Immunotherapy side effects in detail

When can immunotherapy side effects occur?

Side effects can happen at any time during treatment or after treatment has completed so it is important to let your healthcare team know about any changes.

Below we will explain the likelihood of you getting some of the more common side effects that people may experience with immunotherapy treatment.

This likelihood will vary depending on if you have combination treatment with ipilimumab plus nivolumab (higher chance) compared to a newer treatment with relatlimab-nivolumab or just one treatment (nivolumab or pembrolizumab). It can also vary if you have adjuvant treatment after surgery to remove the melanoma (higher chance) compared to having treatment if the melanoma has metastasised or spread to other parts of the body.

We also include information on when these side effects may start, what to look out for and how long it may last. It is important to know that sometimes side effects can occur after many months of treatment, even if you have felt fine before.

Skin problems

Side effects that affect the skin tend to be quite mild to moderate and can show as a red rash, itching or changes in skin colour, and may cover some or all parts of the body.

For 100 people who receive treatment with one immunotherapy we would expect 38 people to experience skin problems. This is 38% of individuals — shown in yellow.

For 100 people who receive treatment with combination immunotherapy (ipilimumab/nivolumab) we would expect 65 people to experience skin problems. This is 65% of individuals – shown in yellow and purple.

This means that in the same group of people 35 (35%) of them will not experience any skin-related side effects — shown in blue.

Skin reactions can generally be seen within 4 weeks of starting immunotherapy treatment and doctors can give treatment with creams or tablets to help to relieve these side effects. Of the people who have experienced problems with their skin, in general, this seemed to get better within around 3 – 4months, however, it can continue for longer.

Bowel, Gut or Gastrointestinal (GI) problems

Gastrointestinal side effects can be experienced as diarrhoea or tummy pains and in more severe cases is known as colitis, which is inflammation of the colon (the lower part of the gut)

For 100 people who receive treatment with one immunotherapy treatment we would expect 18 people to experience bowel problems. This is 18% of individuals — shown in yellow.

For 100 people who receive treatment with combination immunotherapy (ipilimumab/nivolumab) we would expect 46 people to experience bowel problems. This is 46% of individuals – shown in yellow and purple.

This means that in the same group of people 54 (54%) of them will not experience any bowel side effects — shown in blue.

Gastrointestinal or gut problems can generally be seen within 6 weeks of starting immunotherapy treatment and doctors can give treatment to help to relieve these side effects. Of the people who have experienced gut problems, in general, this seemed to get better within around 3 weeks, however for some people it can take a while to improve and might flare up again. Colitis is a more serious side effect, and this may require an inpatient stay in order for you to receive steroid treatment and/or other treatments to dampen down the effects on the bowel/gut.

If you would like to learn more colitis, this blog written by stage 4 patient Charlotte Killeya provides great information and advice. Charlotte suffered from severe colitis and was admitted to hospital.

Low thyroid hormone levels (hypothyroidism)

When the body doesn’t produce enough of the thyroid hormone this is known as hypothyroidism. If you don’t produce enough thyroid hormone you may notice that you feel very tired, cold, slow, put on weight or have constipation. Doctors will regularly test your blood while receiving immunotherapy treatment and so they can quickly see if there are any problems with your thyroid function and can treat it.

Thyroid DiagramFor 100 people who receive treatment with immunotherapy we would expect 15 people to experience low thyroid levels. This is 15% of individuals — shown in yellow.

This means that in the same group of people 85 (85%) of them will not experience low thyroid levels— shown in blue.

Low thyroid levels can generally be seen within 2 – 3 months of starting immunotherapy treatment and in some cases, this may not get better after stopping immunotherapy treatment. Low thyroid levels are very easily managed by taking a small tablet every day to increase the amount of thyroid hormone in the body. This will likely be needed for life, and doctors will take blood tests every now and then to keep an eye on the levels of thyroid hormone in the body.

Other endocrine problems

The endocrine hormones control a lot of processes in the body, like the thyroid. There are some other side effects of immunotherapy, that are less common than low thyroid levels. Doctors will usually notice these from blood tests, but you could also experience some symptoms.

High thyroid levels (hyperthyroidism)

If you produce too much thyroid hormone you could notice that you lose weight, experience nervousness, irritability, trouble sleeping, or a fast heart rate. It’s important to report any symptoms to your doctor as soon as possible so that they can treat it.

Diabetes

Immunotherapy could also affect how the hormone insulin is produced in the body, this controls the amount of sugar that is in the blood. Doctors will take regular blood tests to check that the levels of sugar in the blood are normal. Symptoms of diabetes (high blood sugar) could be, increased thirst, passing more urine than usual (especially at night), extreme tiredness, weight loss, feeling sick, blurred vision or headaches. It’s important to report any symptoms to your doctor as soon as possible so that they can treat it.  The type of diabetes that may occur is type-1 diabetes and the treatment would be with insulin (to replace the insulin production) rather than tablets.

Adrenal gland problems

The adrenal glands produce steroid hormones that control lots of functions in the body, if the adrenal glands don’t work properly, you might experience symptoms of weakness, dizziness, extreme tiredness, low blood pressure, weight loss, muscle aches, low appetite. It’s important to report any symptoms to your doctor as soon as possible so that they can treat it.  This is not a common side-effect of immunotherapy and the treatment is to replace these naturally occurring hormones for life.

Liver problems (hepatitis)

Doctors will regularly test your blood while receiving immunotherapy treatment so they can quickly see if there are any problems with your liver. You may not notice any symptoms at all.

For 100 people who receive treatment with one immunotherapy treatment we would expect 10 people to experience liver problems. This is 10% of individuals — shown in yellow.

For 100 people who receive combination immunotherapy (ipilimumab/nivolumab) treatment we would expect 29 people to experience liver problems. This is 29% of individuals – shown in yellow and purple.

This means that in the same group of people 71 (71%) of them will not experience any liver problems— shown in blue.

Liver problems can generally be seen within 8 weeks of starting immunotherapy treatment and, in general, this seemed to get better within around 5-6 weeks of supportive treatment.

Inflammation of the lungs (pneumonitis)

A less common side effect could be due to inflammation of the lungs, known as pneumonitis. It is important to report to your doctor if you experience any trouble breathing or a cough when receiving immunotherapy treatment as these may be signs of inflammation in the lungs.

For 100 people who receive treatment with one immunotherapy treatment we would expect 4 people to experience lung problems. This is 4% of individuals — shown in yellow.

For 100 people who receive combination immunotherapy (ipilimumab/nivolumab) treatment we would expect 7 people to experience lung problems. This is 7% of individuals – shown in yellow and purple.

This means that in the same group of people 93 (93%) of them will not experience any lung problems— shown in blue.

Lung problems can generally be seen within 12 weeks of starting immunotherapy treatment and of the people who have experienced inflammation in the lungs, in general, this seemed to get better within around 6 weeks of supportive treatment.

Long-term or late effects of Immunotherapy

The side effects of immunotherapy can continue or occur after treatment stops. These long-term effects are sometimes called ‘late effects’. Most people won’t get late effects but it is helpful to be aware of them so that you can ask for help if you have symptoms that you are worried about. Immunotherapy is still quite new, so all of the late effects may not be known yet and and we do not know how common they are so research is taking place to find out about them.  In 2023, Melanoma Focus awarded grants to two research projects looking at the late effects of immunotherapies so we can learn more about these treatments.

The diagram below shows when side effects might happen. Some people won’t experience any side effects and some people only mild side effects, particularly if being treated with pembrolizumab or nivolumab on its own. Acute side effects are side effects that happen early on in treatment and are the most common.  Chronic side effects are those side effects that start during treatment and linger or carry on after treatment has finished, these are less common.  There are some occasional late side effects which occur after your treatment has finished.

The chronic and late effects of immunotherapy can include:

  • skin rashes, tiredness, diabetes, thyroid problems, hormonal problems (including menopausal symptoms or low testosterone levels), fertility problems, difficulty producing the hormone cortisol, diarrhoea/bowel problems, arthritis, liver damage, lung problems, heart problems.

Managing chronic/late effects:

Often long-term effects are detected during treatment but don’t go away when treatment stops. Patients are often referred to other specialists (such as gastroenterologists who specialise in the gut) so there may be other people involved in your long-term care, as well as your GP.  Some centres have long-term follow up clinics or late effects clinics that assess for these effects. These clinics may be specific to melanoma or may be for all cancer patients. It is important to remember that most people won’t experience late effects. After treatment you may experience a mixture of physical and psychological effects related to the melanoma, surgery and immunotherapy. You may have particular concerns about returning to usual activities after treatment.

Relevant References:

Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma; Journal of Clinical Oncology https://ascopubs.org/doi/10.1200/JCO.2015.66.1389?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed [Accessed 30/01/2024]

Study Details Long-Term Side Effects of Immune Checkpoint Inhibitors https://www.cancer.gov/news-events/cancer-currents-blog/2021/immune-checkpoint-inhibitors-melanoma-long-term-side-effects [Accessed 30/01/2024]

Chronic Immune-Related Adverse Events Following Adjuvant Anti–PD-1 Therapy for High-risk Resected Melanoma https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995124/ [Accessed 30/01/2024]

Adjuvant immunotherapy: the sting in the tail https://www.clinicalkey.com/#!/content/playContent/1-s2.0-S095980492030157X [Accessed 30/01/2024]

Nivolumab SPC https://www.medicines.org.uk/emc/product/6888 [Accessed 30/01/2024]

Ipilimumab SPC https://www.medicines.org.uk/emc/product/4683/smpc#gref [Accessed 30/01/2024]

Pembrolizumab SPC https://www.medicines.org.uk/emc/product/2498 [Accessed 30/01/2024]

Opdualag SPC  https://www.medicines.org.uk/emc/product/15383/smpc#gref Accessed 05/02/2024