Immunotherapy and its side effects

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We know that this is an especially worrying time so we have created a key messages document for Health Professionals focussed on safety netting patients presenting with symptoms during the coronavirus outbreak. We have also created a page on the subject specifically for patients on our about cancer hub. We will update that information as guidance changes.

Safety netting patients during covid-19

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Immunotherapy means treatments that use the immune system to destroy cancer. There are different types of immunotherapy 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. 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.

How Checkpoint Inhibitors work

How Checkpoint Inhibitors work

Checkpoint inhibitors are usually used to treat advanced (metastatic) cancers. 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. More recently, checkpoint inhibitors have also started to be used in the adjuvant setting for stage 3 melanoma.

Checkpoint inhibitors can have a significant benefit on survival compared to standard treatment, and in a proportion of patients can produce long term response and even “cure” metastatic disease. 

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.

Checkpoint inhibitors currently in use on the NHS (excluding those used in trials)

Drug Cancer

Ipilimumab (Yervoy)
(targets CTLA-4)

  • Advanced melanoma

Nivolumab (Opdivo)
(targets PD-1)

  • Advanced melanoma
  • Adjuvant treatment for resected melanoma with lymph node involvement or metasatic disease
  • Advanced renal cell carcinoma
  • Relapsed or refractory classical Hodgkin lymphoma
  • Advanced non small cell lung cancer (NSCLC)
  • Squamous cell carcinoma of the head and neck (SCCHN)

Pembrolizumab (Keytruda)
(targets PD-1)

  • Advanced melanoma
  • Adjuvant treatment for stage 3 melanoma with lymph node involvement
  • Advanced NSCLC
  • Relapsed or refractory classical Hodgkin lymphoma
  • Advanced urothelial carcinoma
Ipilimumab and Nivolumab
  • Advanced melanoma
  • Advanced renal cell carcinoma

Avelumab (Bavencio)
(targets PD-L1)

  • Advanced Merkel cell carcinoma

Atezolizumab (Tecentriq)
(targets PD-L1)

  • Advanced NSCLC
  • Advanced urothelial carcinoma*

Durvalumab (Imfinzi)
(targets PD-L1)

  • Locally advanced NSCLC

Cemiplimab (Libtayo)
(targets PD-1)

  • Metastatic or locally advanced cutaneous squamous cell carcinoma
 
*not currently accepted for use in Scotland

The side effects of checkpoint inhibitors are very different to chemotherapy. Importantly 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 and lungs.

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 anti CTLA-4 drugs and 20% of those having anti PD-1/PD-L1 drugs. The number of patients who have severe toxicity with combination therapy is much higher – about 55%.

It’s essential that patients with suspected irAEs are assessed promptly so that they can receive potentially life-saving treatment.

Most side effects are reversible with prompt initiation of corticosteroids. Patients who develop endocrinopathies, such as hypothyroidism and hypopituitarism, usually do not regain function and need long term hormone replacement therapy.

Treatment with checkpoint inhibitors may be withheld for a time, depending on the severity of the side effects. But can generally be restarted once the toxicity has resolved and the steroid dose weaned.

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 asthma or COPD, are at increased risk of developing pneumonitis.

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.