Checkpoint inhibitors are a group of monoclonal antibodies that have become the standard of care for several 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 (lymphocyte activation gene-3) on T cells (and NK cells) has been shown to benefit advanced cancer in combination with anti-PD-1 agents.
Checkpoint inhibitors are also used more before surgery (neo-adjuvant) to improve tumour control, surgical outcomes and boost immune response.
Checkpoint inhibitors are used after surgery (adjuvant therapy) to reduce the risk of recurrence and in treating advanced or metastatic cancers for disease control and survival benefits. 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 the ability to significantly improve survival compared to standard treatment. They can produce a durable long-term response in a proportion of patients compared to other traditional treatments, such as chemotherapy in some cancers.
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 | Melanoma |
Nivolumab (Opdivo) - targets PD-1 | Melanoma Oesophageal or gastro-oesophageal junction cancer Urothelial cancer Renal cell carcinoma Hodgkin lymphoma Non small cell lung cancer (NSCLC) Head and neck cancer |
Pembrolizumab (Keytruda) - targets PD-1 | Melanoma Non small cell lung cancer (NSCLC) Hodgkin lymphoma Renal cell carcinoma Head and neck cancer Bowel cancer Breast cancer Oesophageal and gastro-oesophageal junction cancer Cervical cancer |
Ipilimumab and Nivolumab | Melanoma Renal cell carcinoma Bowel cancer Mesothelioma |
Avelumab (Bavencio) - targets PD-L1 | Merkel cell carcinoma Renal cell carcinoma Urothelial carcinoma |
Atezolizumab (Tecentriq) - targets PD-L1 | Non small cell lung cancer (NSCLC) Small cell lung cancer Urothelial carcinoma* Hepatocellular carcinoma Breast cancer |
Cemiplimab (Libtayo) - targets PD-1 | Squamous cell carcinoma |
Dostarlimab (Jemperli) – targets PD-1 | Endometrial cancer |
Durvalumab (Imfinzi) - targets PD-L1 | Non small cell lung cancer (NSCLC) Biliary tract cancer |
Nivolumab–relatlimab (Opdualag) | Melanoma |
*not currently accepted for use in Scotland
Checkpoint inhibitors have very different side effects from chemotherapy. Importantly, because they stimulate 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 list below. Fatigue is the most common side effect. It is usually mild but can be severe in rare cases. It is important to rule out thyroid, pituitary, diabetes and other endocrine disorders, such as adrenal insufficiency.
Examples of immune-related adverse events (irAEs) and some possible symptoms
Eye (eg uveitis, iritis, episcleritis, conjunctivitis, orbital inflammation, optic neuritis)
Blurred vision
Change in colour vision
Distortion
Eyelid swelling
Bulging eyes
Decreased visual acuity
Dry eyes
Redness
Pain
Photophobia
Endocrine (eg diabetes, hyper or hypo thyroidism, hypophysitis, adrenal insufficiency)
Headaches
Nausea or vomiting
Cold or heat intolerance
Dry skin
Constipation or frequent bowel movements
Weight gain or loss
Palpitations
Insomnia
Abdominal pain
Visual field defects
Fatigue or weakness
Dehydration
Hypotension, orthostasis or syncope
Hyperglycaemia, polyuria or polydipsia
Electrolyte abnormalities
Liver (hepatitis)
Raised LFTs
Jaundice
Fever
Fatigue
Nausea and vomiting
Anorexia
Pain on right side of abdomen
Dark urine
Bleeding or bruising more easily than normal
Skin
Pruritus with or without a rash
Inflammatory dermatoses (maculopapular, psoriasiform, eczematous and lichenoid)
Immunobullous diseases (bullous pemphigoid, vitiligo depigmentation -melanoma only, connective tissue diseases)
Mucosal toxicities (ulcers, periodontal disease, stomatitis, dry mouth related to CPI Sjögren’s Syndrome, vaginal dryness, oral and genital lichen planus)
Hair and nail toxicities
Palmoplantar erythrodysesthesia or hand-foot syndrome
Stevens-Johnson syndrome
Blood
Haemolytic anaemia
Thrombocytopenia or thrombocythaemia
Neutropenia
Haemophilia
Musculoskeletal
Myositis
Arthritis
Myopathies
Polymyalgia-like syndrome
Gastrointestinal (eg colitis, enterocolitis, gastritis, pancreatitis)
Diarrhoea (may include blood or mucus)
Fever
Cramping abdominal pain
Urgency
Nausea and vomiting
Upper abdominal pain
Difficulty swallowing
Renal (nephritis, acute kidney injury)
Urinary frequency
Dark or cloudy urine
Fluid retention in face, abdomen and extremities
Sudden weight gain
Abdominal or pelvic pain
Nausea or vomiting
High blood pressure
Change in mental status
Raised creatinine
Oliguria
Cardiovascular (eg myocarditis, arrhythmias, impaired ventricular function, pericarditis, vasculitis, thromboembolism)
Fatigue, myalgia or weakness
Presyncope or syncope
Shortness of breath
Arrhythmias
Chest pain
Peripheral oedema
Extremity pain or swelling
Increased skin vein visibility or purpuric rash or erythema
Reduced exercise tolerance
Respiratory (eg pneumonitis, pleuritis)
Breathlessness
New or worsening cough
Reduced saturations
Chest pain
Wheezing
Fever
Neurological
Peripheral neuropathy
Guillain-Barré syndrome
Myasthenia gravis with myositis overlap
Aseptic meningitis
Encephalitis
Demyelinating disorders
These irAEs can happen at any time but most often occur within days to a delayed onset of up to 26 weeks after starting treatment. There are reports of some irAEs starting after treatment has finished. Therefore, although rare, patients are monitored for 1-2 years after treatment completion for delayed IRAE onset.
The incidence and severity of irAEs depend on the drug. Anti-CTLA4 drugs usually have more adverse effects (up to 80%) compared to anti-PD1 (27%) and anti-PDL1 (17%) drugs.
Combinations increase the incidence and severity of irAEs, with more than 50% experiencing moderate-severe irAEs with Ipilimumab and Nivolumab, for example.
Many irAEs cause little discomfort to patients if detected early and may be asymptomatic. However, irAEs can affect any organ and be potentially life-threatening.
Most irAEs are reversible when detected early. Therefore, patients with suspected irAEs must be assessed promptly so that they can receive potentially life-saving treatment.
Management of irAEs is based on the severity of toxicity (grade 1 to 4), as graded by the Common Terminology Criteria for Adverse Events (CTCAE).
Treatment with checkpoint inhibitors may be withheld for a time, depending on the severity of the side effects. Most patients with higher grade toxicities (grades 2 to 4) will require prompt initiation of steroids and holding of drugs for reversibility, as guided by their oncology team.
Depending on the severity of toxicity, immunotherapy may be restarted once the toxicity has resolved to grade 1 or below and the steroid dose weaned.
Most 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.
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 the patient system to highlight the 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 and renal insufficiency and thyroid dysfunction.
Initially, mild symptoms such as diarrhoea, breathlessness or headaches can rapidly progress into severe colitis, pneumonitis or encephalitis. Therefore, it is important to have a low threshold for investigation as appropriate.
If you are concerned your patient may have immunotherapy side effects, contact the hospital advice line or oncologist straightaway. They may carry an immunotherapy alert card with details.
Refer to UKONS Oncology/Haematology Treatment Toxicity Risk Assessment Tool regarding side effects (includes immunotherapy).
Cancer Research UK’s About Cancer website
Macmillan Cancer Support website. Haematology and oncology risk assessment tool. 2020
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