A trial of pembrolizumab and lenvatinib for liver cancer (PRIMER-1)

Cancer type:

Liver cancer




Phase 2

This trial is looking at giving pembrolizumab and lenvatinib before surgery for people with liver cancer. 

It is open to people with a type of liver cancer called hepatocellular carcinoma.

More about this trial

Surgery is one of the main treatments for liver cancer. The standard treatment Open a glossary item is to just have surgery. 

In this study researchers want to see if having drugs before and after surgery might help. The drugs they are looking at are pembrolizumab and lenvatinib

Pembrolizumab is an immunotherapy. It works by stimulating the immune system Open a glossary item to find the cancer cells and attack them. Doctors already use pembrolizumab to treat other types of cancer but not liver cancer. 

Lenvatinib is a targeted drug Open a glossary item. It is a cancer growth blocker. Lenvatinib blocks signals that cancer cells need to grow and divide. By blocking these signals it can cause the cancer cell to die.

Lenvatinib also blocks cancer cells from growing new blood vessels. Without new blood vessels the cancer gets less nutrients and oxygen that it needs. This means that it shrinks or stops growing. Doctors use lenvatinib for some cancers including liver cancer that has spread to another part of the body. 

Before surgery you might have:

  • pembrolizumab by itself
  • lenvatinib by itself
  • pembrolizumab and lenvatinib

After surgery everyone has pembrolizumab. 

The aims of the trial are to find out:

  • how well these treatments work
  • whether these treatments reduce the chances of liver cancer coming back after surgery
  • what the side effects are and if they are manageable
  • whether the side effects might delay surgery

Who can enter

The following bullet points are a summary of the entry conditions for this trial. Talk to your doctor or the trial team if you are unsure about any of these. They will be able to advise you. 

Who can take part

You may be able to join this trial if all of the following apply. You:

  • have a type of liver cancer called hepatocellular carcinoma
  • are able to have surgery to remove the cancer
  • have at least 1 area of cancer that the doctor can measure on a scan
  • are willing to have tissue samples (biopsies Open a glossary item) taken
  • have a liver that is working normally. Your doctor will check if it is.
  • are able to swallow capsules
  • have satisfactory blood test results
  • are fully active but might not be able to do heavy physical work (performance status 0 or 1)
  • are willing to use contraception during treatment and for a time after if there is any chance you or your partner could become pregnant
  • are at least 18 years old

Who can’t take part

Cancer related
You cannot join this trial if any of these apply. You:

  • have a mixed type of liver cancer or another type that isn’t hepatocellular carcinoma
  • have cancer that has spread out of the liver or is in a major blood vessel such as the portal vein
  • have had chemotherapy
  • have had treatment that stops cancer growing blood vessels (VEGF Open a glossary item treatment). Your doctor will know if you have had this.
  • have had treatment to the area of cancer in the liver. This includes chemoembolisation (TACE), radiotherapy and heat to destroy the cancer (RFA or MWA).
  • have had an experimental treatment as part of a clinical trial for liver cancer that could not be removed by surgery or that has spread to another part of the body
  • have already had an immunotherapy Open a glossary item drug that works by affecting the T cell Open a glossary item receptors on the cancer cells. Your doctor will know if you have.
  • are bleeding from the cancer within 2 weeks of starting treatment
  • have or had a cancer in the past 3 years that needed treatment or got worse. This is apart from successfully treated non melanoma skin cancer Open a glossary item and carcinoma in situ Open a glossary item

Medical conditions
You cannot join this trial if any of these apply. You:

  • have had bleeding from the veins in your food pipe (oesophagus) or stomach (gastric) within the past 6 months
  • have had an active autoimmune disease Open a glossary item that needed treatment in the past 2 years. This is apart from certain ones such as vitiligo and psoriasis. Your doctor will know what the other ones are.
  • have or have had inflammation of the lungs not caused by an infection or have scarring of the lung tissue and needed steroids to treat it
  • have fluid around the abdomen (ascites) that the doctor finds when they do a physical examination Open a glossary item that cannot be controlled with medication
  • have high blood pressure that isn't controlled. If your blood pressure is controlled with medication there must be no change to the medication within 1 week of randomisation Open a glossary item .
  • have been diagnosed with a change to how your brain normally works due to liver damage in the past 6 months
  • are not able to have a contrast medium Open a glossary item used for scans
  • are not able to have an MRI scan Open a glossary item. This could be because you have a pacemaker, metal in your body such as surgical clips or you have a cochlear implant.
  • have a problem with your digestive system Open a glossary item that could affect how well the body absorbs medication taken by mouth
  • are coughing up blood within the 3 weeks before starting trial treatment
  • have a heart problem Open a glossary item such as a heart attack, congestive heart failure or unstable chest pain (angina) within the past year or you have changes to your heartbeat within 6 months of starting treatment. You might be able to join if the heartbeat changes are controlled with medication. 
  • have a stroke Open a glossary item within 6 months of starting treatment
  • have an abnormal heart rhythm seen on a heart trace (ECG Open a glossary item). Your doctor will do an ECG before you join the trial.
  • have an immune system Open a glossary item that isn’t working well
  • are taking steroids or other medications that damp down the immune system within a week of starting treatment. You might be able to join if you are taking a low dose of steroids. Your doctor will know about this.
  • are at risk of having a major bleed or developing blood clots
  • are taking medication such as warfarin that thins the blood
  • have a large amount of protein in your urine. Your doctor will test a sample of your urine for this.
  • have ongoing side effects from previous treatment that might affect you taking part. Your doctor will know about this.
  • have major surgery to the liver within 4 weeks of starting treatment
  • have ongoing complications from any major surgery
  • have a minor surgery procedure such as removal of a lump within 7 days of starting treatment
  • have a wound, ulcer or broken bone that is not healed or healing
  • have HIV
  • have hepatitis B and hepatitis C or hepatitis B and hepatitis D. You might be able to join if you have hepatitis B only or hepatitis C only as long as they are controlled with medication.
  • have any other active infection that needs treatment such as antibiotics that reaches the whole body (systemic treatment)
  • have a history of active tuberculosis (TB)
  • have had a bone marrow transplant or stem cell transplant from a donor (allogenic transplant Open a glossary item)
  • have had an organ transplant Open a glossary item
  • have had an experimental drug or used a device as part of a clinical trial within 4 weeks of starting treatment
  • have any other medical condition, mental health problem or social situation that could affect you taking part

You cannot join this trial if any of these apply. You:

  • are allergic or very sensitive to pembrolizumab, lenvatinib or any of their ingredients
  • have a live vaccine Open a glossary item within 30 days of joining the trial. The COVID-19 vaccine and some seasonal flu vaccines are not live vaccines. 
  • pregnant or breastfeeding

Trial design

This is a phase 2 UK trial. The team need 60 people to take part. 

This is a randomised trial. A computer puts you into 1 of 3 groups. Neither you nor your doctor choses which group you are in. 

The 3 groups are:

  • pembrolizumab before surgery
  • lenvatinib before surgery
  • pembrolizumab and lenvatinib before surgery

You have pembrolizumab as a drip into a vein. You have it once every 3 weeks. Each 3 week period is a cycle of treatment Open a glossary item. You have 2 cycles of treatment before surgery. 

Lenvatinib is a capsule. You take the capsules once a day every day for 6 weeks before surgery. Your doctor will tell you how many to take. 

After surgery everyone has pembrolizumab every 3 weeks for up to a year. This is as long as it is helping and the side effects aren’t too bad. 

You have a diary to write down any side effects that you might have. If you are taking lenvatinib you also write down when you took the capsules and how many you took. 

You need to bring this diary with you to every hospital appointment. Your doctor or nurse will go through it with you. 

Samples of tissue
The doctor will ask to take a piece of liver cancer tissue (biopsy Open a glossary item):

  • before starting treatment
  • if you don’t have surgery
  • if your cancer comes back

You must agree to have these samples taken to take part in the trial.

Your doctor will only take these samples if they think it is safe to do so. If they think it isn’t safe then you won’t be able to take part in the trial. 

Samples for research
You give several blood samples during the trial. Your doctor will tell you more about how often and when they take the samples. Where possible they take these samples when you give blood as part of your routine care. 

Researchers will use these samples to find out more about liver cancer and how to treat it.

Hospital visits

You see the doctor to have tests before taking part. These include:

  • a physical examination Open a glossary item
  • blood tests
  • urine test
  • CT scan and MRI scan
  • heart trace (ECG)
  • heart scan (ECHO or MUGA Open a glossary item)
  • tissue sample (biopsy Open a glossary item)

You see the doctor regularly before surgery. This is to:

  • take bloods
  • see how you are
  • see if you are having side effects from the treatment

You see the doctor a month after surgery and before starting pembrolizumab. This is to see how well you are recovering from surgery. 

You then see the doctor every 3 months for a year. You have:

  • blood tests
  • scans  

During the follow up if your cancer comes back the doctor will take another tissue sample (biopsy). 

Side effects

The trial team monitor you during treatment and afterwards. Contact your advice line or tell your doctor or nurse if any side effects are bad or not getting better. 

Pembrolizumab can affect the immune system. It may cause inflammation in different parts of the body. This can cause serious side effects. They could happen during treatment, or some months after treatment has finished. Rarely, these side effects could be life threatening. Your doctor or nurse can explain what these side effects are, the risk of them happening and what to look out for.
If you have any of these side effects tell your doctor or nurse as soon as possible. You should tell them that you are on or have been on an immunotherapy.


The most common side effects of pembrolizumab are:

  • diarrhoea
  • a drop in red blood cells causing tiredness
  • high temperature (fever)
  • a lung infection (pneumonia)
  • shortness of breath
  • inflammation of the lungs. This can be serious. Tell your doctor or nurse straightaway if you have a new cough or shortness of breath or they are getting worse. 

The most common side effects of lenvatinib are:

  • diarrhoea
  • high blood pressure

We have more information about:

Your doctor will talk to you about the possible side effects of the treatments before you agree to join the trial.


Newcastle upon Tyne

Recruitment start:

Recruitment end:

How to join a clinical trial

Please note: In order to join a trial you will need to discuss it with your doctor, unless otherwise specified.

Please note - unless we state otherwise in the summary, you need to talk to your doctor about joining a trial.

Chief Investigator

Professor Tim Meyer

Supported by

University College London (UCL)
Merck, Sharp & Dohme
Cancer Research UK & UCL Cancer Trials Centre

If you have questions about the trial please contact our cancer information nurses

Freephone 0808 800 4040

Last review date

CRUK internal database number:


Please note - unless we state otherwise in the summary, you need to talk to your doctor about joining a trial.

Last reviewed:

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