 (0.8%), Grade 4 (<0.1%), and Grade 5 (0.3%) pneumonitis. Pneumonitis led to discontinuation of IMFINZI in 1.5% of the 1889 patients. The incidence of pneumonitis (including radiation pneumonitis) was higher in patients in the PACIFIC study who completed treatment with definitive chemoradiation within 42 days prior to initiation of IMFINZI (34%) compared to patients in other clinical studies (2.3%) in which radiation therapy was generally not administered immediately prior to initiation of IMFINZI. In the PACIFIC study, the incidence of Grade 3 pneumonitis was 3.4% and of Grade 5 pneumonitis was 1.1% in the IMFINZI arm. In the PACIFIC study, pneumonitis led to discontinuation of IMFINZI in 6% of patients.
The frequency and severity of immune-mediated pneumonitis were similar whether IMFINZI was given as a single agent in patients with various cancers or in combination with chemotherapy in patients with ES-SCLC.
IMFINZI can cause immune-mediated hepatitis, defined as requiring use of corticosteroids. Fatal cases have been reported. Monitor patients for signs and symptoms of hepatitis during and after discontinuation of IMFINZI, including clinical chemistry monitoring. Administer corticosteroids for Grade 2 or higher elevations of ALT, AST, and/or total bilirubin. Withhold IMFINZI for ALT or AST greater than 3 but less than or equal to 8 times the ULN or total bilirubin greater than 1.5 but less than or equal to 5 times the ULN; permanently discontinue IMFINZI for ALT or AST greater than 8 times the ULN or total bilirubin greater than 5 times the ULN or concurrent ALT or AST greater than 3 times the ULN and total bilirubin greater than 2 times the ULN with no other cause.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, hepatitis occurred in 12% of patients, including Grade 3 (4.4%), Grade 4 (0.4%), and Grade 5 (0.2%) hepatitis. Hepatitis led to discontinuation of IMFINZI in 0.7% of the 1889 patients.
IMFINZI can cause immune-mediated colitis, defined as requiring use of corticosteroids. Administer corticosteroids for Grade 2 or greater colitis or diarrhea. Withhold IMFINZI for Grade 2 colitis or diarrhea; permanently discontinue for Grade 3 or 4 colitis or diarrhea.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, colitis or diarrhea occurred in 18% of patients, including Grade 3 (1.0%) and Grade 4 (0.1%) immune-mediated colitis. Diarrhea or colitis led to discontinuation of IMFINZI in 0.4% of the 1889 patients.
IMFINZI can cause immune-mediated endocrinopathies, including thyroid disorders, adrenal insufficiency, type 1 diabetes mellitus, and hypophysitis/hypopituitarism. Monitor patients for clinical signs and symptoms of endocrinopathies.
- Thyroid disorders—Monitor thyroid function prior to and periodically during treatment. Initiate hormone replacement therapy or medical management of hyperthyroidism as clinically indicated. Withhold IMFINZI for Grades 2–4 hyperthyroidism, until clinically stable. Continue IMFINZI for hypothyroidism.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, hypothyroidism occurred in 11% of patients, while hyperthyroidism occurred in 7% of patients. Thyroiditis occurred in 0.9% of patients, including Grade 3 (<0.1%) thyroiditis. Hypothyroidism was preceded by thyroiditis or hyperthyroidism in 25% of patients.
- Adrenal insufficiency—Administer corticosteroids as clinically indicated and withhold IMFINZI until clinically stable for Grade 2 or higher adrenal insufficiency. In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, adrenal insufficiency occurred in 0.7% of patients, including Grade 3 (<0.1%) adrenal insufficiency.
- Type 1 diabetes mellitus—Initiate treatment with insulin as clinically indicated. Withhold IMFINZI for Grades 2–4 type 1 diabetes mellitus, until clinically stable. In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, type 1 diabetes mellitus occurred in <0.1% of patients.
- Hypophysitis—Administer corticosteroids and hormone replacement as clinically indicated and withhold IMFINZI until clinically stable for Grade 2 or higher hypophysitis. Hypopituitarism leading to adrenal insufficiency and diabetes insipidus occurred in <0.1% of 1889 patients with various cancers who received IMFINZI.
IMFINZI can cause immune-mediated nephritis, defined as evidence of renal dysfunction requiring use of corticosteroids. Fatal cases have occurred. Monitor patients for abnormal renal function tests prior to and periodically during treatment with IMFINZI. Administer corticosteroids as clinically indicated. Withhold IMFINZI for creatinine greater than 1.5 to 3 times the ULN; permanently discontinue IMFINZI and administer corticosteroids in patients with creatinine greater than 3 times the ULN.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, nephritis (reported as any of the following: increased creatinine or urea, acute kidney injury, renal failure, decreased glomerular filtration rate, tubulointerstitial nephritis, decreased creatinine clearance, glomerulonephritis, and nephritis) occurred in 6.3% of the patients including Grade 3 (1.1%), Grade 4 (0.2%), and Grade 5 (0.1%) nephritis. IMFINZI was discontinued in 0.3% of the 1889 patients.
Immune-Mediated Dermatologic Reactions
IMFINZI can cause immune-mediated rash. Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN) has occurred with other products in this class. Administer corticosteroids for Grade 2 rash or dermatitis lasting for more than 1 week or for Grade 3 or 4 rash or dermatitis. Withhold IMFINZI for Grade 2 rash or dermatitis lasting longer than 1 week or Grade 3 rash or dermatitis; permanently discontinue IMFINZI in patients with Grade 4 rash or dermatitis.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, 26% of patients developed rash or dermatitis and 0.4% of the patients developed vitiligo. Rash or dermatitis led to discontinuation of IMFINZI in 0.1% of the 1889 patients.
Other Immune-Mediated Adverse Reactions
IMFINZI can cause severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system. While immune-mediated reactions usually manifest during treatment with IMFINZI, immune-mediated adverse reactions can also manifest after discontinuation of IMFINZI. For suspected immune-mediated adverse reactions, exclude other causes and initiate corticosteroids as clinically indicated. Withhold IMFINZI for Grade 3 immune-mediated adverse reactions, unless clinical judgment indicates discontinuation; permanently discontinue IMFINZI for Grade 4 adverse reactions.
The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in 1889 patients who received IMFINZI: aseptic meningitis, hemolytic anemia, immune thrombocytopenic purpura, myocarditis, myositis, and ocular inflammatory toxicity, including uveitis and keratitis. Additional clinically significant immune-mediated adverse reactions have been seen with other products in this class (see Warnings and Precautions Section 5.7 of IMFINZI full Prescribing Information).
IMFINZI can cause serious infections, including fatal cases. Monitor patients for signs and symptoms of infection and treat as clinically indicated. Withhold IMFINZI for Grade 3 or 4 infection, until clinically stable.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, infections occurred in 43% of patients, including Grade 3 (8%), Grade 4 (1.9%), and Grade 5 (1.0%). The overall incidence of infections in IMFINZI-treated patients in the PACIFIC study (56%) was higher compared to patients in other clinical studies (38%) in which radiation therapy was generally not administered immediately prior to initiation of IMFINZI. In patients with UC in Study 1108 (n=182), the most common Grade 3 or higher infection was urinary tract infections, which occurred in 4% of patients. In patients with Stage III NSCLC in the PACIFIC study, the most common Grade 3 or higher infection was pneumonia, which occurred in 5% of patients.
IMFINZI can cause severe or life-threatening infusion-related reactions. Monitor patients for signs and symptoms of an infusion-related reaction. Interrupt or slow the rate of infusion for Grades 1–2 infusion-related reactions; permanently discontinue for Grades 3–4 infusion-related reactions.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, infusion-related reactions occurred in 2.2% of patients, including Grade 3 (0.3%).
Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. There are no data on the use of IMFINZI in pregnant women. Advise pregnant women of the potential risk to a fetus and advise women of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of IMFINZI.
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.
Most Common Adverse Reactions
- In patients with UC in Study 1108 (n=182), the most common adverse reactions (≥15%) were fatigue (39%), musculoskeletal pain (24%), constipation (21%), decreased appetite (19%), nausea (16%), peripheral edema (15%), and urinary tract infection (15%). The most common Grade 3 or 4 adverse reactions (≥3%) were fatigue, urinary tract infection, musculoskeletal pain, abdominal pain, dehydration, and general physical health deterioration
- In patients with UC in Study 1108, discontinuation due to adverse reactions occurred in 3.3% of patients. Serious adverse reactions occurred in 46% of patients. The most frequent serious adverse reactions (>2%) were acute kidney injury (4.9%), urinary tract infection (4.4%), musculoskeletal pain (4.4%), liver injury (3.3%), general physical health deterioration (3.3%), sepsis, abdominal pain, and pyrexia/tumor associated fever (2.7% each)
- In patients with Stage III NSCLC in the PACIFIC study (IMFINZI n=475), the most common adverse reactions (≥20% of patients) 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 (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% of patients) 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 (n=265), the most common adverse reactions (≥20%) were nausea, fatigue/asthenia, and alopecia. 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 (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.
IMFINZI is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who:
- Have disease progression during or following platinum-containing chemotherapy.
- Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
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 TO EDITORS
About Study 22
Study 22 is an open-label, multicenter, global, four-part Phase II trial evaluating the safety and efficacy of several treatments in 433 patients with advanced HCC in the 1st- or 2nd-line setting. The first part of the trial evaluated the safety of the tremelimumab plus IMFINZI combination. Parts two and three are evaluating IMFINZI monotherapy, tremelimumab monotherapy, and tremelimumab plus IMFINZI combination therapy, and part four evaluates bevacizumab plus IMFINZI combination therapy. Results presented are for 332 patients in parts two and three, who were evaluated for safety and efficacy with a data cut-off of 28 February 2020. The trial is being conducted in 45 centers across 9 countries, including in the US, Europe, and Asia. Primary endpoints include number of patients reporting adverse events and serious adverse events, and number of patients experiencing dose-limiting toxicities. Secondary endpoints include overall survival, objective response rate, and duration of response.
About Liver Cancer
Liver cancer is the fifth leading cause of cancer death in the US, with approximately 20% of patients alive five years after diagnosis.2,3 HCC represents about 75-80% of all primary liver cancers.1,4 Between 80-90% of all patients with HCC also have chronic liver disease, which is primarily caused by infection with the hepatitis B or C viruses.5,6 Chronic liver disease is associated with inflammation that, over time, results in immunosuppression and can lead to the development of HCC.7,8 The unique immune environment of liver cancer provides clear rationale for researching medicines that harness the power of the immune system to treat HCC.9 A critical unmet need exists for patients with HCC who face limited treatment options. More than half of patients are diagnosed at advanced stages of the disease, often when symptoms first appear.10,11
HIMALAYA is a randomized, open-label, multicenter, global Phase III trial of IMFINZI monotherapy and the T300+D regimen including a single, priming dose of tremelimumab 300mg added to IMFINZI every four weeks versus the standard-of-care medicine sorafenib, a multi-kinase inhibitor, in 1,324 patients with unresectable, advanced HCC who have not been treated with prior systemic therapy and are not eligible for locoregional therapy (treatment localized to the liver and surrounding tissue). The trial is being conducted in 189 centers across 16 countries, including in the US, Canada, Europe, South America and Asia. The primary endpoint is overall survival and key secondary endpoints include objective response rate and progression-free survival. HIMALAYA is the first Phase III trial to test dual immune checkpoint blockade in the 1st-line advanced HCC setting.
About IMFINZI® (durvalumab)
IMFINZI is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumor's immune-evading tactics and releasing the inhibition of immune responses.
IMFINZI is approved in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) after chemoradiation therapy in the US, Japan, China, across the EU and in many other countries, based on the Phase III PACIFIC trial. IMFINZIis approved for the 1st-line treatment of extensive-stage small cell lung cancer (ES-SCLC) in combination with SoC chemotherapy in the US and Singapore. IMFINZI is also approved for previously treated patients with advanced bladder cancer in the US and a small number of other countries.
As part of a broad development program, IMFINZI is also being tested as a monotherapy and in combination with tremelimumab, an anti-CTLA4 monoclonal antibody and potential new medicine, as a treatment for patients with NSCLC, SCLC, bladder cancer, head and neck cancer, liver cancer, biliary tract cancer, cervical cancer and other solid tumors.
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. Tremelimumab is being tested in a clinical trial programme in combination with IMFINZI® (durvalumab) in NSCLC, SCLC, bladder cancer, head and neck cancer and liver cancer.
About AstraZeneca Support Programs
AstraZeneca strives to ensure that appropriate patients and their oncologists have access to IMFINZI and relevant support resources. These include educational resources, an Oncology Nurse Educator program and affordability and reimbursement programs, such as Access 360™.
Additionally, AstraZeneca has launched Lighthouse, a program that provides support to patients during any immune-mediated adverse events they may encounter during treatment, through medically trained Lighthouse Advocates. The program aims to make patients’ treatment experience as comfortable as possible. Find out more about Lighthouse at LighthouseProgram.com or call 1-855-LHOUSE1(1-855-546-8731).
About AstraZeneca’s Approach to Immuno-Oncology (IO)
Immuno-oncology (IO) is a therapeutic approach designed to stimulate the body’s immune system to attack tumors. The Company’s IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumor immune suppression. 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 monotherapy and in combination with tremelimumab in multiple tumor types, stages of disease, and lines of therapy, 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, small targeted molecules from across AstraZeneca’s Oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumors.
About AstraZeneca in Oncology
AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients' lives and the Company's future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca's main capabilities, the Company is actively pursuing innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in hematology.
By harnessing the power of four scientific platforms – Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalized combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.
AstraZeneca (LSE/STO/NYSE: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. 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.
- ASCO. Liver Cancer: Introduction. Available at https://www.cancer.net/cancer-types/liver-cancer/introduction. Accessed May 2020.
- National Cancer Institute. Cancer Stat Facts: Common Cancer Sites. Available at: https://seer.cancer.gov/statfacts/html/common.html. Accessed May 2020
- National Cancer Institute. Cancer Stat Facts: Liver and Intrahepatic Bile Duct Cancer. Available at: https://seer.cancer.gov/statfacts/html/livibd.html. Accessed May 2020.
- ASCO. ASCO Answers Liver Cancer. Available at: https://seer.cancer.gov/statfacts/html/common.html. Accessed May 2020.
- Dos Santos P, et al. Incidence of hepatocellular carcinoma in patients with chronic liver disease due to hepatitis B or C and coinfected with the human immunodeficiency virus: a retrospective cohort study. World J Gastroenterol. 2018 February 7; 24(5): 613-622. DOI: 10.3748/wjg.v24.i5.613.
- Hiotis SP, et al. Hepatitis B vs. hepatitis C infection on viral hepatitis-associated hepatocellular carcinoma. BMC Gastroenterol 12, 64 (2012) doi:10.1186/1471-230X-12-64.
- Makarova-Rusher OV, et al. The yin and yang of evasion and immune activation in HCC. J Hepatol. 2015; 62 (6): 1420-1429.
- Del Campo JA., et al. Role of inflammatory response in liver diseases: Therapeutic strategies. World journal of hepatology. 2018; 10(1), 1–7. doi:10.4254/wjh.v10.i1.1.
- Han Y, et al. Human CD141CTLA-41Regulatory Dendritic Cells Suppress T-Cell Response by Cytotoxic T-LymphocyteAntigen-4-Dependent IL-10 and Indoleamine-2,3-Dioxygenase Production in Hepatocellular Carcinoma. Hepatology. 2014 Feb; 59 (2): 567-79.
- Colagrande S, et al. Challenges of advanced hepatocellular carcinoma. World J Gastroenterol. 2016;22(34):7645–7659 doi:10.3748/wjg.v22.i34.7645.
- ACS. Can Liver Cancer Be Found Early? Available at: https://www.cancer.org/cancer/liver-cancer/detection-diagnosis-staging/detection.html. Accessed May 2020.