Open label, single arm, multi-centre study of pembrolizumab following trans-arterial chemoembolization (TACE). Twenty-six to 32 evaluable participants with primary liver cancer (hepatocellular cancer; HCC) will be assessed. The primary objective is to determine the safety and tolerability of pembrolizumab following TACE. The secondary objective is to evaluate the efficacy of pembrolizumab following TACE by improving progression-free survival rates as measured by modified response evaluation criteria in solid tumours (mRECIST) criteria.

Inclusion Criteria:

1. Be willing and able to provide written informed consent/assent for the trial.
2. Be ≥ 18 years of age on day of signing informed consent.
3. Be willing to provide tissue from an excisional biopsy of a tumour lesion.
4. Have at least one uni-dimensional lesion measurable by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI) based on mRECIST criteria.
5. Be ineligible for surgical resection or liver transplantation.
6. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
7. Demonstrate adequate organ function
8. Have an overall Child-Pugh score <7
9. Female subject of childbearing potential should have a negative urine or serum pregnancy. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
10. Women of childbearing potential must be willing to use a highly effective method of contraception as outlined in Section 6.9.2 for the course of the study through 120 days after the last dose of Investigational Medicinal Product (IMP). Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
11. Sexually active males must agree to use an adequate method of contraception as outlined in Section 6.9.2 starting with the first dose of IMP through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

1. Has extrahepatic metastasis.
2. Prior TACE or systemic anticancer treatment for HCC.
3. Has any contraindication for TACE including portosystemic shunt, hepatofugal blood flow, known severe atheromatosis.
4. Has history of bleeding within the 4 weeks preceding study enrolment.
5. Has hepatic encephalopathy.
6. Has ascites that is refractory to diuretic therapy.
7. Has documented occlusion of the hepatic artery or the main portal vein (segmental portal vein thrombosis does not represent exclusion criterion provided this does not contraindicate TACE).
8. Is currently participating and receiving therapy or has participated or is participating in a study of an IMP or used an investigational device within 4 weeks of the first dose of IMP.
9. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy.
10. Has a known history of active Bacillus Tuberculosis (TB)
11. Hypersensitivity to Pembrolizumab or any of its excipients.
12. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
13. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
14. Has known history of, or any evidence of active, non-infectious pneumonitis.
15. Has an active infection requiring systemic therapy. Exceptions relating to Hepatitis B and C virus infection are documented in Section 5.3.1, Table 5.
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Principal Investigator (PI).
17. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
18. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through to 120 days after the last dose of IMP.
19. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2 agent.
20. Has a known history of Human Immunodeficiency Virus (HIV; HIV 1/2 antibodies).
21. Has received a live vaccine within 30 days of first dose of IMP administration. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

Through study completion , an average of 1.5 years.

CTCAE version v5

Limitations include, limited sample size, lack of control arm and the Impact of Coronavirus disease pandemic, which made recruitment and retention of participants to the investigator-led clinical trial difficult, leading to reduction in the number of sample available for translational analysis.