Immunotherapy and its side effects

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Immunotherapy means treatments that use the immune system to destroy cancer. There are different types of immunotherapies, but this information for GPs and Practice Nurses is specifically about checkpoint inhibitors.

Checkpoint inhibitors are a group of monoclonal antibodies that have become standard of care for a number of cancers in recent years (see table below). These drugs stop the tumour from evading white blood cells and stimulate an immune response against the tumour cells. They target specific checkpoint proteins on white blood cells called CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) or PD-1 (programmed death-1 receptor), or its ligand PD-L1. PD-L1 is also found on the surface of some cancer cells. More recently, a third class of checkpoint inhibitors targeting LAG3 on T cells (and NK cells) has been shown to have benefit in advanced cancer, in combination with anti PD-1 agents.

Checkpoint inhibitors are used after surgery (adjuvant therapy) to reduce the risk of recurrence, and in treating advanced cancers for disease control and survival benefit. They are either given as a single agent or two different agents and can be combined with other treatments such as chemotherapy or targeted therapy. Checkpoint inhibitors have also started to be used more recently in the neo-adjuvant setting.

Checkpoint inhibitors can have a significant benefit on survival compared to standard treatment, and in a proportion of patients can produce a long-term response.

With increasing numbers of cancer patients likely to be treated with checkpoint inhibitors, it’s important to be aware of the side effects and when they might happen.

Examples of checkpoint inhibitors currently in use on the NHS (excluding those used in trials)

Drug Cancer type

Ipilimumab (Yervoy)
- targets CTLA-4

  • Unresectable or metastatic melanoma

Nivolumab (Opdivo)
- targets PD-1

  • Unresectable or metastatic melanoma
  • Adjuvant treatment for resected melanoma with lymph node involvement or metastatic disease
  • Adjuvant treatment for resected oesophageal or gastro-oesophageal junction cancer
  • Adjuvant treatment for muscle-invasive urothelial cancer
  • Advanced renal cell carcinoma
  • Relapsed or refractory classical Hodgkin lymphoma
  • Locally advanced or metastatic non small cell lung cancer (NSCLC)
  • Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN)
  • Unresectable advanced, recurrent or metastatic oesophageal cancer
  • Neoadjuvant treatment (with chemotherapy) for resectable NSCLC
  • Advanced stomach, gastro-oesophageal or oesophageal cancer

Pembrolizumab (Keytruda)
- targets PD-1

  • Unresectable or metastatic melanoma
  • Adjuvant treatment for stage 2B, 2C and 3 melanoma
  • Locally advanced or metastatic NSCLC
  • Relapsed or refractory classical Hodgkin lymphoma
  • Adjuvant treatment for renal cell carcinoma
  • Advanced renal cell carcinoma
  • Metastatic or unresectable recurrent head and neck squamous cell carcinoma
  • Metastatic bowel cancer
  • Neoadjuvant and adjuvant treatment for early or locally advanced triple negative breast cancer
  • Locally recurrent unresectable or metastatic triple negative breast cancer
  • Locally advanced unresectable or metastatic oesophageal and gastro-oesophageal junction cancer
  • Persistent, recurrent or metastatic cervical cancer
Ipilimumab and Nivolumab
  • Unresectable or metastatic melanoma
  • Advanced renal cell carcinoma
  • Metastatic bowel cancer
  • Unresectable pleural mesothelioma

Avelumab (Bavencio)
- targets PD-L1

  • Metastatic Merkel cell carcinoma
  • Advanced renal cell carcinoma
  • Locally advanced or metastatic urothelial carcinoma

Atezolizumab (Tecentriq)
- targets PD-L1

  • Locally advanced or metastatic NSCLC
  • Adjuvant treatment for stage 2 to 3A NSCLC
  • Extensive stage small cell lung cancer
  • Locally advanced or metastatic urothelial carcinoma*
  • Unresectable hepatocellular carcinoma
  • Unresectable, locally advanced or metastatic triple negative breast cancer

Cemiplimab (Libtayo)
- targets PD-1

  • Locally advanced or metastatic cutaneous squamous cell carcinoma
  • Metastatic NSCLC
Dostarlimab (Jemperli) – targets PD-1
  • Advanced or recurrent endometrial cancer
Durvalumab (Imfinzi) - targets PD-L1
  • Locally advanced unresectable NSCLC

*not currently accepted for use in Scotland

The side effects of checkpoint inhibitors are very different to chemotherapy. Importantly, due to stimulation of the immune system, they can cause inflammatory and autoimmune complications, which can affect any part of the body. They most frequently affect the skin, colon, endocrine organs, liver, joints and lungs. The serious toxicities can also include cardiac, neurological and renal impairment as detailed in the figure below.

Fatigue is the most common side effect. It is usually mild, but in rare cases can be severe. It is important to rule out thyroid, pituitary and other endocrine disorders such as adrenal insufficiency.

Examples of immune-related adverse events and some possible symptoms

These immune-related adverse events (irAEs) can happen at any time but most often occur within the first few weeks or months after starting treatment. There are reports of some irAEs starting even a year or more after treatment has finished.

IrAEs are usually mild and generally well tolerated by patients. However they can be severe, even life threatening, in up to 27% of patients having single agent anti CTLA-4 drugs and 20% of those having anti PD-1 or PD-L1 drugs. The number of patients who have severe toxicity with combination therapy is much higher – about 55%.

When detected early, most iRAEs are reversible. Therefore, it’s essential that patients with suspected irAEs are assessed promptly so that they can receive potentially life-saving treatment.

Management of iRAEs is based on the severity of toxicity, as graded by the CTCAE (Common Terminology Criteria for Adverse Events). Treatment with checkpoint inhibitors may be withheld for a time, depending on the severity of the side effects. Most patients with higher grade toxicities will require prompt initiation of steroids for reversibility, as guided by their oncology team. For milder toxicities, immunotherapy may be restarted once the toxicity has resolved and the steroid dose weaned. Patients who develop endocrinopathies, such as hypothyroidism and hypopituitarism, usually do not regain function and may need long term hormone replacement therapy.

Currently it is not possible to predict who will develop irAEs, but patients with pre-existing autoimmune disorders may be at higher risk. Those with a history of lung conditions, such as COPD, may have a predisposition to more severe pneumonitis.

Primary care providers play an extremely important role in early identification of potential toxicities and communication with the oncology teams, in addition to optimising patients’ comorbidities, mental wellbeing and preventative care.

Flag all patients having immunotherapy on patient system to highlight risk of side effects during treatment and for at least 12 months after finishing treatment.
Patients can present with non-specific symptoms so consider blood tests to rule out biochemical-only changes, such as hepatitis, adrenal insufficiency and thyroid dysfunction.
Initially mild symptoms such as diarrhoea, breathlessness or headaches can rapidly progress into colitis, pneumonitis or encephalitis.
Contact hospital advice line/oncologist straightaway if concerned your patient may have immunotherapy side effects –they may carry an immunotherapy alert card with details.
Refer to UKONS Oncology/Haematology Treatment Toxicity Risk Assessment Tool regarding side effects (includes immunotherapy).

Remember - Think possible ‘itis’ for any patient that is on or has had immunotherapy.


Board RE et al (2019) Problem Solving in Cancer Immunotherapy. Oxford: EBN Health

Champiat S, Lambotte O, Barreau E et al (2016) ‘Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper’, Annals of Oncology 27 (4), pp.559-574

Haanen J, Carbonnel F, Robert C. et al (2017) ‘Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow up’, Annals of Oncology, 28 (supplement 4), pp. i119-i142

Haanen J, Obeid M, Carbonnel F. et al (2022) ‘Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow up’, Annals of Oncology, 33 (12), pp.1217-1238

Martins F, Sofiya L, Sykiotis GP. et al. (2019) ‘Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance’, Nature Reviews Clinical Oncology, 16, 563 – 580

Pickwell-Smith BA, Alfred CP and Board RE (2018) ‘Managing side effects of cancer immunotherapy for the acute physician’, British Journal of Hospital Medicine, 79 (7), pp. 372-377

UpToDate website – Toxicities associated with immune checkpoint inhibitors. M Postow et al (last updated March 2023. Accessed 12/05/2023.

Vickers E (2018) A Beginner’s Guide to Targeted Cancer Treatments. Hoboken,NJ: Wiley Blackwell

Guidelines from NICE and SMC website. Accessed April 2023.

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